Promise&Progress FALL 2008/ WINTER 2009
THE SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER
CSI: CANCER-SOLVING INVESTIGATORS BUILDING THE BEST GI CANCER PROGRAM
X-ray of the colon of a patient with cancer of the cecum, the start of the large intestine. A malignant (cancerous) tumor is seen at lower center (pale area). Treatment is with surgery to remove the affected area. Colon cancer is one of the most common cancers in the Western world. It is a disease of late and middle age. Risk factors include a diet high in animal fat and low in fiber and a sedentary lifestyle
Promise & Progress is published by The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Office of Public Affairs Suite 573 Baltimore, Maryland 21231 (410) 955-1287 Stephen Baylin, M.D. Deputy Director, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Amy Mone Director of Public Affairs Valerie Matthews Mehl Editor and Senior Writer Vanessa Wasta Contributing Writer Michelle Barnett, Brandon Chopper, Brittany Paulshock Editorial Assistants Mary Ann Ayd Copy Editor/Proofreader MSK Partners, Inc. Design and Production
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D I R E C TO R â€™ S L E T T E R
IN THE NEWS
The latest cancer discoveries in the news
Partnerships fund new research and therapies
N OT E W O R T H Y
A team of cancer experts is integrating their efforts in hopes of curing gastrointestinal cancers
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D E P U T Y D I R E C TO R ’ S L E T T E R
Moving Forward THE GREAT DISTANCE WE must still travel to prevent and
cure cancer is poignantly highlighted by the death from leukemia, almost one year ago, of our long time friend and Kimmel Cancer Center director, Dr. Martin Abeloff. Our inability to cure his disease illustrates that the origins of cancer, and the process of their progression to metastatic forms that most often take lives of our patients, remain challenging to understand biologically, and most importantly, challenging to prevent and treat. However, our researchers continue to uncover, ever further, the cellular and molecular mechanisms through which cancers are initiated and that they utilize to go unnoticed by the immune system. They also are making substantial progress in unraveling these same aspects as they collaborate to allow cancers to avoid the wrath of chemotherapy and radiation therapy. These advances are heavily tied to our increasing and incredible abilities to decipher the cancer genome and epigenome and translate our findings into new noninvasive cancer screening methods and novel, targeted therapies that are already making a difference in patients. In this issue, you will read about our gastrointestinal (GI) cancer program, including our pancreas cancer clinic which has became a model for interdisciplinary cancer care; a new colon cancer clinic that also incorporates this team approach to bring innovative therapies to metastatic colon cancer patients; the latest surgical techniques that are making inoperable cancers operable again; and advances in pain and palliative care, a cancer subspecialty that helps patients manage the many symptoms related to the presence of cancer and which may arise during treatment. These clinics so clearly illustrate how our Cancer Center builds and uses interdepartmental collaborations and research discoveries to develop combined cancer therapies to treat some of the most resistant cancers. We are in current, trying economic times which have severely diminished the relative support provided by our traditional funding mechanisms, such as the National Cancer Institute. The recent philanthropic support from our many donors provides an invaluable buffer to these problems, and in some cases, has proven transformative making continued progress possible. With the rising costs of everything, from pipettes to high-tech equipment, and federal funding remaining static, the reality is that, without philanthropy, we have less money for laboratory and clinical research. The effects on young investigators entering basic and clinical research are mounting. The generosity of individuals and foundations was critical to establishing the GI cancer programs featured in this issue and is vital to keeping our science moving forward. It
“THE GENEROSITY OF INDIVIDUALS AND FOUNDATIONS WAS CRITICAL TO ESTABLISHING THE GI CANCER PROGRAMS FEATURED IN THIS ISSUE AND IS VITAL TO KEEPING OUR SCIENCE MOVING FORWARD.”
facilitates the entrance of new scientists into our research enterprise, stabilizes established research groups, and ensures that our most promising results receive the highest translation towards the clinic. One palpable example of the philanthropy-scientific collaboration is research funded by the Commonwealth Foundation that was recently published in the New England Journal of Medicine. It provides a major proof of principle step for indicating that epigenetic DNA markers can be used to detect cancer and predict its behavior (see page 2.). Although these are early findings, we have now made a potentially powerful advance in the clinical management of lung cancer, the most lethal and difficult to treat of the common cancers, by using a more accurate molecular staging technique. I am also happy to report that we have made great progress in the search for our new Cancer Center director and expect to have an announcement soon. This is truly an exciting time as we begin to see years, and in some cases decades, of research lead to advances in clinical care. Cancer is an immensely complex disease, and we certainly don’t have all of the answers yet, but it is becoming less of a mystery with each discovery. Dr. Abeloff would be proud of our past year of efforts and especially proud that many of our discoveries are so close to improving patient care.
Virginia and D.K. Ludwig Professor and Deputy Director The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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A Body of Evidence Aggressive Lung Cancers Leave Telltale Trail of DNA Methylation indicators, but in truth, Brock says, tiny tumors, even those as small as a pea, can hardiagnosis and over every presumable cure. bor molecular genetic alterations that can Now, investigators have learned that lung potentially make them very dangerous and cancers, one of the most prevalent and fre- aggressive. quently recurring of all cancers, leave a In a study published March 12, 2008, in molecular trail of evithe New England Journal of M A LCO L M B R O C K , JAMES HERMAN dence that can tell Medicine, Brock and team reported ( B OT TO M ) them that hidden on 157 patients with early stage nontumor cells remain small-cell lung cancer. All of the and the cancer is likely patients had small tumors that were to return. surgically removed. Within about Enter molecular three years, 51 of the patients had staging of cancers, a their cancer return, while 116 form of cancer detecremained cancer free. The team set tion that reveals what out to find, on the molecular level, cannot be seen through the pathologist’s what the microscope did not—what was difmicroscope. “This is DNA forensics for can- ferent about the cancers that returned. cer,” says cancer surgeon Malcolm Brock. The culprit, they found, was in the “While there may be no visible trace of can- methylation patterns of four genes already cer after surgery, DNA evidence of tumor linked to lung cancer. Methylation is a norcells is left at the scene, hiding in tissues such mal cellular process, but when the process as lymph nodes.” goes awry and genes are overmethylated, it, in effect, renders genes invisible to cells, “While there may be no visible often shutting down key tumor suppressing trace of cancer after surgery, functions. Depending on the combination of DNA evidence of tumor cells genes abnormally methylated, the risk of the is left at the scene, hiding in cancer’s returning was increased two- to 25fold. The worst scenario proved to be the tissues such as lymph nodes.” overmethylation of two particular genes, p16 We are accustomed to using tumor size and H-cadherin, which foreshadowed a swift and spread at diagnosis as the prognostic return of the cancer. W I T H C ANCER, THE THREAT OF
RECURRENCE looms heavily over every
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“If these results are confirmed, doctors may need to consider treating patients whose tumors have the genetic alterations more aggressively with chemotherapy and surgery.” Brock believes these findings could lead to new therapies for lung cancer, the leading cancer killer of men and women, claiming more than 162,000 lives annually. “If these results are confirmed, doctors may need to consider treating patients whose tumors have the genetic alterations more aggressively with chemotherapy and surgery,” says James Herman, a lung cancer clinician-scientist and expert on DNA methylation. New therapies that block methylation of genes also are being studied and have worked in other cancers. “We can take these marks of aggressive disease and make them targets of therapy,” says Herman. Brock is optimistic that this approach, if proven, can be applied to other cancers as well. The research was funded by a National Cancer Institute SPORE (Specialized Programs of Research Excellence), the Commonwealth Foundation for Cancer Research, the Hodson Trust, and OncoMethylome Sciences.
Prostate Cancer Gene Test? International Study Reveals Genetic Markers of the Disease New England Journal of Medicine, January 16, 2008 THE FIRST STEPS toward a genetic test for prostate cancer unfolded in a collaborative international study of more than 4,000 men. The work revealed an array of gene markers for a hereditary form of the disease. These markers, along with famiI SAAC S ly history of the disease, translate to a ninefold increase in the risk of getting prostate cancer when compared to men without these markers, say the study’s investigators. “This information is not yet available as a genetic test for risk of prostate cancer, but efforts are under way to rapidly develop one,” says Johns Hopkins prostate cancer expert William B. Isaacs. The Hopkins team collaborated with Wake Forest University and the Karolinska
Institute in Sweden to study more than 4,000 Swedish men. They found that the gene markers they identified were common, potentially accounting for nearly half of the prostate cancers in the study. “While these findings need to be validated and refined, it’s a step in the right direction to revealing what we have been looking for over the past 15 years—the genetic-based reasons for prostate cancer,” says Isaacs. The investigators studied DNA from blood cells of 2,893 men with prostate cancer and 1,781 who did not have the disease. Sifting through the chemical compounds (ATCG) within DNA that make up our gene coding sequences, they found 16 incidences where one of these critical letters in the DNA alphabet was swapped for another. The alterations, known as single nucleotide polymorphisms, or SNPs, were found in five different regions of chromosomes 8 and 17 and
were more common to men with prostate cancer than those without the disease, the investigators found. The researchers chose the best SNPs from each of the five regions and tested their cumulative effect on prostate cancer risk. Men with alterations in all five regions and a family history of prostate cancer were 9.5 times more likely to have the disease, says Isaacs, the William Thomas Gerrard, Mario Anthony Duhon, and Jennifer and John Chalsty Professor of Urology. Isaacs and team say that SNPs themselves may not lead to increased prostate cancer risk but appear to be good markers of cellular changes that do. As a result, a genetic test that screens for these SNPs may help in prevention and early detection of prostate cancer. The research was funded by the National Cancer Institute, Department of Defense, Swedish Cancer Society, and Swedish Academy of Sciences.
Glow Chemical Questioned Cellular Pump Sabotages Cancer Drug Studies Cancer Research, October 1, 2007 IN A CHANCE DISCOVERY, investigators have uncovered a cell mechanism that corrupts a widely used means of illuminating cancer cells, distorting findings in anticancer drug studies. The researchers have identified a cellular pump responsible for sabotaging the drug studies but, at the same time, found it may be a key to reversing anticancer drug resistance in patients. To study cancer cells’ reactions to promising drugs, scientists make the cells glow. They use luciferase, an enzyme that causes the glow in fireflies. The researchers transfer the luciferase gene into the genetic machinery of cancer cells. The cancer cells are injected into rats or mice, and the glowing cells indicate how the cancer is responding to anticancer drugs. But, during a test of an experimental drug on a cancer-causing pathway known as hedgehog, cancer imaging expert Martin Pomper, working with Yimao Zhang and John Laterra, unexpectedly uncovered a cellular mechanism that automatically pumps the glowing contents out of cells, potentially causing investigators to misinterpret results. The glow may not have anything to do with the drug’s interaction with cells but rather the cell simply getting rid of the glow chemical. “Researchers who use markers
involving luciferase may want to doublecheck their findings,” says Pomper. Pomper and team have identified the P O M P E R pump as ABCG2/BCRP, and say it is one of nearly 50 of its “Researchers who use type. He warns researchers and markers involving drug developers to make sure luciferase [an enzyme cells don’t have this pump used to study cancer when testing a drug’s action. On the clinical side, Pomper cells’ reactions to believes shutting down the celpromising drugs by lular pump could make cancer making them glow] cells more vulnerable to antimay want to doublecancer drug therapy, so he is check their findings.” now looking for drugs that turn it off. “An inhibitor of the pump, coupled with standard chemotherapy, could lead to less drug resistance than we now see in most tumors,” says Pomper. This research was funded by the National Institutes of Health and the Dana Foundation.
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Proteinpedia Protein Encyclopedia to Speed Cancer Research Nature Biotechnology, February 2008 CANCER CENTER investigator Akhilesh Pandey has led the work to
compile the largest free resource of experimental information about human proteins. Researchers from around the world can access the data and speed their own research. “We’ve created a repository that incorporates easy-to-use Web forms so that all researchers can contribute and share data,” says Pandey. Like the online encyclopedia Wikipedia, Human Proteinpedia allows researchers to contribute and edit their data as their research progresses. “Researchers will be able to quickly review what has been discovered by others about their protein of interest, speeding their own work,” he says. The current version of Human Proteinpedia contains data from more than 71 laboratories around the world and entries for more than 15,230 human proteins. It has a wealth of information on the proteins, including when and where they are expressed, or not expressed, in diseases like cancer. “With the amount of proteomic data pouring in each day, cataloging all of human protein data by hand is a Herculean task,” says Pandey. “We’re hoping the scientific community will come together to contribute data generated in their individual laboratories. This will not only improve the quality of data but also speed the pace at which data is collected in a common repository.” Pandey is hoping to work with companies like Google and Microsoft interested in enabling data sharing and dissemination. The research is funded by the National Institutes of Health Roadmap Initiative, the National Heart, Lung and Blood Institute, and internal funds from the Institute of Bioinformatics in Bangalore, India, a nonprofit institute founded by Pandey.
PA N D E Y
“WE’RE HOPING THE SCIENTIFIC COMMUNITY WILL COME TOGETHER TO CONTRIBUTE DATA GENERATED IN THEIR INDIVIDUAL LABORATORIES. THIS WILL NOT ONLY IMPROVE THE QUALITY OF DATA BUT ALSO SPEED THE PACE AT WHICH DATA IS COLLECTED IN A COMMON REPOSITORY.”
