Targeting Cancer

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TARGETING CANCER A REPORT ON THE SCIENTIFIC ACCOMPLISHMENTS OF THE

SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER AT J O H N S H O P K I N S

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UNIQUELY KIMMEL “We often hear the words “state of the art” used to reflect those people and institutions doing the most relevant work in any given field. At the Kimmel Cancer Center, state of the art is just the starting point of what we offer. That kind of promise —the latest plus some—is what we have and always will deliver.”

William Nelson, M.D., Ph.D. Director, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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CONTENTS

What Causes Cancer?

Kimmel Cancer Center investigators answer this question, painstakingly uncovering the genetic alterations that lead to the initiation and progression of cancer.

20 How Will We Cure Cancer?

At this very moment, groundbreaking discoveries by our scientists and clinicians are being transferred to patients in the form of innovative new therapies.

32 How Do We Prevent Cancer?

The surest way to cure a cancer is to prevent it from ever occurring. Our investigators develop safe, new ways to stave off cancer.

40 Only at the Kimmel Cancer Center State-of-the-art plus some is what the Kimmel Cancer Center offers to its patients. These unique programs improve cancer detection, research, and treatment.

COVER DESCRIPTION: Circular genetic map, showing human chromosome 17. The chromosome (outer ring) is based on a standard idiogram and arranged in a circle. The colored bands represent genes (green), cancer genes (red), and other disease genes (orange). The graph within the circle shows reference sequence genes, a standard for gene identification, and exons, which are parts of the genes that encode for proteins. Some genes contain many exons and are located nearer to the center of the circle. The numbers on the chromosomes represent scale bars.

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A HISTORY OF RESEARCH

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CANCER POWERHOUSE

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The Harry and Jeanette Weinberg Building, which houses the clinical programs of the Sidney Kimmel Comprehensive Cancer Center

SINCE ITS OPENING in 1973, our Cancer Center

has led the world in deciphering the mechanisms of cancer and new ways to treat it. Early on, the strength of its research and treatment programs were recognized, earning Johns Hopkins comprehensive cancer center designation from the National Cancer Institute and status as a “Center of Excellence.” Johns Hopkins continues to earn more federal research dollars than any other medical institution in the country. For 18 years, it has earned the top spot, and our cancer

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center has been among the top three in the much coveted U.S. New and World Report rankings of the best U.S. hospitals. Calling our center a “cancer research powerhouse,” an exhaustive review of the scientific literature by Thomson Scientific found that the research of five of our investigators was the most often cited in all of cancer research. The findings of our brilliant investigators have become the classic model for determining the mechanisms of cancer initiation and progression.

The name Johns Hopkins has become synonymous with excellence in research and patient care. And, on November 14, 2001, we further strengthened this name and the quality of our research and treatment programs when we partnered with Mr. Sidney Kimmel, one of the country’s leading philanthropists and founder and chairman of Jones Apparel Group.

Mr. Kimmel made Johns Hopkins history when he donated $150 million for cancer research and patient care. It was the largest single gift ever to the Johns Hopkins University. In honor of this great commitment, the cancer center at Johns Hopkins was renamed the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

This investment in our cancer center has allowed us to attract even more of the best and brightest minds in cancer research, improve our facilities, and continue our pioneering role in cancer discovery and therapy.

Now, we embark on a new era of unique scientific collaborations as engineers, physicists, and business experts join the effort to advance cancer discoveries in screening, detection, diagnosis, prevention, and treatment.

With the combined strength of the worldrenowned Johns Hopkins medicine, engineering, physics, and business programs and the support of Mr. Sidney Kimmel, there is no single place in the world as capable of translating these discoveries into clinical cancer care as rapidly and adeptly as the Johns Hopkins Kimmel Cancer Center, an internationally recognized agent for cancer discovery and innovative clinical research.

Sidney Kimmel Mr. Kimmel’s goal is to bring meaningful advances to the knowledge of cancer.

The following pages tell the stories of the Johns Hopkins Kimmel Cancer Center researchers and clinicians who have realized this goal and the patients who have benefitted.

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An International Leader in the Research and Treatment of Cancer

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MESSAGE FROM THE DIRECTOR

THE RIGHT TIME

THERE IS so much we have accomplished,

but we also know there is much more we can do. We have the perfect discovery engine here and tremendous opportunities.

This is a great place to be and the right time to be here.

Right here, right now—discoveries by the most cited cancer scientists in the world are allowing us to define and catalog the defects acquired by these rogue cells we call cancer. Their work is the blueprint for the next generation of cancer treatments.

We often hear the words “state of the art” used to reflect those people and institutions doing the most relevant work in any given field. At the Kimmel Cancer Center, state of the art is just the starting point of what we offer. That kind of promise—the latest plus some—is what we have and always will deliver.

I believe that the Kimmel Cancer Center is shaping the future of cancer medicine—a future that will ultimately see us conquer cancer.

P ETE R H O WA R D

William G. Nelson, M.D., Ph.D. Marion I. Knott Professor and Director The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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There is no more exciting time to be a part of cancer medicine than now. The benefits of decades of work by dedicated investigators and clinicians have truly begun to be realized. Despite the aging and growth of our population, the number of cancer deaths has declined—for the first time. Patients are not just alive, but living quality lives as we refine therapies that are more effective and less toxic.

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CANCER SURVIVOR

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FINDING CANCER What if we could detect cancer with a simple blood test?

She is also a colon cancer survivor.

Her journey begins long before her diagnosis. Her father died of colon cancer when he was in his late thirties. She knew family history put her at higher risk of developing the disease at a young age and was diligent about getting regular colonoscopies.

Despite this, she developed colon cancer more than a year before she was due for her next colonoscopy, and the cancer was not diagnosed until it had grown large enough to cause symptoms.

She was just 37.

Now, Page is part of a clinical trial to study a simple blood test, developed by Kimmel Cancer researcher Luis Diaz, that could have detected her cancer in the earliest stage. The test detects tiny fragments of DNA shed from cancer cells and circulating in the bloodstream. It can pinpoint and track a cancer before it causes any symptoms and while it is still in a curable stage.

“How great would it have been if this test had been available and caught my cancer earlier. Even if this research doesn’t help me, maybe it will help my children or another patient. We all need to work together to cure cancer. If I can spare another family from going through what my family has gone through, it will be worthwhile,” says Page. “The best gifts are those you don’t receive.”

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IVELISSE PAGE IS A young and vibrant wife and mother of four.

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Cancer Biology leaders Victor Velculescu and Stephen Baylin

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Cancer Cells (orange) from the human colon

Kimmel Cancer Center investigators led the way in finally answering the question on everyone’s mind: What causes cancer? By pinpointing key cancer-causing mutations and alterations made directly to the DNA as well as epigenetic changes, or alterations to the environment of genes, our experts created the classic model for cancer initiation and progression.

The difficulty of this work has been compared to finding a single two-letter transposition within 20 volumes of an encyclopedia and then figuring out how it got there.

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CANCER’S BLUEPRINT Bert Vogelstein, M.D., ranks today, as he has for more than two decades, as the pre-eminent international scientist. The discoveries that led the world to understand that cancer is a genetic disease unfolded one by one in his laboratory. cer’s cause, long concealed within the submicroscopic molecules of the cell. A team of researchers, led by Vogelstein, Kenneth Kinzler, and Victor Velculescu, ushered in the age of molecular biology, developing technologies and delivering findings that are unmasking the secrets of the cancer cell.

While other institutions had more money and more resources, our experts were the first to decipher a genetic blueprint for cancer, mapping the genomes of colon, breast, pancreas, and brain cancers. They evaluated all known genes for each of these tumor types. Their work is said to be the most comprehensive results to date.

The new perspective this work provided is changing the way experts think about solid tumors and their management. “Drugs or other agents that target the physiologic effects of gene pathways rather than individual gene targets are likely to be the most useful approach for developing new therapies,” says Vogelstein.

Their findings revealed a complex landscape for human cancers, containing a variety of different, less frequently occurring mutations that vary from patient to patient. This explains why seemingly similar cancers

often respond very differently to standard therapies.

Though cancers from different patients may look the same, the new research indicates that they are genetically distinct. While there are a few “mountains”— those genes that remain the most commonly mutated, there are far more “hills”—less frequently occurring mutations but just as culpable as the mountains in leading to cancer development and progression.

Everest-like genes such as APC and p53 have stood out among other mutations because they were so commonly mutated and, therefore, easier to find.

These genes, and others like them, have been the focus of cancer research for years because they were the only genes known to contribute to cancer. “Now that we can see the whole picture, it is clear that lower peaks or “gene hills”, though mutated less frequently, are the predominant feature,” says Velculescu.

The landscape of human cancer is clearly more complex than was understood before this research and will likely change the way solid tumors are managed, Kinzler says. “The hard part used to be finding the mutant genes linked to cancers. We have done that. Now, our challenge is to find the pathways these many genes have in common and identify drugs that target them.”

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HIS RESEARCH SOLVED the mystery regarding can-

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2009 Compendium of Pancreatic Cancer Biomarkers Provides Strategic Approach to Early Detection Research Akhilseh Pandey, Ph.D., has convinced an international group of colleagues to delay their race to find new cancer biomarkers and instead begin a 7,000-hour slog through a compendium of 50,000 scientific articles already published to assemble, decode, and analyze the molecules that might herald the furtive presence of pancreatic cancer.

“While there may be no visible trace of cancer after surgery, DNA evidence of tumor cells is left at the scene, hiding in tissues such as lymph nodes.”

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2008

Having mined the literature to amass 2,516 potential biomarkers of pancreatic cancer, Pandey and his team systematically cataloged the genes and proteins that are overexpressed in pancreatic cancer patients, then characterized and compared these biomarker candidates in terms of how worthy each is of further study.

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Autopsies Link Prostate Cancer Spread to Single Rogue Cell One cell, one initial set of genetic changes - that’s all it takes to begin a series of events that lead to metastatic prostate cancer, found researcher G. Steven Bova, M.D., after tracking the cancer process, from its inception, in 33 men who died of the disease. Culling information from autopsies, his 14-year study points to a set of genetic defects in a single cell that are different for each person’s cancer.

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CSI—Cancer Scene Investigation Aggressive Lung Cancers Leave Telltale Trail of DNA Evidence With cancer, the threat of recurrence looms heavily over every diagnosis and over every presumable cure. Now, investigators have learned that lung cancers, one of the most prevalent and frequently recurring of all cancers, leave a molecular trail of evidence that can tell them that hidden tumor cells remain, and the cancer is likely to return.

Enter molecular staging of cancers, a form of cancer detection that reveals what cannot be seen through the pathologist’s microscope. “This is DNA forensics for cancer,” says cancer surgeon Malcolm Brock, M.D. “While there may be no visible trace of cancer after surgery, DNA evidence of tumor cells is left at the scene, hiding in tissues such as lymph nodes.”

We are accustomed to using tumor size and spread at diagnosis as the prognostic indicators, but in truth, Brock says, tiny tumors, even those as small as a pea, can harbor molecular genetic alterations that can potentially make them very dangerous and aggressive.

Brock and team reported on 157 patients with early stage non-small-cell lung cancer. All of the patients had small tumors that were surgically removed. Within about three years, 51 of the patients had their cancer return, while 116 remained cancer free. The team set out to find, on the molecular level, what the microscope did not—what was different about the cancers that returned.

The culprit, they found, was in the methylation patterns of four genes already linked to lung cancer. Methylation is a normal cellular process, but when the process goes awry and genes are overmethylated, it, in effect, renders genes invisible to cells, often shutting down key tumor suppressing functions. Depending on the combination of genes abnormally methylated, the risk of the cancer’s returning was increased two- to 25-fold. The worst scenario proved to be the overmethylation of two particular genes, p16 and H-cadherin, which foreshadowed a swift return of the cancer.

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.

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Cause of Deadly Lung Disease Discovered Mary Armanios, M.D., a Kimmel Scholar and researcher who, in 2007, discovered a genetic cause of the inherited from of a deadly lung disease, has now identified the same underlying cause in a majority of patients with the disease. Telomeres, the protective ends on Armanios chromosomes that insure the integrity of genes, have been implicated in a majority of cases of idiopathic pulmonary fibrosis (IPF). IPF causes a progressive and almost always lethal scarring of the lungs, and there is currently no effective therapy.

Understanding the cause means investigators may begin to explore using drugs that prevent telomere shortening and stop cells from dying.

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Gene Packaging Tells Story of Cancer Development To decipher how cancer develops, Stephen Baylin, M.D., says researchers must take a closer look at the packaging. His findings point to the threedimensional chromatin packaging around genes formed by tight, rosette-like loops of Polycomb group proteins (PcG). The chromatin packaging, a complex combination of DNA and proteins that compress DNA to fit inside cells, provides a repressive hub that keeps genes in a low expression state.

“We think the polycomb proteins combine with abnormal DNA methylation of genes to deactivate tumor suppressor genes and lock cancer cells in a primitive state,” says Baylin.

Prior to this discovery, investigators studying cancer genes, looked at gene silencing as a linear process across the DNA, as if genes were flat, one-dimensional objects. Research did not take into account the way genes are packaged.