Swish and Spit It May Be that Easy to Detect Cancer Clinical Cancer Research, January 1, 2008. A SIMPLE MOUTH RINSE could be all it takes to capture genetic signatures com-
mon to head and neck cancers. CRF investigator Joseph Califano envisions using such a test to screen those at risk, particularly heavy smokers and drinkers, for the cancer that strikes about 50,000 Americans each year. “It’s easy to do, painless and cheap,” says Califano. His screening method, which he tested on 211 head and neck cancer patients and 527 healthy people, captures cells from a wide area of the mouth and pinpoints cellular alterations characterized by increased C A L I FA N O methylation of genes, believed to be one of the earliest triggers of cancer. Califano continues to refine the test. The research was funded by the Damon Runyon Cancer Research Foundation, Flight Attendant Medical Research Institute, National Institute of Dental and Craniofacial Research, and National Cancer Institute.
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“It’s easy to do, painless and cheap.”
Stemming Cancer More Evidence of Cancer Stem Cells Uncovered Cancer Research, January 1, 2008 MORE EVIDENCE HAS EMERGED THAT cancer stem
cells, a minute subset of tumor cells within certain cancers, not only drive these cancers but also help them resist therapy. The team that identified the B-cell as the multiple myeloma cancer stem cell has now used mouse models to help prove their theory. While multiple myeloma is seen as a cancer of the blood plasma cells, the investigators, led by cancer stem cell experts Richard Jones and William Matsui, showed it was errant immune system B-cells, not plasma cells, that cause and sustain the cancer.
in mice provides more evidence that B-cells act as cancer stem cells,” says Jones. This research also revealed that multiple myeloma stem cells maintain normal adult stem cell properties that may help them fight off cancer therapies. Like their normal counterparts, cancer stem cells have high levels of enzymes that neutralize toxins, including cancer drugs, which they get rid of through miniature pumps on the cell surface. “Nature made normal stem cells hearty for a reason, namely to survive and help repair damaged tissues and organs after injury or illness,” says Matsui.
“Recreating the disease in mice provides more evidence that B-cells act as cancer stem cells.”
‘We need to develop new ways to target the specific biology of cancer stem cells to prevent the continued production of mature tumor cells and disease relapse.” M AT S U I
In this most recent study, the researchers isolated B-cells from the blood of four multiple myeloma patients and transplanted the cells into mice. All of the mice developed hindlimb paralysis and showed signs of cancer in the bone marrow. However, when the team transplanted plasma cells from the patients into mice, nothing happened. “Recreating the disease
“So, it makes sense that the same processes that protect normal stem cells also exist in cancer stem cells to help make them resistant to chemotherapy. We need to develop new ways to target the specific biology of cancer stem cells to prevent the continued production of mature tumor cells and disease relapse.”
The research was funded by the National Institutes of Health, the American Society of Clinical Oncology, and the Pearse family.
V E LC U L E S C U
Picture This Scientists Create 3-D Image of Cancer Initiator Science, January 4, 2008 A GROWTH-PROMOTING gene called PIK3CA, linked to cancer by investigator Victor Velculescu, is believed to be one of the most frequently mutated in cancer, and now we know what the enemy looks like. A research team from the Johns Hopkins University biophysics and biophysical chemistry department,
including L. Mario Amzel and Sandra Gabelli, created a 3-D picture of PIK3CA and, onto the model, mapped all cancer-associated mutations. “We tried to guess how its activity was affected by the mutations, but without a 3-D structure it’s hard to do. It’s like having a puzzle with pieces miss-
ing,” says Amzel. PIK3CA is known to be mutated in colon, brain, stomach, breast, and lung cancers. “Now that we have a better picture of the protein and how it is altered in cancer, we can envision development of mutation-specific inhibitors for cancer therapy,” says Velculescu.
This research was funded by the Virginia and D.K. Ludwig Fund for Cancer Research and National Institutes of Health.
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headline makers U P DAT E
Same Location, Two Very Different Cancers New Information on HPV-Related Head and Neck Cancer Journal of the National Cancer Institute, March 12, 2008, and February 12, 2008 Journal of Clinical Oncology, February 1, 2008 New England Journal of Medicine, May 2007 HEAD AND NECK CANCER EXPERT
Maura Gillison has redefined the disease using a virus and risk factors to reveal two separate and distinct types of cancer. The cancer that once primarily affected older men after years of smoking and drinking is now a menace to young professionals.
Gillison, a clinician-scientist who began her research in 2000, was the first to link the human papillomavirus (HPV) to oral cancer. In fact, she identified the HPV-related cancer as a specific subset of head and neck cancer with its own unique risk factors, prognosis and treatment recommendations. This body of work was named by the American Society of Clinical Oncology (ASCO) as one of the top cancer advances of 2007, and Gillison continues to build upon it. More recently, her research has shown that HPV-positive and HPV-negative head and neck cancers have different risk-factor profiles. “They should be considered two distinct diseases,” says Gillison. “What they have in common is that they occur in the same place.” As a result of her findings, the American Joint Committee on Cancer is now considering incorporating HPV status in its guidelines for determining clinical
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stages of head and neck cancer, she says. Her latest study found that head and neck cancers caused by HPV were most often linked to multiple sex partners and marijuana use, while those not caused by HPV were associated with alcohol use and smoking. In addition, she found that people with the HPV-linked cancer were younger, more likely to be white, married and college-educated with an annual income of $50,000 or more. By contrast, head and neck cancers not caused by HPV were associated with smoking, alcohol use and poor oral hygiene. “It just kind of rocks the whole paradigm,” says Gillison. “Everyone thinks of the long-term smoker, the long-term drinker. Now, we’re seeing the movers and shakers in the prime of life.” Gillison’s research showed that head and neck cancers, specifically oral cancers of the upper throat and back of the tongue, known as oropharynx cancers, were caused by the common, sexually transmitted human papillomavirus. Infection with HPV was occurring through oral sex. In the June 2007 New England Journal of Medicine, Gillison reported multiple oral sex partners as the overriding risk factor for the disease, superseding any other risk factor, including alcohol and smoking, which were long held as the most significant risk factors for all head and neck cancers. In their most recent research, Gillison and team studied 240 people diagnosed at Johns Hopkins with head and neck cancers between 2000 and 2006, differentiating those with HPV-positive cancers from those with HPV-negative cancers. The team also studied cancer-free people of the same age and gender as study participants. All participants completed a computerized interview that asked questions related to known risk factors. The researchers detected HPV in 92 cancer patients and found that the association
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between sexual behavior and marijuana use and cancer became stronger with increasing numbers of sex partners and with longer or more intense use of marijuana. In fact, Gillison says, non-tobacco users who smoked marijuana for at least five years were 11 times more likely to develop HPV-positive cancers. Gillison’s study is one of the first to link marijuana use with HPV-related head and neck cancers. “Some reports show that chemicals in marijuana could affect the immune system’s ability to clear a viral infection,” says Gillison, “but it’s possible that other behaviors associated with marijuana use could be the real culprit. Our results will need to be confirmed.”
“They [HPV-positive and HPV-negative head and neck cancers] should be considered two distinct diseases. What they have in common is that they occur in the same place.” About 35,000 Americans are diagnosed with head and neck cancer each year, and Gillison says the HPV-associated variety has nearly doubled in incidence over the last 30 years. On the up side, patients with HPV-positive cancers tend to survive longer and have better responses to treatment. Gillison believes these patients may do well with less intensive therapy. This is good news for a cancer where treatment can sometimes be disfiguring and often has long-lasting side effects, including trouble speaking or swallowing. This research was funded by the Damon Runyon Cancer Research Foundation, Maryland Cigarette Restitution Fund, and National Institute of Dental and Craniofacial Research.
Catching Cancer Stem Cells New Findings in Pancreas Cancer and Multiple Myeloma A report from the American Association of Cancer Research annual meeting, April 12—16, 2008 WHILE CANCER stem cells are believed to fuel cancer growth and spread, they represent a tiny, almost undetectable portion of tumor cells within a cancer. But, Kimmel Cancer Center investigators have now used HUFF two techniques, one developed here and one at the University of Michigan, to bring deadly pancreas cancer stem cells out of hiding. One method catches cells marked with proteins CD44 and CD24, while the other screens for cells with high levels of the enzyme aldehyde dehydrogenase. Using both methods, the investigators were able to capture cancer stem cell populations two to 10 times more concentrated than when they used either technique alone. In addition, they found that pancreatic cancer stem cells marked with aldehyde dehydrogenase translated to decreased survival.
A cancer that spreads is a cancer that kills, say researchers, and they believe cancer stem cells have properties similar to the types of cells that are invasive and likely to spread to distant sites. “Purifying this stem cell population even further is key to identifying the ultimate pancreatic cancer stem cell and eventually identifying the processes that control it,” says cancer stem cell expert William Matsui. Matsui and team were also the first investigators to study the therapeutic benefits of targeting cancer stem cells. In what is believed to be the first clinical trial of a cancer stem cell-targeting agent, the team tested the drug rituximab against multiple myeloma stem cells. While the drug did not prolong survival of patients, its ability to suppress cancer stem cells was impressive enough to send the investigators looking for a better drug to try. “We found cancer stem cells coated with rituximab, but the drug wasn’t killing the cells,” says Carol Ann Huff, who headed the clinical trial. “We think the idea is correct, but the drug itself wasn’t the right one.”
Multiple myeloma is a cancer of the blood plasma cells, but investigators believe it is caused and maintained by immune system B-cells, now known as the multiple myeloma stem cell. Standard therapies target malignant plasma cells, and Matsui, Huff and team say curing the disease requires a dual therapeutic approach—one that targets the plasma cells, or bulk of the tumor, and another that targets the cancer stem cells, smaller in numbers but responsible for the growth and spread of tumor cells. Huff’s study of a combined therapy of rituximab and cyclphosphamide reduced cancer stem cells by up to 1000-fold during the initial treatment. Unfortunately, stem cell quantities eventually crept back up, and the disease progressed. In fact, investigators were able to predict when a patient’s cancer would recur by tracking the number of cancer stem cells. The research was funded by the National Institutes of Health, National Cancer Institute, American Society of Clinical Oncology, Commonwealth Foundation, and Genentech.
Hit-and-Run 3-D Analysis of Enzyme Reveals How It May Influence Cancer Nature, February 2008
USING A VARIETY OF technical methods developed over seven years, investigators have deciphered a cancer-promoting enzyme. “We’ve had a chemical inhibitor of p300 for about nine years now, but without COLE the structure, we had no idea how it was working or, more importantly, how to improve it,” says pharmacology and molecular sciences expert Philip Cole. The enzyme, p300/CBP is one of several HATs, or histone acetyltransferases, so called because they add chemical
groups, known as acetyl groups, to chromosomes. Adding these acetyl groups to chromosomes turns genes on. This is known as acetylation, and drugs that can inhibit the process, called HDAC or histone deaacetylase inhibitors, have shown promise for the treatment of cancer. “Some cancers, like melanoma, appear to be driven by acetylation,” says Cole. “Inhibiting such enzymes might be useful anticancer therapies.” Working with colleagues at the University of Pennsylvania and Wistar Institute, Cole and team solved the 3-D structure of the enzyme, and using computers, assembled a model of p300/CBP. Once they had the structure, they were able to
compare it with other enzymes and found a unique method for adding the acetyl groups. Cole says p300/CBP uses a hit- andrun approach, transferring the acetyl to the chromosome without lingering or hanging on like other enzymes. Ongoing research involves developing improved chemical inhibitors for p300/CBP. “We learn something new every day about how to go after cancer,” says Cole. “This is definitely a step in the right direction.” The research was funded by the National Institutes of Health, Flight Attendants Medical Research Institute, the Kaufman Foundation and the Keck Foundation.
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Immune System On Protein Offers Clue to Cancer’s Hold on the Immune System The Journal of Clinical Investigation, November 2007 UNDERSTANDING WHY the immune system ignores cancer cells and figuring out how to activate an immune response to the disease has been the focus of continuing research at the Kimmel DRAKE Cancer Center. Physician-scientist Charles Drake believes at least part of the answer may lie in a protein called LAG-3.
Drake believes that T-cells, the foot soldiers of the immune system, can be inactivated against cancer by LAG-3. While he has not yet discovered what sets LAG-3 in motion, his studies found that blocking the protein turns on nonfunctioning T-cells. Drake tested his theory in mouse models by adding a LAG-3 antibody to an immuneboosting vaccine for prostate cancer. The result was a fourfold increase in the number of active T-cells that migrated into the prostate when compared to mice that received the vaccine alone. “With the
vaccine alone, T-cells hover along the tumor’s perimeter,” says Drake. “When we blocked LAG-3, they migrated to the center of the tumor.” Investigators also found that mice that got the LAG-3 blockade/vaccine combo had less aggressive prostate tumors. Drake is now working to find LAG-3 blocking agents that may work in humans. Charles Drake is a Damon Runyon Lilly Clinical Investigator. This research also was supported by the National Institutes of Health, William and Betty Topercer, Dorothy Needle, Jack Goldsmith, and the Janey Fund.