International Study Reveals Genetic Markers of Prostate Cancer 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 family history of the disease, translate to a nine-fold increase in the risk of getting prostate cancer when compared to men without these markers, says William B. Isaacs, Ph.D. “This information is not yet available as a genetic test for risk of prostate cancer, but efforts are under way to rapidly develop one,” he says. “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 geneticbased reasons for prostate cancer,” says Isaacs.

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Swish and Spit to Detect Head and Neck Cancer A simple mouth rinse could be all it takes to capture genetic signatures common to head and neck cancers. Researcher Joseph Califano, M.D., 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 methylation of genes, believed to be one of the earliest triggers of cancer.

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Personalized Blood Test for Cancer Virtually all cancers arise through mutation of genes that control cell growth.

As the cancers grow, they shed fragments of DNA, biological evidence of these mutant genes, into the bloodstream.

Diaz Now, researchers have developed a novel test to measure tumor-derived DNA in the bloodstream.

The researchers, led by Luis Diaz, M.D., say the blood test, based on the unique genetic fingerprint contained within the genome of every cancer, can not only detect the presence of tumor but track its progress.

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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,” says James Herman, M.D., 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.

Knowing the Enemy Scientists Create 3-D Image of Cancer Initiator A growth-promoting gene called PIK3CA, linked to cancer by Victor Velculescu, M.D., Ph.D., is believed to be one of the most frequently mutated in cancer, and now we know what the enemy looks like. Working with a research team from the Johns Hopkins University biophysics and biophysical chemistry department, a 3-D picture of PIK3CA and all of its cancer-associated mutations was created. “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 missing,” says Velculescu.

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Breast Cancer Drug Side Effect is All in the Genes Up to 80 percent of women taking the commonly prescribed drug tamoxifen to prevent breast cancer recurrence report problems with hot flashes, which can significantly impact on quality of life, says Vered Stearns, M.D. Leading a group of researchers from the Kimmel Cancer Center, Indiana University, and the University of Michigan, Stearns and team identified subtle differences in a common breast cancer gene that can predict who will get hot flashes.

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2006 Lung Cancer Uses Cell Detoxifier to Evade Anticancer Drugs On any given day, our bodies are assaulted by a number of environmental pollutants—cigarette smoke, diesel exhaust, carbon monoxide, and more. But the same processes our body uses to protect itself from these outside assaults have been corrupted by lung cancer cells to help them evade anticancer drugs. Shyam Biswal, Ph.D., is the leading expert on a gene called NRF2 that protects our cells from these pollutants. He found that NRF2 directs proteins to absorb pollutants and chemicals and then pump them out, clearing

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2007 A Better Test for Prostate Cancer Researchers believe they have developed a better blood test for prostate cancer and think it will change the way men are screened for the disease.

A new blood test that screens for a blood protein, called EPCA-2, appears to be more prostate cancer-specific than PSA (prostate specific antigen), the current standard for prostate cancer screening. Robert Getzenberg, Ph.D., believes his test could curtail unnecessary biopsies, commonplace with PSA testing.

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A new blood test that screens for a blood protein, called EPCA-2, appears to be more prostate cancer-specific than PSA Biswal

Gene Expression Pattern Helps Pinpoint Deadly Melanomas “Two melanoma patients with cancers of the same Alani invasion depth and appearance under the microscope can have completely different outcomes,” says melanoma expert Rhoda Alani, M.D. The difference between the two cancers is in their genetic makeup, and now Alani is creating a genetic fingerprint to identify tumors that are more likely to kill.

cells of toxins. Another gene, KEAP1, he says, lets cells know when the toxins are removed, shutting down NRF2 and stopping the cell-cleansing process. In lung cancer, however, Biswal discovered that cancer cells manipulate these genes to view lung cancer-attacking drugs as toxins and pump them out before they can get to cancer cells.

Calculating Pancreas Cancer Risk Allison Klein, Ph.D., and team has developed a risk “calculator” for one of the most lethal forms of cancer. Called PancPro, the novel computer software tool will help identify people at risk of developing pancreatic cancer due to an inherited genetic predisposition. Physicians and genetic counselors can use the tool to decide who would benefit from early screening.

Unlikely Protein Implicated in Prostate Cancer A quirky muscle protein known as myosin VI may help prostate cells become cancers and help them stay that way. In laboratory studies of human prostate cancer cells, investigators led by Jun Luo,

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Ph.D. and Angelo DeMarzo, M.D., Ph.D., found overproduction of myosin VI in prostate cancer cells and precancerous prostate lesions. When they altered the cells to shut down production of myosin VI, the cells lost some of their cancer characteristics. The team believes targeting myosin VI production as part of prostate cancer detection and therapy could help combat the cancer.

Creating a laboratory test to identify high or low levels of myosin VI in urine or blood could aid in the early detection of prostate cancer.

This comes into play in cancer when key tumor suppressor genes are overmethylated, and so they are not seen by cells.

Abnormally high levels of methylation have been identified as an early indicator of a developing cancer—one that occurs even before the formation of tumor cells. The research has now moved to the clinic as drugs that block methylation and restore the function of key tumor suppressor genes are now being tested in patients. In clinical trials of patients with leukemia and a preleukemic condition known as myelodysplatic syndrome (MDS), demethylating agents have led to partial or complete remissions in up to half Baylin of patients treated. These findings have resulted in the first FDA approval of a demethylating agent, 5-aza-cytidine, for clinical use in patients with MDS.

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Molecular “Magnet” May Be New Diagnostic Tool for Cancer A new molecular tool dubbed “LigAmp” appears to be able to pinpoint DNA mutations among thousands of cells, making it possible to detect microscopic cancer and even HIV drug resistance. The test works by creating a molecular “magnet” that attaches itself to DNA mistakes known as point mutations.

Once attached, it inserts a bacterial gene that produces a fluorescent color visible to physicians through special computerized equipment. “The molecular code of normal cells may look identical to cancer cells except for a single rung in the DNA ladder structure. This test finds that one defective rung,” says James Eshleman, M.D., Ph.D. Gene Marks Most Lethal Ovarian Cancers Alterations in a gene called Rsf-1 are linked to the most deadly ovarian cancers. Scientists say the discovery is the first to establish a role for the gene in ovarian cancer and may lead to a test that can predict, early on, which patients will develop aggressive disease. The gene could also be a target for new therapies.

Calculating Cancer Risk There are about 600,000 people in the United States who have gene mutations linked to a hereditary form of colon cancer known as Lynch syndrome. About half of them will develop colon cancer by the time they are 70. Women with the mutations are not only at risk for colon cancer but have an added risk of developing endometrial cancer by age 70. The problem has been finding a way to efficiently identify families who would most benefit from gene testing because they likely have one of these culprit gene mutations.