Biotech Update Business Education Helps Researchers Take New Treatments to Market EPHRAIM FUCHS HAS a score to settle with cancer. And he’s looking to the Carey Business School as a chief ally in his fight. Fuchs, an associate professor of oncology in the Kimmel Cancer Center, is a stu- F U C H S dent in the Carey School’s new MBA in the Life Sciences program. The oncologist is counting on the program to give him the business skills he needs to move his promising cancer-fighting research from the bench to the bedside. “It’s been a lifelong goal of mine to develop better cancer treatments, having several family members who have died of the disease,” says Fuchs, who is investigating drug therapies to fight cancer. “One critical, missing element for me was the business aspect of medicine—I needed to learn that.” Fuchs is in his second year of the new part-time program, which unfolds over three years. Students (physicians,
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researchers, lab techs, career changers) move through it as a cohort, tackling a series of “modules” that build on each other. “The first module is the foundation, focusing on the basics of the language and translation between science and business—accounting, finance, leadership, ethics,” explains Douglas Hough, associate professor and chair of the Business of Health department. Next, the students form teams and spend the spring coming up with a financially viable idea. “After six months,” says Hough, “they develop and present a business plan to a panel of representatives in the industry.” The goal: to convince the panel that the proposal is worthy of fictional “funding.” During the second year, the “funded” proposals become the basis for “companies,” and the teammates take on leadership roles within those companies, tackling obstacles devised by Carey School faculty members. In the final year, the teams craft long-term vision for their companies, while mentoring first- and second-
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year students and taking on internships. The program’s extensive exposure to real-world business challenges is what sets the MBA in the Life Sciences apart, according to Hough. “No other universities I know of are doing anything like this,” he says. Fuchs is already seeing a return on his educational investment. Thanks in large part to the skills he’s learned through the MBA program, he’s in the process of launching his own company. It is incorporated, he is filing patents to protect intellectual property, and he has started negotiating with several partners to further develop his fledgling anticancer therapies. “If scientific discoveries are to make an impact on cancer treatment, there needs to be an economic impact as well,” says the physician. “Stakeholders need to be invested financially as well as emotionally. This program is giving me the tools I need to motivate people to sign on to the cause.” This article was reprinted from the Winter 2008 issue of Business Matters, a publication of the Carey Business School.
honors and awards Deborah Armstrong, M.D., received the Rosalind Franklin Excellence in Ovarian Cancer Research Award from the Ovarian Cancer National Alliance. She was recognized for her work in enhancing treatment options and improving women’s understanding of ovarian cancer. Benjamin Carson, M.D., was awarded the Presidential Medal of Freedom, the nation’s highest civilian award, last June by President George Bush in recognition of groundbreaking contribuCARSON tions to medicine and inspiring efforts to help America’s youth fulfill their educational and personal potential. In February, Carson received the Ford’s Theatre Lincoln Medal at a White House Ceremony. This annual award is given to individuals whose work, accomplishments, or personal attributes exemplify the character and legacy of President Abraham Lincoln. Postgraduate student Ian Cheong, Ph.D., was grand prize winner of the 2007 Collegiate Inventors Competition hosted by the National Inventors Hall of Fame. He won for a new combined approach to kill cancer using bacteria and drug-filled molecular capsules. The American Association of Cancer Research honored Nancy E. Davidson, M.D., Breast Cancer Research Chair in Oncology, with the Women in Cancer Research-Charlotte Friend Memorial Lectureship. This honor is given to an outstanding scientist who has DAV I D S O N made exceptional contributions to cancer research and who has, through leadership or example, furthered the advancement of women in science. Davidson also was recently presented with the Rosalind E. Franklin Award for Women in Cancer Research.
for Academic Excellence from the Carey School of Business also went to Varner.
Thomas Kensler, Ph.D., received the 16th annual American Association for Cancer Research-American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention. Kensler was honored for his work developing and implementing practical and effective approaches for protection against environmentally induced cancers throughout the world.
Kristen Johnson, R.N., B.S.N., was honored with the Jennifer L. Brager Humanitarian Award for Clinical Service. The recipient of this award is selected from nominations made by patients and their families.
The laboratory of David M. Loeb, M.D., was awarded a $37,800 grant from the Liddy Shriver Sarcoma Initiative to help fund his research of Ewing LO E B sarcoma stem cells. Also participating in the research are Saul J. Sharkis, Ph.D., Chi Van Dang, M.D., Ph.D., and Jason T. Yustein, M.D., Ph.D. The Alliance, a group of business executives who assist Johns Hopkins School of Medicine faculty in commercializing inventions, awarded $50,000 to Anirban Maitra, M.B.B.S. Maitra used nanobiotechnology, the science of matter on the atomic and molecular scale, to develop a drug delivery system to make cancer drugs more efficient MAITRA at killing cancer cells and less toxic to normal cells. Ashley Varner, M.S.W., L.C.S.W.-C., O.S.W.-C., received the Jennifer L. Brager Memorial Research Award for her study Improving Financial and Legal Knowledge of Brain Cancer Caregivers: Impact on Caregiver Stress. Varner also was awarded the NeuroOncology Social Worker of the Year Award from the Association of Oncology VA R N E R Social Workers for her leadership in the field of neuro-oncology social work. The award is sponsored by the National Brain Tumor Foundation. The Edward J. Stegman CPA Memorial Award
Victor Velculescu, M.D., Ph.D. won the Judson Daland Prize of the American Philosophical Society, awarded for outstanding work in patient-oriented research. The newly created Baltimore Jewish Hall of Fame included Bert Vogelstein, M.D., Clayton Professor of Oncology and Director of the Ludwig Center for Cancer Genetics, among its inaugural honorees. The organization recognizes Jewish Baltimoreans who have VO G E L ST E I N made a difference in the arts, science, education, community services and medicine. In addition, Vogelstein received a $100,000 award from the Miracle Foundation for his bacteria-based cancer therapy known as COBALT. Nurse manager Gina Szymanski, M.S., R.N., received the Linda Arenth Excellence in Cancer Nursing Management Award from the Oncology Nursing Society. The award recognizes cancer nursing administrators at the local, state and national levels as well those who SZYMANSKI mentor others in the field of cancer nursing administration. Linda Arenth died in 1982 of cancer at age 59. She was the vice president of nursing and patient services at Johns Hopkins. Earlier, she served as director of nursing at the Cancer Center, then known as the Johns Hopkins Oncology Center, where she developed the system now used nationally to designate nursing services for different types of cancer patients.
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CANCER-SOLVING INVESTIGATIONS BUILDING THE BEST GI CANCER PROGRAM
Fall 2008 —Winter 2009 I PROMISE AND PROGRESS
METASTATIC—it’s a word often feared more by patients than cancer itself. It is a word inextricably connected to cancer because it distinguishes a cancer that can be cured from one that cannot. It means that the cancer has spread, and doctors and TOUGH CASES REQUIRE INNOVATIVE MEDICINE patients alike have learned that a cancer that has spread is the Diaz’s focus is on colon cancer patients whose cancer has most dangerous cancer. It attacks vital tissues and organs, already spread at the time of diagnosis, patients like Christine interferes with normal cell function, and often does not Myers and Raymond Nkemanteh. respond to therapy. And, it is a wily Myers is a 56-year-old wife and GI CANCERS BY THE NUMBERS opponent. Even to the most skilled mother of three grown daughters. YEARLY YEARLY surgeon’s eye and pathologist’s She waited six months to get INCIDENCE* DEATHS* microscope, the cancer is COLORECTAL approved for an experimental 48,810 49,960 37,680 34,290 undetectable. Researchers have PANCREAS treatment with C. Novyi-NT. At 21,500 10,880 learned, however, that often there STOMACH/GASTRIC first, it sounds a bit like science ficLIVER 21,370 18,410 are stealth cancer cells that remain, ESOPHAGEAL tion because at the center of this 16,470 14,280 and these micrometastases, as they GALL BLADDER treatment developed by Kimmel 9,520 3,340 0 SMALL INTESTINE 6,110 1,11 are called, invisible to the eye and Cancer Center researchers is a the microscope, travel through the *SOURCE: THE NATIONAL CANCER INSTITUTE live, flesh-eating bacteria called blood stream, lodge in other parts Clostridium novyi-NT. However, of the body and grow. So while much success has been made researchers have taken the teeth out of the bacteria, selecting treating localized cancers—tumors that have not spread-- a strain without a lethal toxin. In animal studies, the advances against metastatic cancers have come much more reined-in bacteria selectively targeted colon cancer cells and slowly. Cancers that have spread are still the cancers that kill. showed no interest in normal cells. Taking on this uphill battle, however, is a young, darkThe investigators happened upon the bacteria somewhat haired oncologist who exudes energy. Luis Diaz has a different serendipitously, borrowing the idea for the therapy from take on things. He intends to cure metastatic colon cancer. He nature itself. When a colon cancer patient became infected, knows that it won’t be easy, but he already has some promising his doctors noticed the bacteria eating away at the cancer. In leads, and more importantly, he is not deterred by naysayers. a CT scan, they saw that the tumor was disappearing, literally “When I walk into patients’ rooms, I don’t think of death,” devoured by the bacteria. This was the naturally-occurring says Diaz. “I think what am I going to do to cure them? I know variety, however, not the kinder, gentler version the scientists it’s difficult, but I’m going to give it a shot,” have since engineered. Once doctors began treating the Quips Diaz, “That’s the kind of defiance you get with youth.” patient with antibiotics to clear up the infection, the bacteria Whether he is an optimist or realist is up for debate. The disappeared, and the remaining cancer began to grow. This truth is that it is probably a little bit of both. Certainly work- patient soon died, but what the physicians learned from him ing in his favor is that he is a product of the renowned gave rise to the investigative bacterialytic therapy. Ludwig Center for Cancer Genetics and Therapeutics. It is a The therapy itself is simple to deliver—a single laboratory started over 20 years ago by Bert Vogelstein, a intravenous injection. But because it involves live bacteria, world-famous cancer researcher widely held as the man who getting to that point is much more complicated. Patients must defined cancer as a genetic disease. Working with other great be approved by a FDA advisory panel and two internal review minds he has brought to his laboratory throughout the years, boards before they can be treated. In the two years since the Vogelstein has mapped the genetic causes of colon cancer, clinical trials were approved, Diaz and his research nurse and he has handpicked Diaz to move these laboratory Dana Heslop have only been able to get two patients on discoveries from mice to humans. the therapy.
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Their frustration is palpable as Diaz holds up a DVD of a former patient’s funeral, sent to him by the patient’s family. She died, Heslop says, waiting for the therapy. After, contacting her Congressman, she was approved for compassionate use. However, Heslop says this took six months, lost time that allowed her cancer to grow. Once she finally got approved for therapy, she was too sick to receive it. She died just days after compassionate use approval came through. These patients have cancers that do not respond to currently available therapies. “Surgery cannot cure them. Radiation cannot cure them. Chemotherapy cannot cure them,” says Diaz. “This may. The FDA considers it high risk because it uses live bacteria, but metastatic colon cancer is high risk also. Left alone, it will definitely kill.” Patients like Myers believe the risks involved when receiving C. Novyi.NT therapy are more acceptable than the risk of not getting it. “Am I nervous, yes. But I gave this a lot of thought, and I discussed it with my family. I’m going into this with my eyes wide open, and I wanted this therapy. There is nothing else for me.” Since the trial is currently in the safety or phase I stage where investigators must prove that patients can tolerate the therapy without suffering harmful side effects, they are required to give patients antibiotics if they develop a fever. As the therapy involves a bacterial infection, reactions such as a fever are anticipated, but the FDA wants to be sure the team can control the bacteria before they will allow treatment without antibiotics or scaled-back use of antibiotics. Diaz, says this will probably mean that it will not significantly benefit patients treated in these early, safety trials because once you get rid of the of the bacteria with antibiotics, you get rid of the cancer-fighting part of the treatment. Myers has developed a fever, and now her biggest concern is that the antibiotics she receives will completely get rid of the bacteria that are eating away at her colon cancer. Diaz and Heslop have the same concern. Diaz also worries that, in current times, there is a tendency to completely err toward safety at the cost of clinical progress. “There is always a trade off between safety and therapeutic benefit,” he says. “If bone marrow transplantation and heart transplants were just being developed today, we wouldn’t have
From right to left: LU I S D I A Z , O N CO LO G I ST DA N A H E S L O P, R E S E A R C H N U R S E M A R T I N M A K A R Y, S U R G E O N J O E H E R M A N , R A D I AT I O N O N C O L O G I S T T I M O T H Y PAW L I K , S U R G E O N
Cancer experts are integrating their efforts in hopes of curing metastatic cancers
them. They would never make it through the regulatory agencies.” Diaz says the current regulatory climate prevents some patients from getting the best care, and he worries that this mindset could have far-reaching effects. “It is tough to do risky science today, and it is affecting junior faculty and the next generation of researchers and clinicians that will lead us. Pharmaceutical companies see this, and are moving toward ‘gentle’ therapeutics. We have to get brave, because if we don’t, the cost will be in human lives.” Patients are exasperated and so is Heslop who speaks almost daily with patients waiting to hear whether they have been accepted for treatment. She is a small-framed, calm, and soft-spoken woman, but she fights like a giant for her patients. It is not completely clear what is most dangerous to patients, the cancer or the regulatory measures put in place to protect patients. “The regulatory process, in theory, is good,” says Heslop, “but it has gone too far.” She says it is no longer helpful, and patients like Myers argue that it is actually harmful. As they wait to receive approval for treatment, their cancer continues to progress. “On one hand, we have been asked to speed the pace of transferring research results to the bedside, but on the other hand, the pace of clinical trials has been slowed to a crawl because of regulatory processes,” says Diaz.
“We are integrating more with surgeons and radiation oncologists, and as a result, cures are coming more and more. In my mind, metastatic colon cancer no longer means death. We can control it.” —LUIS DIAZ
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“I appreciate that Dr. Diaz and his team was willing to try. Not everything has worked, but they have always been willing to try. I am so grateful to be alive, and I know I am alive today because of them. I think every hospital should follow this example. They are my heroes.” — R AY N K E M A N T E H
Now, in an effort to move things forward, investigators have developed a different kind of animal model to help prove their case to the FDA. They are working with veterinarians, treating canine sarcoma with C. Novyi-NT and hoping that if they can show they can safely treat dogs, the FDA will give them more leeway in humans. A BOUTIQUE OF A CLINIC
In the meantime, Diaz is attacking the cancer on other fronts. “We are working more closely with surgeons and radiation oncologists,” Diaz says, “and as a result, cures are coming more and more. In my mind, metastatic colon cancer no longer means death. We can control it.” His bright outlook on what has been viewed for years as a hopeless cause does not end there. Even the way he describes his colon cancer clinic is uplifting. “I envision a boutique of sorts,” he says. When patients come to the clinic, while they are waiting to see the doctor, they will meet with a nutritionist, pain specialist, a palliative care specialist, and other members of the supportive care team. “All of this will take place before the patient even sets foot in my door,” says Diaz. “More than an hour may pass between when the patient arrives and sits down with the doctor. I want to use this time to allow the patient to take advantage of all of the supportive services we have,” he says. Diaz doesn’t want his patients sitting in the waiting room worrying about the cancer. Rather, he wants them meeting with caregivers that can make their treatment experiences better. NOT END-OF-LIFE, BUT QUALITY-OF-LIFE CARE
Often, the services he describes occur quietly behind the scenes, but at other times, they become the front line of therapy. Such was the case with Ray Nkemanteh. The 49-year-old was first diagnosed and treated for colon cancer in 2004 at a community hospital near his home. After a number of surgeries and failed therapies, he was discharged by his doctor in August 2007 and told there was nothing more they could do “They were sending him home to die,” said his wife Thecla. But she wasn’t having it, and the next morning she drove him to the emergency room at The Johns Hopkins Hospital. He was near death, suffering from many complications, including sepsis and severe dehydration. He was admitted to the Kimmel Cancer Center, but doctors could not treat his cancer because he was so sick.
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Nkemanteh was not ready to give up. He had four daughters at home and a mother in Cameroon who was not even aware he was ill. Diaz came to see him the next day. He saw a spark, and issued a challenge. He told Nkemanteh, “If you can walk into my office, I’ll treat you.” To get him to that point, staff at the Harry J. Duffey Family Pain and Palliative Care Program joined forces with the medical team. While the term palliative care has become associated with end-of-life care, nurse coordinator Lynn Billing says it is really about helping patients feel better— physically, spiritually, and emotionally and to live well with their cancer. This is how they intended to help Nkemanteh. “Ray had a lot of problems causing many symptoms—an intestinal blockage, sepsis, nausea and vomiting, severe pain, and intractable hiccups,” says Billing. He wanted to get chemotherapy, but he could not be treated unless these symptoms could be managed. And, manage them they did. The team, including nurses, physicians, nutritionists, a pharmacist, a social worker, and a chaplain attacked what seemed like insurmountable obstacles to take this patient from the brink of death to the clinic for therapy. It took nearly a month and treatment with three to four different antibiotics, several procedures and medication to manage the intestinal blockage, acupressure for his persistent hiccups, and a pain management plan, but Nkemanteh walked into Diaz’s clinic on day 28 and began treatment for his colon cancer.
R AY N K E M A N T E H SURROUNDED BY H I S FA M I LY
The team’s social worker Donald List spent hours with Nkemanteh and his wife discussing their concerns, fears, and goals. During this, time, List and the medical team were able to get his mother from Cameroon to be with her son. With his mother and daughters with them, Father Paul Sparklin blessed Raymond and Thecla as they renewed their wedding vows. “Sometimes we can’t change the outcome,” says palliative care nurse Colleen Apostol. “This time we could.” Their goal was to meet his goal, and that was to get well enough to receive treatment. The team struggles with the misperceptions about palliative care. Many patients have misguided ideas about pain and palliative care, misconstruing their involvement to mean the doctors have given up, and they’re going to die. In fact, Billing says, it isn’t palliative care that takes away hope, but rather the debilitating symptoms that patients endure. “Palliative care is not about how you die. It’s about how you live,” she says. Diaz believes so strongly in the new medical subspecialty, only recognized in 2006, that he has incorporated it into his clinic. Not every patient will need the amount of care that Nkemanteh required, but he wants all patients to be able to take advantage of the services they offer. Diaz is now treating Nkemanteh with an aggressive weekly chemotherapy regimen, instead of the standard two-week cycles. His cancer is not cured, and he may never be cured. He understands that, but for now, his cancer is under control, an almost unbelievable change from where he was a year ago. “I appreciate that Dr. Diaz and his team was willing to try. Not everything has worked, but they have always been willing to try. I am so grateful to be alive, and I know I am alive today because of them. I think every hospital should follow this example. They are my heroes,” says Nkemanteh. “We thought he was going to die, and here he is,” adds Thecla. “Our community, our friends, our family cannot believe it. Everyone is amazed.” To Diaz, this is nothing more than what should be expected at a place like Johns Hopkins. He understands firsthand what it is like to be the patient, and he has used this experience to build his clinic. When he was a resident, Diaz stuck his hand with a syringe. The syringe was filled with blood from a patient with treatment-resistant HIV. He was treated with four different kinds of drugs and every three months had an HIV test. “It was the worst experience of my life,” he recalls. “I was constantly looking in my mouth for signs of thrush. With every ache or pain, I was certain that I had HIV.” He did not, and now more than 10 years has passed, but Diaz remembers what it felt like to be the waiting, wondering patient and believes it has made him a better doctor. “How I felt when I was waiting for my HIV test results is just how my patients are feeling when they are waiting for their CT results and living in fear of those dreaded words ‘your cancer is back or your tumor has grown’.”
L T O R : B E T H O N N E R S , DA N I E L L A H E R U , E L I Z A B E T H J A F F E E , K AT H L E E N D O W E L L , A N D B A R B A R A B I E D R Z YC K I
B E AT I N G PA N C R E AT I C C A N C E R : K AT H L E E N D OW E L L H AS A R A R E D I ST I N C T I O N . S H E I S A LONG-TERM SURVIVOR OF PANCREATIC CANCER. I N 1 9 9 7, A N N OYING itching all over her body drove her to see
her doctor. A suspected gall stone turned out to be something more sinister. When routine surgery at a community hospital to remove her gall bladder resulted in a burst small intestine, a surgeon called in to repair the intestine found pancreatic cancer. The surgeon broke the devastating news to Kathleen’s husband and 25 and 21-year-old daughters. He recommended Dowell go to Johns Hopkins for surgery. “He told us they could do the surgery, but they weren’t as skilled as Hopkins surgeons because they didn’t do as many of these procedures. He said Hopkins surgeons had the most expertise in doing this surgery,” Dowell says. The next day, she was taken by private ambulance to Johns Hopkins Hospital and a meeting with world-famous GI surgeon John Cameron. Cameron removed Dowell’s cancerous pancreas, part of her stomach, and several lymph nodes. Most of the lymph nodes were positive for cancer cells, so her medical team knew that the pancreatic cancer had begun to spread. She could not be cured by surgery. Six weeks later she began chemotherapy and radiation therapy, but still the odds were not in her favor. Few patients were cured, and though Dowell, who says she knew very little about pancreatic cancer, was not aware of the cancer’s deadly reputation, she sensed it was not good. “At the time I was diagnosed, I didn’t understand the gravity of pancreatic cancer,” says Dowell. “I had heard of breast, colon, and lung cancers—the big ones, but I really wasn’t familiar with pancreatic cancer. I didn’t know anyone who had it, so I didn’t really understand how bad it was.” She recalls a doctor telling her it was not a good one to get. GI cancer expert Ross Donehower spoke to Dowell about a clinical trial of a new cancer vaccine. “He said it might keep my cancer from coming back,” Dowell recalls. She eagerly accepted. After two doses of the vaccine, she developed a condition called TTP that causes blood clots to form throughout the body. Though the condition was not caused by the vaccine, it had caused to her have seizures and a stroke, so she could not receive more vaccine. Remarkably even the small dose of vaccine she received was enough to get her immune system working against the cancer. More than ten years later, 61-year-old Dowell is enjoying her job with the Federal government, gardening, crafts, and work with a women’s group at her church, and even housework. “I won’t say I’m as good as new. I have to take pancreas enzymes to digest food. But, I have a good life,” says Dowell. She looks back on her diagnosis ten years ago and recalls questioning Cameron about the cancer’s terrible survival rates. “Dr. Cameron told me it was true, but he also told me I could be the one to survive it,” she recalls. “He was right.”
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C H OT I
G I A R D I E L LO
A CONCERTED EFFORT
Once patients’ symptoms are managed, Diaz’s plan is to attack these cancers with an intelligent but aggressive approach, integrating surgeons and radiation oncologists and using genetic findings to create better therapies. “We are talking about life and death here. There is basic science information that could make a real difference, and the medical community is ignoring it,” he says. One example of this is genetic testing for Kras mutations. Diaz says it is widely known that mutations of the Kras gene can predict if patients will respond to drugs known as EGFR inhibitors. A test for the mutation is already available. Insurance companies even pay for the test, but doctors aren’t using it. “It is as important as a CT scan in the treatment of colon cancer, but right now, patients are not getting the test,” Diaz says.
UNFORGETTABLE SURGERY T H E R E A R E T H O S E A M A Z I N G cases that a surgeon
never forgets. Marc Duncan doesn’t recall the name of the Buffalo surgeon who called him five years ago, hoping he could operate on his patient. Exploratory surgery found a tumor in the 76-year-old man’s duodenum entwined in blood vessels. “I looked at the scans, and I thought we might be able to get the tumor out,” says Duncan. The man drove from Buffalo, N.Y. to Johns Hopkins Bayview after being told by experts there that Johns Hopkins was the best place to get treatment for intestinal cancer. “It was a huge operation,” recalls Duncan. “We didn’t just take out the tumor in the duodenum. We had to remove the bypass where the stomach had been sewn to the intestine, we took out additional lymph nodes, a mass that developed, a gall bladder, a segment of his small bowel, a segment of his colon, and part of the peritoneum. Plus there was scar tissue from his initial operation that we had to get through.” Duncan says his approach was systematic. “Surgery is the cumulative effect of hundreds of tiny details.” Duncan says the odds of him being able to cure this patient were remote. His doctors in Buffalo had already told him he had terminal cancer. “But, here it is five years later, and he’s totally healthy,” says Duncan. Duncan no longer sees the patient for follow-up visits, but he still gets cards from his brother. Tucked inside is money to buy donuts. He buys them and retells the story to his new residents—over donuts.
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Another test checks for an enzyme that causes a terrible reaction to 5FU, a mainstay drug for colon cancer. Patients who have the enzyme, Diaz says, would definitely end up in the hospital if they got the drug and could potentially even die. Testing for this, they can know in advance which patients would suffer a reaction. Diaz wants genetic analysis for every patient. “This is where Johns Hopkins needs to be, and this is where we are going,” he says. He believes that the secret to why patients’ cancers don’t respond or stop responding to treatment is revealed in alterations in their tumor’s gene code. These gene codes are as unique as a fingerprint. While there are several gene mutations that occur widely across all colon cancers, there are far more mutations that occur less often overall but are instrumental in controlling how a tumor behaves. “We used to think there were three or four key mutations in colon cancer, but now we know there are maybe 20 key mutations,” says gastroenterologist Francis Giardiello. “Now that we know the genes, we can figure out the pathways they work through and use them as targets for treatment.” Historically, cancer treatment has focused on drugs that kill rapidly-reproducing cells—cancerous ones and normal ones. Now Diaz and team are looking at new drugs like Avastin and Erbitux that appear to work through molecular pathways and shut the tumor down by putting the brakes on the genetic mistakes that cause it and drive it without harming normal cells. Just as all other body parts and functions have a multiplicity of actions and reactions, so too does colon cancer, Giardiello says therapies that hit just one molecular pathway or cell activity won’t work because the body has many systems in place that protect key functions and, like other normal cellular mechanisms, cancer has hijacked these protective properties to act as barriers to therapy. “There are multiple pathways involved in colon cancer, so we have to target them all and that means using multiple drugs,” says Giardiello. “Up until 2000, we used one or two drugs to treat colon cancer, with 5FU being the main one. It wasn’t that great, but nobody had a better drug,” says Giardiello. “It is a targeted drug, so if we use it in combination with other drugs, it could hit more pathways and be more effective.” Along, these lines, Diaz and leading colon cancer surgeon Michael Choti have developed a blood test that detects genetic mutations found in colon cancer. When cancers grow, they shed their DNA into the bloodstream. While not
all colon cancers can be cured with surgery, it is often the first course of treatment. With their test, which measures levels of known cancer-causing mutations in the blood, Choti and Diaz can tell within 24 hours after surgery if any microscopic cancer was left behind. “Basically, we count the mutations in the bloodstream,” says Choti. “The more you see, the more likely the cancer is to come back.” It is the cancer doctors can’t see that kills, so uncovering these hidden cells is key to curing the cancer. “It is these cells that get into the lungs, liver, and brain and clog normal functions in normal tissue,” says Diaz. He likens it to the viral load in HIV. “We’ve learned that if you keep the virus in check, it doesn’t kill. We can apply this same approach to cancer.” Choti says the same test can be used to tell if drug or radiation therapy is working. Typically, physicians rely on imaging, such as CT scans, to see if the tumor is getting smaller. Choti says, since the scans are not done frequently, as much as two months of therapy could go on before the doctors realize that it’s not working. “With this blood test, we could potentially know after one week, maybe after one dose, whether therapy is working,” he says. CURING BY CONTROLLING
Colon cancer is unique among cancers in that patients get what Choti calls controlled metastases. “We can cut out or destroy spots on the liver with such techniques as liver resection and ablation and cure many patients,” he says. This approach is now becoming standard care, and Choti says it’s being expanded to other GI cancers. “We have more and more data to support surgical therapy for metastases to the liver and the lung,” says Choti. It significantly improves survival.”