Using a computer software model called MMRpro, which incorporates a person’s detailed family history of colon and endometrial cancers and most up-to-date knowledge about mutations of the mismatch repair genes linked to Lynch syndrome, our Bioinformatics research team is now able to quantify who will likely develop cancer.

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New Treatment Target for Brain Cancer The identification of new mutations in two kinase genes could pave the way for more effective treatments of glibolastoma, a form of brain cancer often unresponsive to current therapies. The discovery of these mutations is especially significant, says lead investigator Gregory J. Riggins, M.D., because tyrosine kinases can be targeted using pharmaceuticals.”

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Passive-Aggressive Cancers Trick Immune System Drew Pardoll, M.D., Ph.D., found that STAT3 protein levels were increased in cancer patients, stimulating cancer cell growth, making Pardoll cancer cells invisible to immune cells and suppressing the immune system. Deactivation of STAT3 in laboratory models restored immune function against tumor cells, significantly slowing cell growth and spread. Pardoll believes finding a way to safely shut down STAT3 could give cancer patients a tremendous boost in their fight against the disease.

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Silent Genes A pioneer in the study of epigenetics, Stephen Baylin, M.D., earned National Cancer Institute recognition in 2004 for the most outstanding research in its SPORE program. His work focuses on mishaps in a cellular process known as DNA methylation. Methylation, particularly when it is located in the start sites of genes, helps tell cells what they need to do. A gene with too much methylation at the start site is invisible to cells.

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2004 Gene Hunters Pinpoint New Cancer Gene Target Victor Veclulescu , M.D., Ph.D., and team have identified mutations in a gene known as PIK3CA and linked them to the progression of colon and other cancers. Their discovery identifies this gene as one of the most highly mutated genes in human cancer and say it could serve as a target for new cancer therapies and diagnostic tests.

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New Test for Ovarian Cancer Often referred to as the silent cancer, ovarian cancer is well known for its ability to remain hidden until it has advanced. But, researchers Daniel Chan, Ph.D., and team have developed a test that may be able to uncover the stealth cancer.

It is a simple blood test that detects three blood proteins that are unique to ovarian cancer.

Telomeres are the end caps on chromosomes designed to preserve genetic integrity. Now researchers believe they play a role in the early development of many types of cancer.

Finding Breast Cancer Finding breast cancer in a tiny drop of breast fluid may now be possible. A new method of analyzing multiple genes in a sample as small as 50 cells was developed by breast cancer expert Sara Sukumar, Ph.D. The test, called QM-MSP, simultaneously determines Sukumar the percentage of a biological process known as methylation (increased methylation is known to shut down key tumor suppressor genes) in each of four to five known breast cancer genes. The percentages are added together for a cumulative score, which is then compared to a threshold value. A percentage above the threshold indicates the potential presence of cancer cells, according to Sukumar. Investigators tested QM-MSP on tissue samples and successfully detected breast cancer in 16 of 19 breast tumor samples. One false-positive result occurred when the test was used on nine normal tissue samples. When used on breast duct fluid, the test detected breast cancer in two of four breast cancer patients.

Sukumar believes these early findings warrant larger studies, and if results are confirmed, she believes the test also could be applied to oral lavages for head and neck cancer and sputum samples for lung cancer detection.

Size Matters: Shortened Chromosomes Linked to Early Cancer Development One could compare their function to the plastic protective coverings on the end of shoelaces. They are called telomeres, and they are the end caps on chromosomes designed to preserve genetic integrity. Now researchers believe they play a role in the early development of many types of cancer.

Telomeres protect the interior, gene-containing parts of the chromosome from being accidentally lost. As normal cells divide and age, some of the telomere DNA is lost, and the telomeres get progressively shorter. Normal cells monitor the length of their telomeres and initiate cell death if they get too short. If this monitoring system breaks down, cancer can be initiated, found researcher Alan K. Meeker, M.D., Ph.D. He believes intervention strategies aimed at preventing or reversing telomere shortening could be effective in lowering cancer incidence and that assessing telomere length could provide a new direction for cancer prevention and early diagnosis studies.

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Putting the Brakes on Colon Cancer Most gene discoveries today focus on finding increased or decreased activity that may or may not affect cancer progression. Investigator Victor Velculescu, M.D., Ph.D., likens these genes to passengers on a bus that can’t control the vehicle’s speed or direction. But, he says he’s found the equivalent to the broken brakes on the bus, a finding that could directly affect cancer development. He has discovered mutations in six genes that make tyrosine phosphatases. They normally work by turning off tumor growth, but in colon cancers, they are mutated and don’t work. It is difficult to repair inactive proteins with cancer drugs, but blocking protein function is a real possibility. “This gives us more options for creating personalized therapies to counteract mutated gene pathways present in individual tumors,” says Velculescu.

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“Switched-Off” Genes May Put First Chink in Colon Cell’s Anti-Tumor Armor Scientists have uncovered a family of genes that are “switched off,” potentially contributing to the earliest cellular changes leading to colon cancer. The genes, called SFRPs, help control cell-growth genes, but when turned off, this protection is lost and early events in colon cancer initiation, occurring even before the formation of colon polyps, can begin. Study director Stephen Baylin, M.D., says the genes are altered through a reversible process called methylation and suggests that certain natural compounds, including green tea, as well as synthetic compounds like aspirin and nonsteroidal anti-inflammatory drugs, may block methylation and reactivate the genes.

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Premature Aging Gene Could Have Implications for New Cancer Therapies Robert Arceci, M.D., Ph.D. identified a gene, that, when altered, makes cells and animals age prematurely and die. The gene, called PASG, could be a target for new cancer therapies that force cancer cells into an early death.

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Angiogenesis Gene Linked to Boimarkers in Breast Cancer Sara Sukumar, Ph.D., made what is believed to be the first link between a gene that controls blood vessel growth and increased activity in a panel of breast cancer biomarkers that regulate tumor cell growth. The HOXB7 (or homeobox B7) gene appears to drive tumor development by increasing the production of growth factors that affect blood vessel development. Sukumar believes HOXB7 is important for the early development of breast cancer and may be a good target for detection and therapeutic tools.

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Velculescu’s Research Called Brilliant Victor Velculescu’s way of identifying cancer-related genes is brilliant so said Popular Science magazine. He was named by the publication in its second Brilliant 10, a survey of researchers and academics in fields from geophysics to quantum origami identifies scientisits whose work is, according to POPSCI’s editor, “just plain brilliant.” Velculescu is recognized for his “maverick approach, which ushered in a new way to finger cancer genes,” reports POPSCI. This approach is known as SAGE (Serial Analysis of Gene Expression).

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Analysis of Gene Family Points to New Treatments for Colon Cancer In what appears to be the first systematic analysis of a disease-related gene family, Victor Velculescu, M.D., Ph.D., uncovered gene mutations linked to more than 30 percent of colon cancers. These genetic alterations could serve as targets for new treatments.

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Common Thyroid Cancer Gene Mutation Found David Sidransky, M.D., found a single genetic mistake responsible for about two-thirds of papillary thyroid cancers. New therapies to Sidransky counteract the mistake are now being studied. A mutation of the BRAF gene was found in 68 percent (24 of 35 samples) of papillary thyroid cancers. It is the first major genetic event identified for common thyroid cancers and could lead to better diagnostics and drug therapies designed to target the effects of this mutation.

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Fanconi’s Anemia Genes are Culprits in Early Onset Pancreatic Cancer Three genes, long linked to a rare inherited disease known as Fanconi’s anemia (FA), appear to play a role in ten percent or more of pancreatic cancers.

Scott Kern, M.D., says that while the genes cause the disease they are also its Achille’s heel, making the cancer more responsive to treatment. Those affected are born with only a single normal copy of one or more of the three genes, known as BRCA2, FANCC, and FANCG. Though they do not develop FA, these people often develop pancreatic cancer, usually in their 40s and 50s, about a decade earlier than the average.

New Prostate Cancer Gene Identified Juon Lo, Ph.D., Angelo DeMarzo, M.D., and William B. Isaacs, Ph.D., led the research team that identified a new genetic culprit—with dietary links—in the initiation of prostate cancer.

The gene, AMACR (a-methylacyl-CoA racemase), is over-expressed by as much as nine times in prostate cancers and a precursor to prostate cancer known as prostatic intraepithelial neoplasia or PIN. The gene appears to play an important role in the oxidation or metabolism of fatty acid molecules, such as those found in dairy products and beef. The investigators believe AMACR could be a potential early marker for prostate cancer and a useful target for prevention.

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2002 Solving the Mystery of Melanoma Melanoma can progress very rapidly and spread to other parts of the body. When this occurs, few people can be cured. If diagnosed and treated in an early stage, however, melanoma can be cured most of the time. Rhoda Alani, M.D., has discovered a gene, called IDH1, that may help distinguish between precancerous moles and those that are really early-stage melanoma. Alani says the gene leaves its fingerprint when the melanoma is in its early stage, and if proteins produced by this gene are detected in a mole, it is probably an early-stage melanoma.

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Acute myeloblastic leukemia

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Heart Disease Gene Linked to Prostate Cancer William B. Isaacs, Ph.D., implicated a “heart disease” gene in hereditary prostate cancer, offering new evidence that at least some prostate cancer cases begin with an infection and inflammatory response. The Isaacs gene, called macrophage scavenger receptor-1 (MSR1), was identified more than 20 years ago for its role in plaque formation in coronary arteries or so-called hardening of the arteries.

Now, Isaacs and team believe the same gene may be mutated in some prostate cancers, disabling the immune system’s ability to clean up properly after prostate infections. This inadequate immune response to infection may produce inflammatory lesions in the prostate, a common precursor to prostate cancer.

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Pancreatic Cancer Linked to Errant Reactivation of Cell Pathway Steven D. Leach, M.D., uncovered a novel pathway that triggers the development of pancreatic cancers. Working with cancer cells from 55 patients, he found that a growth signal normally turned off in adult tissues is mistakenly turned back on after injury or inflammation of the pancreas.

This reactivation may be a first step in initiating pancreatic cancer, well before the onset of any alterations to the pancreatic cells’ genetic material.

Using drugs to deactivate the pathway could prevent these cancer-causing events from occurring, says Leach.

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Gene Target for Leukemia A new gene-targeted therapy may transform AML, the most common form of adult leukemia, from one of the most lethal types of leukemia to one of the most treatable. The new therapy focuses on a specific subtype of AML referred to as FLT3-positive. Right now, less than 10 percent of people with this form of AML are cured, but this new therapy could help most of them, says Donald Small, M.D., Ph.D., the researcher who first cloned the FLT3 gene. Small and team, including Kimmel Scholar Mark Levis, M.D., are testing a drug that interferes with abnormal FLT3 function. Small says, “Now, we have turned it around so that the very abnormalities that cause the disease to progress are now a part of the cure.”

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SURVIVING CANCER When her ovarian cancer came back in 2001, two years after having surgery at a local hospital near her home, her doctor essentially gave up on her. She wondered if she would see her three children grow up and graduate from high school.

BUT, JANICE PAULSHOCK did not give up on herself. Instead,

she came to the Johns Hopkins Kimmel Cancer Center seeking out leading ovarian cancer experts Robert Bristow and Deborah Armstrong. “Don’t tell me how bad it is. I’ve heard all of that,” she told Bristow and Armstrong. “Just tell me how you are going to fix it.”

Giving up never entered Bristow and Armstrong’s minds as they combined the latest surgical techniques with standard chemotherapy drugs and newly-developed targeted anticancer agents to manage several recurrences and keep Paulshock’s ovarian cancer in check, allowing her to stay healthy and active.

Today, Paulshock says she feels great. She has not only reached her goal of seeing her children graduate from high school, but she now travels to her daughter’s college lacrosse games helping with pre-game tailgating. “Life goes on. I know I have cancer, but I am active and healthy,” she says. “People need to understand, that with the right doctors, cancer does not have to be a horrible debilitating disease. It’s something you can live with.”

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JA N I C E PAU L S H O C K

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What Kimmel Cancer Centers investigators have discovered about the cancer cell and the myriad ways it works to grow and spread are leading to unprecedented gains in the clinical care of cancer.

How will we cure cancer? Our experts agree, it will not be a single approach but a combination of approaches. In some cases, it may mean getting rid of the cancer by targeting gene alterations and the pathways they use to turn on the cancer process, in others it may mean using cancer vaccines and medicines to keep a cancer in check so that it cannot continue to grow and spread.

At this very moment, groundbreaking discoveries by our scientists and clinicians are being transferred to patients through clinical trials. Brilliant minds here have led the world in deciphering and, now, disarming the cancer cell. So if knowledge is power, than the Johns Hopkins Kimmel Cancer Center has the power to ultimately cure cancer.

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HOW WILL WE CURE CANCER?