A new colon cancer vaccine, monoclonal antibody therapy, radio-immunotherapy, imaging-guided and robot-assisted surgery, and molecular-targeted therapies are all new approaches to treating advanced colon cancer. One of the more interesting efforts is being led by Choti and a young surgeon Timothy Pawlik. It is directed at cancers of the liver—ones that originate there and ones that begin in the colon or other organs and spread to the liver. The liver is a vital organ that humans cannot live without. Liver transplantation is an option for some patients with primary liver cancer, but not for patients with colon cancer that has spread to the liver. These patients are often told there is no surgical therapy for them. Not at Johns Hopkins, however, where Choti and Pawlik are doing what others said could not be done. As a result, they are attracting patients from around the country. One good thing about the liver is that it can regenerate itself. If there are a limited number of tumors in the liver, surgeons can take them out, and the organ rather quickly repairs itself. “We are helping patients who have tumors that require removing 70 to 80 percent of the liver, a surgery the liver could not recover from without some help,” says Pawlik Using CTs of the liver tumors and working with radiologists Pawlik determines how much of the liver will have to be removed to get all of the cancer. If it is too much, he turns to interventional radiologists for a technique called portal vein embolization that actually grows the liver. The liver has two halves, and each has a portal vein that carries blood and the critical growth factors that give the liver its unique rejuvenation abilities. The interventional radiologist uses embolization to clot and cut off the blood supply to the tumor-filled side of the liver, redirecting the blood supply to the normal side, causing it to grow. It must grow to where it repre-
“A new colon cancer vaccine, monoclonal antibody therapy, radio-immunotherapy, imaging-guided and robot-assisted surgery, and molecular-targeted therapies are all new approaches to treating advanced colon cancer. ” — M I C H A E L C H OT I
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“Our philosophy is to attack the disease on all fronts. We want to get the disease so we are controlling it, not it controlling us.” —ELIZABETH JAFFEE
sents 20 percent to 30 percent of the total liver before Pawlik can operate and remove the tumors, which can require him to take out as much as 80 percent of the original liver. In some instances the same approach is used to treat patients with breast and melanoma skin cancers that have spread to the liver. Among his success stories is an 80-year old North Carolina man who traveled to Johns Hopkins after being told his metastatic melanoma skin cancer was untreatable. Pawlik removed the cancer that had spread to the man’s liver, and two years later, the patient remains disease free. “We are one of the few Centers in the country doing this, so I am seeing more and more patients who have been told they are unresectable because of the type of cancer they have or because of the technical aspects of the surgery,” says Pawlik. For patients considered by most to be inoperable because they have tumors throughout the entire liver, Pawlik takes a two-step approach. First, he removes all of the cancer from one side of the liver. He waits for the patient to recover and the liver to re-grow, and then he operates again to remove the cancer remaining in the other half of the liver. This procedure has cured some patients who had been told they had no options. The introduction of new anticancer drugs and surgical approaches over the last 10 to 15 years is beginning to make a real difference in patient outcomes. “Survival rates for patients with metastatic disease to the liver have doubled,” says Pawlik. To help patients with primary liver cancers who are not candidates for transplantation and whose cancers are too advanced to be surgically removed, Pawlik has teamed with radiologist Jeff Geschwind on a new clinical option. It is called TACE for trans arterial chemo embolization. Clinicians insert a catheter through the groin into the femoral artery and into the blood vessel feeding the tumor so that they can deliver chemotherapy directly into the tumor. Then they clot off, or embolize, the vascular escape route making sure the anticancer drugs stay in the tumor. “This is such an exciting time in GI cancer,” says Diaz. “There are strategies available now that did not exist even a year ago.”
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BUILDING A MODEL CLINIC
As co-directors of the gastrointestinal program, Scott Kern and Elizabeth Jaffee have one main requirement: that is that the clinical programs are as strong as the basic science research programs. With the depth of the colon cancer and pancreatic cancer laboratory discoveries, this is a tall order but one that both clinics are well on the way to achieving. On the pancreas side, the clinical push is being driven in large part by the success of a pancreatic cancer vaccine. The vaccine, spearheaded in the clinic by cancer immunology experts Jaffee and Dan Laheru, turns on the immune system, and leads immune cells, typically blind to cancer, to attack the cancer cells in the pancreas and throughout the body. With pancreatic cancer being one of the deadliest cancers and few treatments making any real difference in long-term survival, the vaccine discoveries resulted in a barrage of patient inquiries and appointments. Clinic coordinator Barbara Biedrzycki receives more than 60 calls each month and even more e-mails from patients wanting the pancreatic cancer vaccine. When Jaffee and Laheru’s work makes news, the calls increase. Jaffee and Laheru had to come up with a way to triage patients, getting those who were candidates for the vaccine into trials as quickly as possible, but just as important, getting the right care for patients who were not candidates. Joe Herman, a young radiation oncologist envisioned a new type of clinic, in which patients would come to the Kimmel Cancer Center, and after a single day’s visit, receive an integrated plan of treatment. This required getting all of the experts—surgeons, pathologists, gastroenterologists, radiologists, oncologists, radiation oncologists, and more—in one room together one day a week to review patient records and determine the right course of treatment for each. “I thought this is a great idea and told him to go for it, but we wondered whether he could really pull it off,” says leading pancreatic cancer surgeon Richard Schulick. It seemed like an impossible feat because the clinic Herman was envisioning involved a team of experts considered the best in their fields. Finding a day that all of them
NANOPILL COULD PREVENT PANCREATIC CANCER PANCREATIC CANCER IS among the most feared of all
cancers. With survival rates of less than five percent, one doesn’t need wonder why. Standing as a roadblock between
cancer, or not, is the lack of warning
could meet seemed unlikely. Herman succeeded, however, making possible a pancreatic cancer clinic encompassing all specialties and one that could become a model for essentially every cancer program. In the early days of cancer care, and even the not too distant past, cancer therapy involved a singular approach. If a tumor could be surgically removed, the patient would be treated first by a surgeon and then handed off to medical and radiation oncologists for chemotherapy and radiation therapy. The radiologist would image the tumor and send a report to the oncologist. Each would do his and her part well, but there was no formal concerted effort. The pancreatic cancer clinic is blazing new trails. Cancer clinicians and researchers are learning that cancer therapy transcends the boundaries of medical disciplines and so it is imperative to have all of the key players involved in the plan and execution of therapy from the onset. The idea for the multi-disciplinary clinic is born. “The department lines have really been blurred here,” says Jaffee. The Kimmel Cancer Center is so invested in a multidisciplinary attack on cancer that it pays the rent of Schulick, a surgeon, Ralph Hruban, a pathologist, and other nononcologists whose laboratories and offices are located in the Center’s cancer research buildings. “It works because everyone is an equal member, and the proximity makes for easier and greater communication,” says Jaffee. Every Tuesday at 12:30, the team meets. Sometimes there are heated debates about the course of action, but by the time they all leave the room, they have agreed on a treatment plan. Patients can be confident that all of the experts played a role in the decision. Also having a seat at the table are research nurses, genetic counselors, social workers, nutritionists, the pain management team, and others. “They are getting a first, second, and third opinion all at the same time,” says Schulick. By the time a physician meets with the patient, a CT scan has been done, a fellow or resident has done a physical examination, and a full history has been taken. In a single day, patients receive a comprehensive
signs. It is a cancer that exhibits few symptoms until it is already well advanced. Prevention offers the best opportunity to improve the bleak MAITRA
survival rates that plague this cancer, says pancreatic cancer researcher Anirban Maitra. Joining together the principles of nanoscience with the Indian spice curcumin, he believes he may be heading in that direction. Curcumin, Maitra says, has been found to activate detoxifying enzymes that rid the body of carcinogens, but it is poorly absorbed once it is eaten and never gets the chance to go to work. Working with his father Amarnath Maitra at the University of Delhi in India and colleagues at the Johns Hopkins Institute for NanoBioTechnology, he has created a nanoparticle carrier for curcumin to overcome the absorption problem. Nanoscience involves the extension of the existing sciences into the study of ultra-tiny structures, materials, and devices. The engineered nanocurcumin could be given intravenously or orally like a vitamin pill.
evaluation, involving all the resources available for the education, diagnosis, treatment and research of pancreatic cancer. With patients traveling from all over the country and the world, the team not only wants to ensure the best and most advanced care but efficient care as well. The ultimate goal of the clinic is to seamlessly incorporate all elements of pancreatic cancer care, from detection through therapy. The National Familial Pancreas Tumor Registry is based at Johns Hopkins. The first of its kind, it was started in 1994, and today more than 3,000 families are registered. With the help of these families, Kern, Hruban, Michael Goggins, and others have been uncovering the molecular genetic causes of pancreatic cancer while registry director Allison Klein has developed a novel computer software tool that helps identify people at risk of developing the disease.
“Most will need novel therapies. Other [cancer] centers are doing the same thing they were doing 20 years ago. We’ve shifted the paradigm here.” —RICHARD SCHULICK
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Patients also are helping investigators get to the root causes of this disease through a rapid autopsy program. In this selfless endeavor, those who lose their fight against the disease are allowing investigators to study their tumors, cells, and genes to help save the lives of others. More than 80 rapid autopsies have already been done, allowing investigators to look for genetic differences in pancreatic cancer. The program helped investigator Christine Iacobuzio-Donohue and team link a gene discovered by Kern to pancreatic cancer metastasis. Investigator Jim Eshleman has engineered a mouse that grows pancreatic cancer providing some of the groundwork for a massive exploration of the pancreatic cancer genome. Hruban, Kern, and Eshleman are working with Vogelstein on the Goldman Pancreas Cancer Genome Initiative. It is the largest cancer gene project ever undertaken, involving the sequencing of all 24,000 known genes in a series of 24 pancreatic cancers followed by validating the findings in an additional 96 cancers. Marcia Canto runs an endoscopy center that helps people with a family history of pancreatic cancer learn if they have treatable precancerous lesions before they develop into cancer. Sometimes Schulick can remove the precancerous lesions and save the pancreas, but other times patients are faced with a gut-wrenching decision to have their pancreas taken out before it can turn on them. Those who opt for the prophylactic removal of the organ face diabetes and lifetime dependence on insulin, but even that seems like a victory when faced with the alternative: an almost certain battle against lethal pancreatic cancer. After all, this is better than having no chance to fend off the cancer. That is the position most patients are in when they come to clinic. Having already learned they have pancreatic
Experts from all areas—surgery, pathology, gastroenterology, radiology, oncology, and more—meet regularly to discuss cases and determine the right course of treatment.
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cancer, they come to the Kimmel Cancer Center clinic to get the best treatment available. Here they will learn if their cancer can be treated with an intensive but potentially curable surgery known as the whipple procedure, or if their cancer cannot be treated with surgery, maybe a combination of chemotherapy and radiation therapy can at least buy them some time. What most want to hear—the reason they came to the Kimmel Cancer Center—is that they are a candidate for the pancreatic cancer vaccine. About 20 percent of patients will go directly to the OR and be cured after surgery. “Most will need novel therapies”, says Schulick. Other centers are doing the same thing they were doing 20 years ago. Here, we’ve shifted the paradigm.” They’ve done that by altering the ordered regimen of surgery followed by chemotherapy and radiation therapy. In the newest vaccine study, patients are given the vaccine two weeks before surgery. Jaffee says it gets the immune system juiced up. Even at Johns Hopkins, where surgeons have dropped the surgical death rate to 1 percent to 2 percent, the whipple is still one of the most complicated and difficult procedures to perform. As a result, patients require two months to recuperate, but this lag time without additional therapy gives any remaining microscopic cancer cells time to travel, spreading the cancer. and Laheru say pancreatic cancer is notorious for being in areas outside of the pancreas, and giving the vaccine before surgery may allow them to get ahead of the disease and attack these microscopic renegades before they can take hold. With promising results from early vaccine studies, including a modest but real improvement in survival time, the investigators continue to tweak the vaccine. One approach they are trying is a chemotherapy-vaccine combo. They alter the tumor’s environment by treating patients with the drug cyclophosphamide before giving them the vaccine. It seems to make the tumor more responsive to the vaccine. Doing this before surgery not only gives them an advance attack on the lethal tumor but also allows them to see what impact the treatment has had when they do operate. The team also has found that giving radiation therapy sequentially to vaccination, also improves vaccine effectiveness. “Our philosophy is to attack the disease on all fronts,” says Jaffee. “We want to get the disease so we are controlling it, not it controlling us.” More recently, Jaffee and Laheru have begun working with new faculty recruit Dung Le in an approach that combines targeted therapy with vaccine therapy. The protein mesothelin is believed to play a role in causing pancreatic cancers to grow and spread. Hruban’s studies found high levels of the protein on the surface of tumor cells in many patients. The team hopes that shutting down mesothelin will slow the growth of the tumor and give the vaccine more traction. It is a delicate dance to turn on the immune system and turn off cells standing in the way. The team must activate the immune to system to recognize pancreatic cancer cells, but at the same time they must suppress cells hijacked by the tumor
“We’re in this for the long haul. If it doesn’t work the first time, we don’t give up. And, of course, we can’t overemphasize the importance of our generous donors. It is their support that makes it possible to do this work and to keep trying these novel things.” —ELIZABETH JAFFEE
to protect it from the immune system. Without attacking the cancers many mechanisms, the investigators know that the vaccine will never be fully effective against the disease. Yet another attempt to strengthen the vaccine includes another live bacterium listeria. “It’s pretty wimpy,” says Schulick. “If you eat bleu cheese dressing, you have been exposed.” In fact, listeria is almost everywhere and resides throughout the GI tract. For most people, it is harmless, and the version the pancreatic cancer team is using is even more so because they have genetically engineered it to remove the nasty genes. So far, they have treated nine patients with no adverse effects. In two patients whose cancer had not responded to any other therapies, biomarkers indicative of the pancreatic cancer have declined. And, Jaffee notes, these patients did not even receive the maximum dose of the vaccine. The team is now looking at whether the vaccine can prevent cancer in high risk patients and if it may help colon cancer patients with liver metastases. “You almost have to be willing to stake a career on your research,” says Jaffee referring to the vaccine studies she began in 1991. And, that is exactly what she did. To make vaccine therapy a reality, Jaffee became an expert in vaccine manufacturing, opening a GMP facility (good manufacturing processes) at the Kimmel Cancer Center to make the vaccine and learning the huge compendium of FDA regulations. “We’re in this for the long haul,” says Jaffee. “If it doesn’t work the first time, we don’t give up. And, of course, we can’t overemphasize the importance of our generous donors. It is their support that makes it possible to do this work and to keep trying these novel things.”