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Breast Cancer Experts Saraswati Sukumar and Vered Stearns

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A CANCER VACCINE

THE VACCINE, developed in the laboratory by cancer immunologists Drew Pardoll, Hyam Levitsky, and Elizabeth Jaffee, and moved into the clinic by 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. The clinic receives more than 60 calls each month and even more emails from patients wanting the pancreatic cancer vaccine. When Jaffee and Laheru’s work makes news, the calls increase.

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 cyclophasphomide 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 Li 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, and the UNIQUELY KIMMEL I Targeting Cancer

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 to protect it from the immune system. Without attacking the cancer’s many mechanisms, the investigators know that the vaccine will never be fully effective against the disease.

Yet another attempt to strengthen the vaccine includes the live but mild bacterium listeria. For most people, it is harmless, and the version the pancreas 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 pancreatic cancer has not responded to any other therapies, biomarkers indicative of the pancreas 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.

Vaccine studies began in 1991 and are now making a clinical difference. Building on the success of the pancreatic cancer vaccine, similar approaches are being studied in breast cancer, leukemia, prostate cancer, and cervical cancer. “You almost have to be willing to stake a career on your research,” says Jaffee. And, that is exactly what she did. To make vaccine therapy a reality, Jaffee became an expert in vaccine manufacturing, opening the GMP facility (good manufacturing processes) to make the vaccine and learning the huge compendium of FDA regulations. She says, “We’re in this for the long haul.”

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As director of the gastrointestinal program, Scott Kern has one main requirement. That is that the clinical programs are as strong as the basic science research programs. It is a goal the pancreatic cancer clinic, driven in large part by the success of a pancreatic cancer vaccine, has already achieved.

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Dan Laheru and Elizabeth Jaffee developed a pancreatic cancer vaccine

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when he began feeling run down. What he thought was the flu was shockingly revealed as acute myeloblastic leukemia (AML). Too ill to return to the United States, Valenzano began chemotherapy at Gemelli Hospital, a teaching hospital in Rome.

Back home at the Archdiocese of Baltimore, plans were already in motion. Deacon Greg Rausch, who also happens to be Dr. Greg Rausch, a Johns Hopkins Kimmel Cancer Center community physician, was consulting with his cancer center colleagues.

Doctors at Gemelli treated Valenzano with a standard chemotherapy regimen and thought he was in remission. Now well enough to travel home, he was discharged from Gemelli hospital believing once back in the U.S., he would get one more round of chemotherapy and be done.

Kimmel Cancer Center leukemia expert Javier Bolanos-Meade delivered the unexpected news that doctors at the Gemelli hospital were wrong. He was not in remission, and furthermore, another round of chemotherapy would have little benefit. Valenzano would need a bone marrow transplant, but he did not have a fully matching bone marrow donor.

Cutting-edge research at Kimmel Cancer Center by Ephraim Fuchs and Leo Luznik has led to haploidentical or half-identical transplants. Investigators have learned how to control a complication known as graft versus host disease (GVH), where donor immune cells received during the transplant reject their new host. Our doctors allow the GVH to ramp up just enough to wipe out any remaining leukemia cells but not enough to damage vital tissues and organs. This type of transplant has provided a much-needed option to patients, like Valenzano, who do not have matching donors, but whose only hope is a bone marrow transplant. In fact, most recent findings reveal that haploidentical transplants may actually produce better results than perfectly matched transplants.

Pioneers in the field of bone marrow transplantation, Kimmel Cancer Center experts have taken what was once the most intensive of cancer therapies, requiring months of hospitalization, and moved it to the outpatient setting. Unlike the transplants of decades earlier, the Center’s IPOP (inpatient/outpatient) program allows bone marrow transplant patients to receive much of their care as an outpatient.

It has been more than two years since his transplant, and Valenzano says he feels completely healthy. He resumed his duties as pastor of the 13,000-member St. John Roman Catholic Church of Westminster, Maryland, and even manages to squeeze in an occasional golf game.

“I can’t say enough good things about this Cancer Center,” says Valenzano.

“I was very aware that I could not have been in a better place.”

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MONSIGNOR ARTHUR VALENZANO was on sabbatical in Rome

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2009 Figuring Out How Chemotherapy Helps Personalize Cancer Treatment Researchers have discovered how a whole class of commonly used chemotherapy drugs can block cancer growth. Their findings suggest that a subgroup of cancer patients might particularly benefit from these drugs. “We’ve shown how it happens and what players are involved, which could help shape future clinical trials for those with certain types of cancers,” says Gregg L. Semenza, M.D., Ph.D.

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2008 Breakthrough Against a Relentless Leukemia For elderly patients, those over 70, acute myelogenous leukemia (AML) is a difficult diagnosis.

The intensive chemotherapy that works well for their younger counterparts, may be intolerable for older patients, and on top of this, AML in older patients is a genetically more complex and very resistant to traditional chemotherapy drugs.

These elements combine to make for a relentless disease. A new therapeutic approach combines Etoposide (VP16), a leukemia standard, with a new targeted drug called Tipifarneb.

Judith Karp, M.D., and her team undertook the largest phase I clinical trial for AML in history, testing the drug combination in 84 patients over age 70. Complete remissions occurred in 25 percent of all patients treated across many dose levels of both drugs, with a 40 to 50 percent complete remission rate in patients treated with intermediate doses of both drugs.

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Cancer Stem Cells Although 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, Jones Matsui Huff investigators Richard Jones, M.D., Kimmel Scholar William Matsui, M.D., and Carol Anne Huff, M.D., used two techniques, including one developed at the Kimmel Cancer Center, to bring deadly pancreatic cancer stem cells out of hiding. Purifying the stem cell population is key to identifying the pancreatic cancer stem cell and eventually identifying the processes that control it. In similar research, the team also identified the B-cell as the multiple myeloma cancer stem cell and used mouse models to help prove their theory. While multiple myeloma is seen as a cancer of the blood plasma cells, the investigators showed it was errant immune system B-cells, not plasma cells, that cause and sustain the cancer. New therapies that target the B-cell are currently be tested.

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2007 Breast-Saving Breast Cancer Treatment 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 be on my wish list,” says Sara Sukumar, Ph.D. “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, M.D., 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 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.”

Sukumar and Stearns, with help from radiologist Nagi Khouri M.D., and surgeon Theodore Tsangaris M.D., 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 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.

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Purifying the stem cell population is key to identifying the pancreatic cancer stem cell and eventually identifying the processes that control it.

Patients receiving the abdominal chemotherapy remained cancer-free for an average of 23.8 months, while those receiving intravenous chemotherapy alone stayed cancer free for 18.3 months.