At the Kimmel Cancer Center, however, we are catching up with the help of philanthropic support. Peter Kovler, Chairman of the Board of the Blum Kovler Foundation, had for some time supported Kern’s research. His mother and grandfather died of pancreatic cancer years UNDERWRITING THE WORLD’S LARGEST GENE STUDY J A N E G O L D M A N H A S A H I S TO R Y of pancreatic cancer
in her family. She also has a history of using her family’s resources to make a difference in cancer treatment and other human causes. She has combined both of these passions to help Johns Hopkins cancer researchers and clinicians make progress against pancreatic cancer, a lethal cancer and one where advances have been hampered due to funding limitations. Though pancreatic cancer is the fourth leading cause of cancer death in the United States, less than one percent of the National Cancer Institute’s budget goes to research of this cancer. Jane’s mother Lillian died of pancreatic cancer in 2002. Although her mother was never treated at Johns Hopkins, Jane, trustee of the Sol Goldman Charitable Trust, recognized Hopkins as a place that was doing pioneering research and making clinical advances. In 2005, she and her family donated $10 million to establish the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins. “By partnering with this team of Johns Hopkins scientists, we hope to attract new faculty and young researchers into this less studied field of research,” says Jane. “This research center fits into my parents’ understanding of what it took to build an enterprise that could grow beyond any one lifetime. We predict that its results will benefit future generations of pancreatic cancer patients.”
SOMETIMES IT IS ALL ABOUT THE MONEY
While the Kimmel Cancer Center has led the way in successful attacks against the lethal cancer, Jaffee says there is still a lot of ground to cover, and it all comes down to funding. Pancreatic cancer is one of the most underfunded cancers, according to experts. Because it is relatively rare, it does not attract the attention from the public or the research world that other cancers like prostate, breast, and colon cancers do. What’s more, pancreatic cancer patients don’t usually survive their disease, so there aren’t enough of them to form activist groups or speak out and demand the attention that’s needed. “We are so far behind in understanding the biology of this cancer compared to breast or prostate cancer,” Jaffee says.
The Goldman family’s generosity continues. The Sol Goldman Charitable Trust and the Lillian Goldman Charitable Trust are the lead funders for a pancreatic cancer genome study, the largest cancer gene study ever conducted. “In addition to performing the most complete genetic analysis of any tumor type, this effort will lay the groundwork for uncharted areas of pancreatic cancer research,” says Ralph Hruban, director of the Goldman Center. “With support from the Goldman Trust, our team of young and established researchers will advance our understanding of this cancer. Our hope is that the discoveries made by this team will also benefit patients fighting other forms of cancer.”
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With gastric cancers, it all comes down to the lymph nodes. These bean-size organs of the immune system located throughout the body can be filters for cancer cells, gathering them up and providing the vehicle for them to travel from the main tumor to other tissues and organs. ago, so he had a personal interest. After reading an article about the disease in the New York Times, he was struck by how little money was available for pancreatic cancer research. After meeting with Kern and other leading researchers, he was even more inspired to take action. “Their expertise was quite impressive,” says Kovler. “They were very persuasive about the need and timing for funding, and I believe what Johns Hopkins offers is as good as it gets anywhere in the world.” His goal was to ensure continuity of funding, so his family’s foundation donated $2.5 million to establish the Everett and Marjorie Kovler Professorship in Pancreas Cancer Research. Kern, who is funded through the professorship, says it is the only fully-funded chair for pancreatic cancer research, a commentary to the money issues facing this cancer. “It seems to me that the philanthropic community has an obligation to help when there is a good chance for progress,” Kovler says. He calls it venture philanthropy. “Here is an opportunity for philanthropists to step up and take a leadership role in moving things forward. In this disease, the numbers run against you. Despair is deep, but there is real hope if we invest in the research. This Johns Hopkins team is making great progress. Maybe success is five years away, or maybe it doesn’t come for 20-30 years, but someone has to do this or we’ll never get there.” Other champions of the cause include the Goldman family, who have most recently provided lead funding for a pancreatic cancer genome study, the largest gene study every conducted, and whose earlier gift established the Sol Goldman Pancreas Cancer Research Center. The Commonwealth Foundation supports both cancer vaccine research and C.Novyi-NT research, and the Lustgarten Foundation, the Skip Viragh Charities and the Viragh Family Foundation have been major contributors to pancreatic cancer research, patient care and clinical studies. Just as important to the fight are donors like Russell Weisman. Weisman came up with $100,000 to cover the costs of therapy for a friend whose insurance company had denied payment. When the insurance company finally came through, instead of taking his money back, Weisman donated it to the Kimmel Cancer Center.
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MAKING THE CUT
For GI cancers, the critical role of surgery cannot be overstated. With gastric cancers, it all comes down to the lymph nodes. These bean-size organs of the immune system located throughout the body can be filters for cancer cells, gathering them up and providing the vehicle for them to travel from the main tumor to other tissues and organs. The number of lymph nodes containing cancer can tell if it has just begun to spread or it has already made a complete escape. The American Society of Clinical Oncology (ASCO) reports, however, that a quarter of surgeons (and many experts believe it is actually as high as one-half) do not take out the adequate number of lymph nodes during surgery, and as a result, they don’t get an accurate assessment of the cancer and how far it has progressed. Yet data show that the number of lymph nodes removed directly correlates with longer survival, says gastric cancer expert Mark Duncan, so patients suffer when surgeons aren’t aggressive enough. “It’s simple math,” he says, “I would be more confident that the cancer was not widespread if I found that just two out of 19 lymph nodes were positive for cancer as opposed to two out of nine. Maybe two out of nine was really three out of 21. Or zero out of six could really be two out of 21. You won’t know unless you take out the right number of lymph nodes,” says Duncan Duncan, who performs more than 300 gastric surgeries a year, says patients need to be aware that it does matter where they go to be treated. The ASCO report found that surgeons outside of major medical and academic centers were not even getting lymph nodes adjacent to the stomach. Johns Hopkins surgeons take an aggressive approach because the current statistics are dismal for the rare cancer. Of the more than 21,000 people diagnosed each year, only about 25 percent will be cured. The rest—75 percent—will die from the cancer. Surgery may be the only opportunity to cure the patient because, for now, chemotherapy and radiation have shown minimal benefits. So, Duncan and colleagues take out all lymph nodes near and around the stomach in an effort to change the direction of these numbers. “Gastric cancers all behave the same and respond to the same anticancer drugs, so we are looking for better drugs,” he
JAFFEE AND LAHERU
says. Duncan is experimenting with treating patients with chemotherapy and radiation before surgery. He is also working with epigenetic experts Jim Herman and Stephen Meltzer to better understand the biology of these cancers. Patients can give an extra tube of blood during their regular blood work so that Herman and Meltzer can explore the DNA for markers of the cancer that could be targets for early detection and treatment. “It probably won’t lead to a clinical change within the next five years, but it could make a real difference in 10,” says Duncan. Gastric cancers occur either in the bottom of the stomach or at the top where the stomach joins the esophagus. When the cancer is in the bottom of the stomach, the surgeon removes the tumor and pieces the stomach back together. When the cancer occurs at the junction of the stomach and esophagus, the surgeon removes the esophagus, and pulls the stomach up to create a new one joined directly to the intestine. Duncan cautions patients to be wary of hospitals that tout minimally invasive gastric surgeries.“The incision for minimally invasive surgery in stomach cancer is just slightly smaller than the incision for an open procedure,” Duncan says. “So, there really is not much additional benefit to the patient. The goal should be a safe operation. Surgeons should not be committed to a minimally-invasive or open procedure. Sometimes you need a little of both. The key is to do what is best for the patient.” Leading esophageal cancer surgeon Stephen Yang feels
the same way about minimally-invasive esophageal operations. “They don’t really change the hospital stay,” he says. “It’s about 7-10 days either way.” Yang operates on one to two esophageal cancer patients each week, and his mortality rates, less than 1 percent, are excellent. However, he says, there is a marketing benefit to community hospitals that attract patients with the idea of smaller incisions and shorter hospital stays. He recalls a community hospital that widely publicized that it was the first to perform minimally invasive esophageal cancer surgery. What it didn’t report was that the patient ended up at Johns Hopkins with Yang to undergo extensive reconstructive surgery to repair the botched, minimally-invasive attempt. It took Yang five operations to correct the mistakes made in the minimalist approach in which the sole aim was to give the patient a shorter hospital stay and recovery time. “Don’t be fooled,” Yang warns patients. “Good advertising does not necessarily equal good care.” When it comes to surgery, study after study shows that higher volumes translate to better outcomes, says Yang, who recently participated in another study that found teaching hospitals to be the best place for these surgeries. That study was prompted by repeated questions from patients concerned about having surgery at a teaching hospital where a resident could be operating. Yang believed that a teaching hospital was the best place to have surgery, particularly for difficult operations such as those performed to remove cancers, but he wanted to back his hunch with real
“Here is an opportunity for philanthropists to step up and take a leadership role in moving things forward. In this disease, the numbers run against you. Despair is deep, but there is real hope if we invest in the research. This Johns Hopkins team is making great progress. Maybe success is five years away, or maybe it doesn’t come for 20-30 years, but someone has to do this, or we’ll never get there.” — P E T E R KO V L E R
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data. So, he and a group of Johns Hopkins surgeons crunched the numbers for lung cancer, tracking discharge and death information from different types of hospitals. They found that patients treated at hospitals with residents-in-training have a 17 percent less chance of dying after lung cancer surgery compared with patients having their surgery at non-teaching hospitals. “It’s like cooking,” Yang says, “I can take a recipe from Emeril and follow it step by step, but it’s probably going to taste better if Emeril makes it. It’s the same with surgery. There is a lot of complex reconstruction involved in these surgeries, and expertise through volume of surgeries does relate to better outcome. Academic centers do better. The data prove it. We have excellent surgical results at Johns Hopkins because we have developed expertise. We do these procedures over and over.” Yang also has received national attention for his willingness to treat older patients turned away by other hospitals and achieving outcomes comparable to those of younger patients. This proficiency, as well as good supportive care, has translated into the lowest morbidity and mortality rates in Maryland. His surgical expertise and aggressive approach to cancer surgery have resulted in some of the highest patient volumes in the region for Johns Hopkins, but only about 5 percent to 10 percent will be cured with surgery alone. About 30 percent to 40 percent of patients will need chemotherapy and radiation therapy to shrink their tumors before Yang can even attempt to cut them out. Esophageal cancers are not very common, and they are hard to detect. By the time there are symptoms, surgery is often not going to cure them. So, with incidence and death rates from esophageal cancer almost equal, and with rates increasing among younger people in their 30s and 40s and in women, Yang and a multidisciplinary team of esophageal cancer experts that includes Arlene Forastiere, Ros Juergens, and Larry Kleinberg are eager to bring new ideas to the clinic. The team is working with surgeon Malcolm Brock and cancer biologist Jim Herman on a test that can predict a patient’s response to anticancer drugs, known as taxanes. Taxanes work by stopping cancers cells ability to divide and
grow. In a study of esophageal tumor specimens, Brock and Herman found that a particular gene was affected by a cellular function known as methylation. The methylation of the gene translated to greater sensitivity to taxanes and, as a result, improved survival. “Methylation of this gene,” says Forastiere, “is a major indicator of long-term survival, actually doubling survival time.” Patients get chemotherapy and radiation therapy before surgery, and if a biopsy of their tumor reveals the methylated gene, they are treated with taxanes. This one finding is expected to increase survival rates in patients with the gene alteration from 30 percent to up to 70 percent. Methylation may also be the key to early detection. Barrett’s esophagus, a condition in which the cells lining the esophagus begin to change their composition, can sometimes progress to esophageal cancer. Herman believes that epigenetic markers may be the key to sorting it all out, that dangerous lesions that are likely to progress to esophageal cancer have a unique molecular signature characterized by methylation of the p16 and APC genes. When analyzed over time in laboratory studies, led by Jean Wang from the Division of Gastroenterology, lesions with no methylation of p16 or APC rarely progressed to cancer, while those with methylation of the genes did. The team is evaluating the use of demethylating agents in Barrett’s esophagus patients who have the molecular signature as way to stop progression to esophageal cancer. The team also is eager to bring to esophageal cancer the “DNA forensics” that Brock and Herman have pioneered in lung. The duo uses methylation patterns deciphered from patients’ tumors to pinpoint cancers that are likely to come back. Patients with these markers may benefit from more aggressive surgery and chemotherapy. MANY APPROACHES MEANS MORE CURES
With all of the gastrointestinal cancers, it is clear that a single approach will not cure most of them. By creating disease-specific GI cancer clinics, we have gathered together the wealth of knowledge and expertise that exists at Johns Hopkins and funneled it towards these relentless cancers. Our approach just might cure these cancers—even the metastatic ones.•
“It’s like cooking. I can take a recipe from Emeril and follow it step by step, but it’s probably going to taste better if Emeril makes it. It’s the same with surgery. We have excellent surgical results at Johns Hopkins because we have developed expertise. We do these procedures over and over.” — S T E P H E N YA N G
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After a national search, Nilofer Azad, M.D., assistant professor of oncology, has been recruited to develop a translational program in colorectal cancer. She will be developing a Phase I/II drug program in gastrointestinal oncology. Janet Briel, R.N., M.B.A., was named senior clinical program manager for the hematologic malignancies division. She will oversee data management and research nursing and coordinate the implementation of clinical trials. Sonia Franco, M.D., Ph.D., has joined the Cancer Center as an assistant professor of radiation oncology and oncology. She has an impressive resume, including fellowships at Memorial Sloan Kettering Cancer Center and Harvard Medical School. Franco’s work is focused on DNA double-strand break repair. Christopher Gamper, M.D., Ph.D., has been appointed instructor in oncology. A clinician-scientist, his work focuses on the biology of immunotherapy and transplant. He plans to develop novel protocols for malignant and non-malignant transplants. DRESSMAN
Kimmel Cancer Center Goes Green WHEN POSTDOCTORAL FELLOW Devin
Dressman realized how many recyclable plastic pipette tip boxes his lab threw in the trash each month, he decided something had to be done. “The sheer volume of what we were wasting was annoying to me,” says Dressman, a researcher in the busy Ludwig Center for Cancer Genetics and Therapeutics. Dressman put reusable cardboard receptacles for the pipette tip boxes in the lab and began hauling what he collected to a local recycling pickup site. With some persuasion from Dressman, the entire Johns Hopkins medical campus soon began a formal program for collecting and transporting the pipette boxes for recycling. Removing these harmless but plentiful pipette boxes from the biohazard trash Johns Hopkins pays to have removed and destroyed has also saved the institution money. The program has now expanded to include recycling of paper, cans, plastic, and glass. In the first four months of 2008, 60 tons has been recycled from the medical campus, compared to 110 tons in 2007 and 18 tons in 2006. Dressman has recently turned over the recycling reigns to building administrators, and they are being helped by a grass roots organization called Hopkins LIFE (Leadership Initiative for the Environment). For more information on Hopkins LIFE, visit www.hopkinslife.org.
Christine Hann, M.D., Ph.D., joins the Upper Aerodigestive Cancer Program as an assistant professor of oncology. Her primary focus is on developing novel therapeutics for lung cancer, particularly small cell lung cancer. She has received several awards, including an ASCO Young Investigator Award and a FAMRI Young Clinical Scientist Award.
Sushant Kachhap, Ph.D. has joined the faculty as an instructor in oncology in the Prostate and Genitourinary Cancer Program. Kachhap, who was a postdoctoral fellow in Dr. Michael Carducci’s laboratory, will explore the role of chromatin remodeling agents on several important cell pathways related to cancer metastasis and DNA repair and radiosensitization. The Breast Cancer Program welcomes Josh Lauring, M.D., Ph.D., as an assistant professor of oncology. He is a graduate of the prestigious Johns Hopkins University School of Medicine M.D.-Ph.D. program and is completing his postdoctoral training in the laboratory of Dr. Ben Park. Will Parsons, M.D., Ph.D., was appointed instructor in oncology. During the research portion of his fellowship training, he worked in the VogelsteinKinzler laboratory, where he was an integral part of a team studying genomic changes in cancer. He was the first author on several related papers in Science and Nature. He is now collaborating on the sequencing of more than 15,000 genes from glioblastoma multiforme and medulloblastoma.
T H O R N TO N
Katherine Thornton, M.D., has joined the faculty as assistant professor of oncology. She is a clinical investigator who has led multidisciplinary clinical research in connective tissue cancers. Her recruitment is the culmination of a concerted effort by Cancer Center leadership and the departments of Orthopedic Surgery and Radiation Oncology.
Cynthia M. Williams, D.O., M.A., has joined the Harry J. Duffey Family Pain and Palliative Care Program. Previously, she was the medical director of Casey House, the inpatient hospice for Montgomery Hospice. From 2005 to 2006, she held a pain and palliative medicine fellowship at the National Institutes of Health. She was named a diplomate by the American Board of Hospice and Palliative Medicine in 2006. She joins the team of Sydney Dy, M.D., M.Sc., Suzanne Amato Nesbit, Pharm.D., B.C.P.S., Donald List, L.C.S.W.-C., Lynn Billing, B.S.N., C.H.P.N., Rhonda Cooper, M.Div., Colleen Apostol, R.N., O.C.N., and Andrea Cox, B.S.N.
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noteworthy Pilomyxoid Astrocytoma Registry Healing Music What are Pilomyxoid Astrocytomas (PMA)? A type of brain cancer largely seen in children, PMAs were first identified by pathologist Peter Burger, M.D., and colleagues at the Johns Hopkins Hospital in 1999 [PubMed ID:10515229]. These cancers often were classified with other brain tumors called pilocytic astrocytomas, but the Johns Hopkins experts noted a difference in some of the patients’ samples, and a new type of brain cancer emerged. Now recognized by the World Health Organization as a distinct type of glioma, PMAs can occur anywhere in the brain but most often in the optic pathway or the hypothalmus. They tend to be more aggressive than pilocytic astrocytomas and are characterized by similar cellular shape and surrounding “myxoid” matrix. The incidence of PMAs is currently unknown, but the number of cases is growing as PMAs are increasingly recognized by pathologists.
ACOUSTIC URBAN blues musician and singer Chic Street Man delighted the crowd at a recent Art of Healing Performing Arts Series performance. His bluesy ballads and original compositions bridge cultural and attitudinal barriers with entertaining and spirited messages of racial harmony and equality. Patient Angela Rock brought the crowd to its feet as she joined Chic in singing “Stand by Me.” The Art of Healing Performing Arts Series is supported by the Emmert Hobbs Foundation.
Why join the Johns Hopkins PMA Registry? Despite the growing recognition of PMA, scientists understand little about the natural behavior of this tumor, its response to different treatments and the long-term outlook for patients with PMA. The Johns Hopkins PMA Registry will gather information over time from patients’ families and their physicians about the tumors’ presentation, treatment and response to those therapies. The registry will provide a growing resource to patients, families and physicians with the goal of refining current treatments and developing new ones.
CHIC STREET MAN
How to Join If you or your child has been diagnosed with a PMA, we welcome your participation in the registry. To learn more about the registry requirements and to consider enrollment, please visit www.hopkinskimmelcancercenter.org/kpr/pmaregistry.cfm If you have questions regarding the registry, please contact Patricia Goldthwaite at 410-955-8378.
Beaming with Pride Progress in Patient and Family Pavilion Construction WORKERS SET THE last beam in the new Hackerman-Patz
T H E I N A U G U R A L Isadore Brodsky, M.D. Lecture in
Hematology was held May 5, 2008. The lecture is funded by Michael and Patty Kirschner. From left to right: Robert Brodsky, M.D., Michael Kirschner, Patty Kirschner, Richard Jones, M.D.
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Patient and Family Pavilion, scheduled to open in 2009. Johns Hopkins representatives and contractors signed the steel beam before it was lifted and set. Designed like a house, the pavilion will have private guest suites, shared living rooms and large shared kitchens and will accommodate 39 patients and their families.
REMEMBERING KIMMEL CANCER CENTER HEROES
In recent months, the Kimmel Cancer Center has lost several champions in our fight against cancer. Some served on the front lines, while others worked behind the scenes, but, each, in his or her own way, helped improve cancer care and made a real difference in the lives of patients with cancer. Their memories will live on through the caregivers, researchers, students, patients and programs their work and generosity have inspired and supported. VICTORIA MOCK, PH.D., R.N., F.A.A.N.
Victoria Mock, or Vicki as she was known to colleagues, students and patients, died of cancer on November 15, with her family by her side. She was 65. A pioneer in nursing research, Mock was internationally known for her studies of symptom management for patients undergoing cancer therapy. She was a principal investigator on numerous National Institutes of Health-funded MOCK cancer research projects. She was chair of Johns Hopkins’ new Department of Health Systems and Outcomes and director of nursing research at the Kimmel Cancer Center. Throughout her long career, Mock earned accolades and national acclaim for her work in oncology nursing. She chaired the National Comprehensive Cancer Network Cancer-Related Fatigue Guidelines Panel, received a Distinguished Researcher Award from the Oncology Nursing Society, and was honored with an American Cancer Society (ACS) Professorship of Oncology Nursing from its Mid-Atlantic division. Alva Hutchinson, regional vice president of the ACS, recalled that Mock used her award to continue her research of exercise in reducing fatigue in women undergoing treatment for cancer. “She had 48 women in her study, and she found that simply walking reduced their fatigue and anxiety, made them feel stronger and more capable, reduced sleeping problems and improved their overall quality of life,” says Hutchinson. “She continued this work, and it led to changes in the counseling patients receive today.” In addition to her own research, Mock was instrumental in obtaining funding for many graduate nursing students for whom she served as an advisor. She not only personally advanced the field of nursing research,
improving the lives of countless patients, but furthered the effort by mentoring new investigators and launching new studies. Sharon Krumm, Ph.D., R.N., Administrator and Nursing Director at the Kimmel Cancer Center, worked closely with Mock and witnessed her positive influence on the nurses in the Cancer Center. Krumm says, “Vicki highly valued the work and insight of nurses at the bedside, and believed that the most important research arose from the questions that these nurses raised about clinical care. Vicki tirelessly gave of her time and knowledge to mentor and encourage nurses in their research efforts, publications, and professional presentations. Her extensive contributions to the field of oncology nursing research and oncology nursing practice will significantly influence patient care for many years to come.” ANNE JENNINGS KRUSH
Anne Jennings Krush was an unsung hero of cancer research. In 1967, Krush began her research career working alongside acclaimed cancer genetics expert Dr. Henry Lynch at Creighton University, a KRUSH renowned expert in familial predisposition to cancer. It was during this collaboration that Krush developed an interest in familial colorectal cancer syndromes. In 1973, she came to Johns Hopkins and working with Dr. Victor McKusick continued her study of hereditary colorectal cancer. At Hopkins, she served as Polyposis Registry Coordinator and was a force behind the formation of the Bowel Tumor Working Group, a multidisciplinary team focused on hereditary colon cancer. It was this interaction that initiated her collaboration with leading researchers in the field of cancer genetics, including Drs. Francis Giardiello, Bert Vogelstein,
Stanley Hamilton and Gloria Petersen. With painstaking attention to detail, she pieced together the medical histories of several hundred families, uncovering what would become the basis for the Cancer Center’s world-renowned discoveries of the genetic basis for hereditary colon cancer. Krush died last September at 93. NORMAN E. ROCKWELL
Norman Edwin Rockwell, who founded and headed Chesapeake Builders Corporation for 43 years, died of cancer last December. Rockwell lost his beloved wife to cancer in June 1983, and it was then that he conceived the idea for the Joanne Rockwell Memorial House, which he then built and donated to Johns Hopkins. The Rockwell House, built on Johns Hopkins property, is a 10-unit, residence that serves as a home away from home for cancer patients and families traveling to Johns Hopkins for treatment. Rockwell said the house was his proudest achievement. LOIS SALMON DUFFEY
Lois Duffey, the generous benefactor of the Harry J. Duffey Family Patient and Family Services Program, died last October at 96. More recently, her generosity brought to fruition the Harry J. Duffey Family Pain and Palliative Care Program, an idea that had long been in planning but was in need of funding. The Patient and Family Services Program provides education, counseling, spiritual guidance and other support services to patients and families. The new Pain and Palliative Care Program provides expert pain and symptom management for cancer patients. Duffey is described as a generous woman who always found ways to give back to her community. In addition to her gifts to the Kimmel Cancer Center, Duffey supported local charities and educational institutions near her home on Maryland’s Eastern Shore. Duffey loved horses and was the owner of Mr. Frisk, the 1990 winner of the Grand National Steeplechase in England.
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philanthropy S H I R L E Y H O WA R D ( C E N T E R ) , R O N A L D P E T E R S O N ( L E F T O F H O WA R D ) A N D T H E 2 0 0 7 C H I L D R E N ' S C A N C E R F O U N DAT I O N G R A N T R E C I P I E N T S .