Early Results of Pancreatic Cancer Vaccine Trials Promising Vaccine studies are providing new hope for treatment of a cancer with few options and low odds of survival. Until recently, most studies have shown pancreatic cancer survival rates at about 63 percent one year after diagnosis and 42 percent at two years. So, Johns Hopkins Kimmel Cancer Center researchers are encouraged by early results of a treatment vaccine. At about two years into a study of 60 patients, the researchers report that 88 percent survived one year and 76 percent are alive after two years. “Even though our results are preliminary, the survival rates are an improvement over most published results of pancreatic cancer treatment studies,” says Daniel Laheru M.D. Laheru and colleagues combined an immuneboosting vaccine with surgery and conventional postoperative chemotherapy and radiation.

Protein Offers Clue to Cancer’s Hold on the Immune System Understanding why the immune system ignores cancer cells and figuring out how to activate an immune response to the disease Drake has been the focus of continuing research at the Kimmel Cancer Center. Physician-scientist Charles Drake M.D., Ph.D., 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 is now working to find LAG-3 blocking agents that may work in humans.

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Cellular Pump Sabotages Cancer Drug Studies In a chance discovery, investigators led by Martin Pomper, M.D., 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.

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Soaking Ovarian Tumors in Anticancer Drugs A 50-year-old method for delivering chemotherapy directly into the abdomen is being re-evaluated for patients with ovarian cancer. A seven-year study of more than 400 women led to renewed interest in the abandoned method after findings revealed increased survival rates in patients with advanced ovarian cancer.

A spaghetti-like tube inserted into the abdomen of newly-diagnosed women with stage III ovarian cancer was used to bathe their entire abdomen with high concentrations of anticancer drugs over a long period of time. “This method appears to be better at destroying lingering cancer cells,” says Deborah Armstrong M.D., the ovarian cancer expert leading the study.

Patients also receive a round of intravenous chemotherapy to destroy cancer cells that might have spread beyond the abdomen. Patients receiving the abdominal chemotherapy remained cancer-free for an average of 23.8 months, while those receiving intravenous chemotherapy alone stayed cancer- free for 18.3 months. “This is a significant improvement in survival for women with this disease, which is most often diagnosed at an advanced stage,” Armstrong says.

The Gynecologic Oncology Group now recommends the therapy, also known as intraperitoneal or IP therapy, as the new standard for many women with ovarian cancer. Many institutions have already adopted this practice, Armstrong says. However, she says, some clinicians are deterred by the increased expense and lack of familiarity with this method.

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2005 Armstrong says more studies are needed to determine whether abdominal chemotherapy has any benefit for recurrent disease or patients with large amounts of residual disease after surgery.

“The first and most important step is good surgery,” says Robert Bristow M.D., director of the Johns Hopkins Ovarian Cancer Center.

“If you don’t start with a surgeon specializing in gynecologic oncology who can effectively remove most of the tumor, then intraperitoneal chemotherapy may not work.”

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Cancer-Eating Bacteria The immortal cancer cell may have found its match. In the right form, germs, those nasty infection-causing organisms that we try to wash or medicate away, may be good to have around when it comes to getting rid of cancer cells. Researchers, led by Shibin Zhou, M.D., Ph.D., and Bert Vogelstein, M.D., genetically modified bacteria called Clostridium novyi so that they would not harm normal, healthy cells, instead giving them free reign over cancer cells. In mouse experiments, the bacteria destroyed cancer cells in the oxygen-starved core of tumors but showed no interest in tissues not harboring cancers. In their latest work, the researchers administered the bacteria together with anticancer drugs specially formulated to take advantage of the bacteria’s properties. This combined germ/chemo approach temporarily wiped out both large and small tumors in almost 100 percent of mice and permanently cured more than two-thirds of them.

Clinical trials to test the safety of the new therapy have recently begun in a limited number of cancer patients.

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A Heated Approach Usually, a cancer that has spread to other organs, such as the brain or lungs, is nearly impossible to cure. However, that’s not the case with testicular cancer. Investigators Robert Getzenberg, Ph.D., Donald Coffey, Ph.D., and Theodore DeWeese, M.D., believe they have uncovered the reason for this unprecedented success against an advanced-stage cancer. They are deciphering the changes to the nuclear structure of the cancer cell when it is heated.

The researchers call their model TEMT (temperature enhanced metastatic therapy) because it explains how even advanced cancers that have spread beyond the original tumor site can be reined in with heat. They used a testicular cancer model to prove that cancer cells exposed to heat are easier to kill with drug and radiation therapies.

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Getting Right to the Source of Breast Cancer The breast ducts, or channels that produce milk and carry other secretions throughout the breast tissue, are most often where breast cancer originates.

Now, investigators are exploring the benefits of delivering chemotherapy directly to these ducts. The technique, developed by Sara Sukumar, Ph.D., uses a tiny catheter inserted through the nipple to deliver anticancer drugs directly into the breast ducts. Promising animal studies of this method of delivering anticancer drugs, known as intraductal chemotherapy, have led to Phase I clinical trials in women with very early breast cancer.

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Engineering Cancer Therapies We don’t think of cancer as an engineering problem, but sometimes its treatments can be. To overcome obstacles of treatment delivery in prostate cancer, radiation oncologist Danny Song, M.D., is working with engineer Gabor Fichtinger, Ph.D., and robotics expert Dan Stoianovici, Ph.D. Song is an expert in brachytherapy, a prostate cancer therapy that involves inserting radioactive seeds into the prostate to destroy the cancer. Song and Fichtinger have developed a computer-assisted device to guide precise placement of seeds. Song and Stoianovici also are working on an even more precise MRI (magnetic resonance imaging)-assisted process.

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Leukemia Target Leads to Treatment for MS A genetic culprit in a type of acute myeloid leukemia (AML) is now a treatment target for multiple sclerosis and other autoimmune diseases. Investigators found that FLT3, which they formerly linked to a treatment-resistant form of AML, is activated in a type of immune cell known as the dendritic cell and leads to an unwarranted attack on patients’ healthy tissues and organs. Donald Small, M.D., Ph.D., who first cloned the FLT3 mutation and whose laboratory was the first to develop drugs targeted against it, says using a drug to block FLT3 signaling in dendritic cells could prevent these harmful immune responses against a patient’s own body.

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Two Drugs Better Than One in Colon Cancer Interferon, a drug used for 30 years to treat blood cancers, appears to selectively kill colon cancer cells when combined with irinotecan, another standard chemotherapy agent. Researcher Betsy Barnes, Ph.D., says the findings suggest that the combination tactic, which targets a common gene pathway in colon cancer cells, could be more potent than either drug alone, and has fewer side effects.

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Tool Helps Doctors Pinpoint Lethal Prostate Alan Partin, M.D., Ph.D., and colleagues have identified three risk factors and developed a simple reference tool that doctors can use to manage prostate cancer. The new tool assesses blood tests, surgical pathology, and time following surgery in men whose cancer comes back after surgery to determine if their cancer is a more lethal form.