Something to Celebrate Children’s Cancer Foundation Awards $1.2 Million for Building and Research Grants S H I R L E Y H O WA R D , president of the Children’s Cancer Foundation (CCF), awarded more than $1.2 million in building and research grants to Johns Hopkins at the Foundation’s 2007 gala. Ronald Peterson, president of the Johns Hopkins Hospital and Health System, accepted $300,000 towards CCF’s $5 million pledge being used to build the pediatric oncology inpatient unit in the new children’s hospital scheduled for completion in 2010. Also receiving grants that evening were:
Drs. Benjamin Carson and Gregory Riggins: $151,887 Drs. George Jallo and Alfredo Quinones-Hinjosa: $105,000 Dr. Donald Small: $132,018 Dr. Alan Friedman: $100,000 Dr. David Loeb: $104,634 Dr. Patrick Brown: $100,000 Drs. Charles Eberhart and Peter Burger: $79,000 Drs. David Berman and Nicholas Gaiano: $45,000 Dr. Jason Yustein: $11,480
Landmark Prostate Cancer Study Safeway and the Prostate Cancer Foundation Fund Research Collaboration THE JO HNS HOPKI N S Kimmel Cancer
Center will be at the helm of a new prostate cancer research initiative that explores the role of a targeted heat treatment as well as other potential new therapies. Safeway Inc. and the Prostate Cancer Foundation have teamed up to fund the $6 million STAR program (Special Team Amplification of Research). The Hopkins team will coordinate a multi-institutional team of investigators, including researchers from the University of Michigan, and the University of British Columbia. “Similar to the program that Robert Goddard put in place to make space flight a reality, everyone that has input will be invited to the table to be a part of the solution,” says Jonathan Simons, CEO and David H. Koch Chair of the Prostate Cancer Foundation.
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STAR also convened a think-tank of experts in different areas of oncology to figure out why current therapies cure some types of cancers but not others. What they learn will lead to new research ideas for prostate and other common cancers. “We are honored to be associated with the pioneering work of some of the world’s top cancer researchers,” says Steve Burd, Safeway chairman, president and CEO. “This program is evidence of what can happen when you link the fund-raising power of a major company like Safeway with the research vision of the Prostate Cancer Foundation,” adds Simons. In earlier research, a Kimmel Cancer Center team showed that cancer cells exposed to heat are easier to kill with radiation therapy and chemotherapy. They are now working to find the best way to deliver
heat directly to cancer cells, preventing damage to nearby normal tissue. Their research uses new, cutting-edge work with nanoparticles, microscopic particles just one billionth of a meter in size. The nanoparticles are engineered to be attracted to specific proteins expressed by cancer cells. “Once the nanoparticle locates the cancer protein, it enters the cancer cell,” explains Robert Getzenberg, director of research for the Johns Hopkins Brady Urological Institute. “Exposing the cells to a magnetic field causes the nanoparticles to heat the cancer cells up from the inside out. Because of Safeway’s leadership and their customer’s support and the Prostate Cancer Foundation, we will be able to develop this unique approach and other new concepts and take them from the laboratory to clinical trials in patients.”
Triple Winner Campaign Could Mean Big Win for Kids With Cancer SECOND-GRADER GAVIN loves to collect and study rocks and minerals. He hopes to be a geologist one day. Six-year-old Aaliyah loves to dance and sing along to her favorite Beyonce songs. Michael is in fourth grade and enjoys playing video games but hopes to soon get back to playing his favorite sports, football and basketball. And 10-yearold Justin dreams of becoming a left-handed pitcher for the Baltimore Orioles. It is for these children and the many others battling cancer that local Giant Food stores kicked off their fourth year of the Triple Winner Program, pledging $1 million to pediatric cancer research at the Kimmel Cancer Center and $500,000 to the Children’s Cancer Foundation. The Baltimore Orioles helped launch the campaign on March 13, at Oriole Park at Camden Yards, along with Donald Small, acting director of pediatric oncology, and Shirley Howard, president of the Children’s Cancer Foundation. The campaign was so successful that by June 9, a month earlier than anticipated, Giant announced that it had already reached its $1.5 million goal.
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V I S VA N AT H A N
B AY L I N
DAV I D S O N
Breast Cancer Partnerships for Life Safeway Helps Fund New Therapies “OUR MISSION IS TO PREVENT and control breast cancer
through research, clinical care and educating physicians,” says Nancy Davidson, director of the Kimmel Cancer Center Breast Cancer Program. “We get closer to accomplishing this mission through the continued support of partners like Safeway.” Since 2003, Safeway has donated more than $833,000 for cancer research at the Johns Hopkins Kimmel Cancer Center. The company’s most recent donation of $489,425 was recognized on Feb. 7, 2008. In total, Safeway has contributed more than $41 million since 2001 to breast cancer research at cancer centers throughout the United States. “This has become a passion of ours,” says Steve Burd, Safeway Chairman and CEO who has taken a national and local leadership role in health care reform. About 20 Safeway employees, including cashier Michele DeLoach from Eldersburg, Md., who raised $8,186, the most of all cashiers in Safeway’s eastern division, was on hand to hear about the exciting Kimmel Cancer Center discoveries Safeway’s fund-raising initiatives have generated. DeLoach and other Safeway cashiers raise money for cancer research by asking customers to donate during check-out. “While we can see cancer mortality is dropping, there is still a lot that needs to be done,” says Davidson. “With the help of research funding by partners like Safeway, we are closing the gap between breast cancer incidence and mortality, but of course, our job will not be done until we bring that number to 0.” Davidson, along with program co-director Sara Sukumar, has built a 30-member breast cancer team, including surgeons, radiation oncologists, medical oncologists, radiologists, basic scientists and public health experts to attack the problem. Several of these members have used Safeway funding to support their work. S A F E WAY- F U N D E D I N V E S T I G AT O R S REPORT THEIR FINDINGS There is about one new case of breast cancer diagnosed every three minutes. This means that in just the time it takes to read this article, at least three women will learn they have breast cancer. “I asked myself, if I were one of these women, what would
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be on my wish list,” says Sukumar, who is also a Safeway-sponsored investigator. “I would want to treat the breast cancer without having a mastectomy, a treatment with no side effects and very high cure rates.” She is working with clinician-scientist Vered Stearns on a therapy that she believes could make these wishes a reality. Sukumar says the majority of breast cancers—up to 95 percent—begin in the breast duct epithelial cells. While epithelial cells are at the root of the cancer, they account for just 5 percent to 10 percent of total breast cells. “So, if you get rid of the epithelial cells,” she says, “the cancer-causing cells are gone, but the breast stays intact.”
“While we can see cancer mortality is dropping, there is still a lot that needs to be done.With the help of research funding by partners like Safeway, we are closing the gap between breast cancer incidence and mortality, but of course, our job will not be done until we bring that number to 0.” — N A N C Y DAV I D S O N
Sukumar and Stearns, with help from radiologist Nagi Khouri and surgeon Theodore Tsangaris, are testing a technique to deliver anticancer drugs directly to the epithelial cells using a tiny catheter inserted through the nipple and directly into the breast ducts. In animal models, the technique worked better than traditional intravenous drug therapy. And in early
“I would want to treat the breast cancer without having a mastectomy, a treatment with no side effects and very high cure rates. —SARA SUKUMAR
clinical trials in patients, Stearns showed that the drug goes to the ducts and cleans out cells that are thinking about becoming tumors without causing any adverse side effects. BLOCKING CANCER PROMOTERS Stearns also is studying a drug that targets epigenetic changes in breast cancers. Epigenetic changes are alterations that occur without mutating the DNA. “Genetic changes are hard to reverse because they change the DNA sequence,” explains Stearns, “but epigenetic changes are potentially reversible because they do not alter the DNA.” Methylation—or specifically, too much methylation—is the most common culprit in epigenetic alterations in cancer. If a key tumor-suppressing gene is over-methylated, it gets turned off. Stearns is studying a drug that blocks methylation and gets cells working right again. Stearns is now studying a drug already on the market and approved for the treatment of other cancers for its ability to block methylation of breast cancer genes. To evaluate the drug’s effectiveness, Stearns is looking at tumor samples taken from newly diagnosed women before surgery. The women will take the drug orally in the days leading up to surgery. After surgery, Stearns and team will compare the tumor taken before they were given the drug with one taken afterwards to see the drug’s effect on breast cells. The hope, of course, is that it will re-activate tumor-suppressing genes shut down by epigenetic alterations. MAPPING THE BREAST CANCER GENOME Ben Ho Park is a cancer geneticist working to uncover the differences between normal DNA and breast cancer DNA. “We know that genes are mutated in cancer and that just one mistake in the genetic alphabet can lead to lots of problems,” says Park. “We want to take advantage of the mistakes that are unique to cancer cells so that we can target them and leave healthy, normal cells unharmed.” Park has collaborated in identifying breast cancer genes that are mutated only in cancer cells. He is currently screening drugs to see what they do to these mutated genes and has identified
several compounds he believes may be useful in the treatment of breast cancer. He is also working to develop a test for detection and management of early breast cancers. “Cancer has a unique genetic signature,” says Park. “We can look in the lymph nodes and blood, where cancer DNA is shed, for this signature.” He says breast cancers behave a certain way depending on the genes that are mutated within the cancer. It helps explain why seemingly similar cancers often respond quite differently to treatment. Park believes that individualized therapies based on an individual cancer’s genetic signature could dramatically improve breast cancer survival rates. BLOOD EVIDENCE Antonio Wolff’s research could make it possible to detect breast cancer from the DNA contained within a single drop of blood. Working with Sukumar, he has developed a method to analyze multiple genes from small samples of blood, serum or breast fluid. Called QM-SNP, the method allows them to find cancer cells hidden within large numbers of normal cells. “In other words, it finds the needle in the haystack,” says Wolff. Such a method, he says, could be used to diagnose patients, to see if cancer cells still remain after therapy, and to monitor patients for recurrence of their cancers. IMMUNE TO BREAST CANCER Cancer immunology expert Leisha Emens is using her funding to develop vaccines that change the way the body responds to cancer. Tumors are usually not recognized as dangerous by the immune system, and Emens says, “If for some reason the immune system does marshal the force to go after the cancer, the tumor cells change to avoid attack.” Her work focuses on tricking the immune system into recognizing and going after breast cancer cells. She is using a vaccine that boosts the immune system and activates the T-cells, the immune system’s foot soldiers, to search out and kill cancer cells. She has begun clinical trials of the vaccine, which is being given in conjunction with chemotherapy. NATURAL CURES Kala Visvanathan is interested in what causes breast cancer and how to prevent it. “We need less toxic approaches and ones that are cheap and safe,” she says. In broccoli sprouts, she may have found an approach that fits the bill. “Broccoli sprouts are cheap, safe, oral, natural, inexpensive and high in a cell-detoxifying agent called sulforaphane,” she says. In animal models, sulforaphane has been shown to prevent breast cancer by turning on enzymes that protect cells. Now, she is looking for the same evidence in people. With the help of women coming to Johns Hopkins for breast reduction surgeries and prophylactic mastectomies, Visvanathan will compare the breast tissue of women taking a broccoli-preparation prepared by the team to the breast tissue of women not eating broccoli sprouts to look for increased activity of the cancer detox enzymes.
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NANCY E. DAVIDSON , director of the Kimmel Cancer Center Breast Cancer Program greets actress Reese Witherspoon as program co-director Sara Sukumar looks on at the closing ceremony of the Avon Walk in Washington, D.C. The walk raised more than $135,000 for the Avon Foundation Breast Center at Johns Hopkins
Hopkins 4K for Cancer
Joanna M. Nicolay Melanoma Foundation Supports Alani Lab
The Hopkins 4K for Cancer is a completely student run, non-profit organization dedicated to uniting communities across the country in the fight against cancer. Their mission is spreading awareness, raising funds, and fostering hope. Now in their 7th year, the students have raised over $511,000 for cancer prevention and control. In addition to supporting the American Cancer Society’s Hope Lodge, which provides housing for many patients of the Kimmel Cancer Center, they also support Dr. Jean Ford’s work in providing free prostate, colon, and breast cancer screenings in underserved communities in Baltimore.
L to R: Dr. Landon Grills, Mr. Robert Nicolay, Mr. Jason Howard, and Dr. Rhoda M. Alani. Joanna M. Nicolay Melanoma Foundation funds research in the Alani Laboratory. Grills and Howard work in the Alani lab and were recipients of the Foundations Research Scholar Award.
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Let’s Dish! Meals Donated to Patients and Families Customers at Let’s Dish! in Columbia and Timonium are preparing delectable meals— some of the company’s most popular menu items—and donating them to patients at the Kimmel Cancer Center. Patients and families staying at the Rockwell Memorial House and Hackerman-Patz House, homelike residences for patients and families traveling to Johns Hopkins for cancer treatment, are feasting on basil chicken with lime, ravioli del sol, oven-roasted veggie pockets, and more thanks to the generosity of Let’s Dish! patrons. Anyone interested in donating a meal can contact the Columbia store at 410-309-3415, or the Timonium store at 410-560-5634, or check out www.letsdish.com.
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CREDIT: PHOTO RESEARCHERS, INC.
CANCER CELLS (ORANGE) FROM THE HUMAN COLON (LARGE INTESTINE). COLON CANCER ARISES IN THE EPITHELIAL CELLS LINING THE LARGE INTESTINE. THESE LARGE MALIGNANT TUMOR CELLS HAVE A ROUGH SURFACE DUE TO ABNORMAL CYTOPLASMIC PROJECTIONS. THEY ARE ALSO DISPLAYING TYPICALLY CHAOTIC AND UNCONTROLLED CANCEROUS GROWTH.
For additional copies of this publication or further information about the center, contact: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Office of Public Affairs 901 South Bond Street Suite 573 Baltimore, Maryland 21231 (410) 955-1287 www.HopkinsKimmelCancerCenter.org © The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
The Sidney Kimmel Comprehensive Cancer Center Magazine, Fall 2008/Winter 2009