This information would help doctors determine which patients would benefit from further, aggressive therapy.

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The breast ducts, or channels that produce milk and carry other secretions throughout the breast tissue, are most often where breast cancer originates.

Now, investigators are exploring the benefits of delivering chemotherapy directly to these ducts.

2004 Low-Dose Radiation Evades Cancer Cell’s Protective “Radar” We have a tendency to think that more is better, but in terms of radiation therapy, that is not the case. Lower doses of radiation appear to result in the death of more cancer cells than higher doses by eluding cells’ damage detection “radar.” The “radar” is actually a protein known as DeWeese ATM that detects DNA damage, such as that caused by radiation, and begins to repair it. Small amounts of radiation do not trigger the protein and its repair process, says Theodore DeWeese, M.D.

University of Michigan found that women taking both drugs had decreased levels of a newly identified molecule called endoxifen, a byproduct of tamoxifen in its processed form, which could indicate that the tamoxifen is not being fully metabolized in these people.

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Origin of Multiple Myeloma Found in Rare Stem Cell Investigators have identified a cancer stem cell most likely responsible for the development of multiple myeloma, a cancer of the bone marrow that destroys bone tissue. Their findings suggest that long-term cures for this disease will likely involve targeting this stem cell. Current treatments target malignant plasma cells and may miss errant multiple myeloma stem cells, allowing the cancer to come back, according to Richard Jones, M.D., who led the study.

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One Physician’s Quest for a Treatment for the Worst Kind of Pediatric Brain Tumor For Kenneth Cohen, M.D., M.B.A., one of the more difficult aspects of his job as director of pediatric neuro-oncology is telling parents that their children have brain stem gliomas. Cells from these cancerous tumors invade a portion of the brain called the pons. “Surgery isn’t an option because you can’t live without your pons,” says Cohen. For the first time in years, Cohen is excited about a new therapy he’s developed and is now making available to patients. The key element in his new therapy is arsenic. “Arsenic has been used successfully for many years to treat certain types of leukemia.

It may directly poison abnormal glial cells of the brain, the same cells affected by brain stem gliomas, as well as working in combination with radiation therapy.” says Cohen. He is hopeful that this new aresenic therapy will get the hypoxic, or oxygen-deficient, areas of the tumor.

New Prostate Cancer Drug Extends Life, Eases Pain Michael Carducci, M.D., reported that the drug atrasentan stabilizes the spread of cancer in many men with advanced prostate cancer who have stopped responding to hormone therapy. The three-year international study of more than 1,000 men opens the door to potential new treatment options for this subset of patients. “Some of these men are looking for less-toxic alternatives to chemotherapy at this point in their lives,” says Carducci. “By keeping the cancer from spreading to the bone, atrasentan can help prevent their pain and potentially Carducci postpone when they will need more aggressive treatment,” he says.

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Vaccine for Chronic Leukemia Johns Hopkins Kimmel Cancer Center researchers are testing a vaccine to recruit the immune system in fighting chronic myeloid leukemia (CML). The Phase I/II study will test the vaccine in 20 patients who have been taking the anticancer drug Gleevec for one year but may still have detectable disease in their blood. The vaccine uses lab-grown irradiated chronic myeloid leukemia cells genetically modified with the immune-boosting gene GM-CSF. Immune cells are attracted to the vaccine and recognize its antigens, which serve as red flags that cause the immune system to seek out and destroy cancer cells elsewhere in the body.

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Arsenic Part of Novel Treatment for Leukemia Chi V. Dang, M.D., Ph.D., has uncovered the reason arsenic has long been a successful treatment for certain types of leukemia and combined it with a second toxin to develop a new, more potent therapy. Dang and colleagues discovered that arsenic activates the same self-destruct mechanism in acute promyelocytic leukemia (APL) cells as a toxin called bryostatin found in coral-like marine organisms.

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2002 Getting Rid of Larynx Cancer While Saving the Voice Box In an eight-year trial of more than 500 patients, Arlene Forastiere, M.D., has shown that by giving chemotherapy and radiation therapy Forastiere at the same time, many larynx cancer patients are able to retain their larynxes and preserve their voices. About 85 percent of patients remain disease-free after receiving the combined drug-radiation therapy. The simultaneous treatment works because the chemotherapy makes the cancer cells more sensitive to radiation. Standard treatment for advanced cancer of the larynx, or voice box, was removing the entire organ, often leaving patients depressed and reluctant to communicate. Forastiere and team have changed this, going from everyone needing their larynxes out to just 15 percent requiring the radical procedure.

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2003 Possible Interaction Identified Between Tamoxifen and Hot Flash Drug Researchers are investigating interactions between the commonly used breast cancer drug tamoxifen and the antidepressant drug paroxetine, used to treat hot flashes. The interactions could potentially alter the effectiveness of tamoxifen.

A team of scientists from the Johns Hopkins Kimmel Cancer Center, Indiana University, and the

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One of the first things that went through 13-year-old Lauren Murphy’s mind when she learned she had cancer was “Am I going to die?” Knowing that her cancer was in her brain brought added worries. She wondered, “If I survive, will I be the same person.” After all the brain is the sanctuary for all things that made her uniquely Lauren —her memories, her talents, her likes and dislikes, her dreams for her future, her bubbly and vivacious personality.

A golf ball-sized tumor in the middle of her cerebellum threatened to rob her of it all.

When Lauren’s pediatrician found the tumor, her advice to Lauren’s mother Ruth Taylor was to “take her, right now, to Johns Hopkins.”

Pediatric experts at the Johns Hopkins Kimmel Cancer Center performed surgery on Lauren’s brain to remove the tumor and followed up with radiation therapy and chemotherapy to make sure all of the cancer cells had been destroyed.

Five years later, Lauren is a college student at Towson University studying public relations and American sign language. She was inspired to study sign language after suffering some hearing loss as result of her cancer treatment. Once a gifted dancer, the tumor that struck the balance center of her brain has caused her to pack away her ballet shoes and pursue other interests.

Among these new interests is advocate for childhood cancer survivors. Because pediatric cancers are rare, they do not receive the attention or funding that adult cancers receive. Testifying before Congress with the Children’s Cause of Cancer Advocacy, Lauren has become a voice for all children suffering from cancer calling for increased funding for basic research, drug discovery, and ways to prevent and manage the lasting side effects caused by treatment.

Lauren says, “I focus on the positives. There are far more positives. After all, I don’t have cancer anymore.”

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We often hear cancer referred to solely in terms of numbers—in the hundreds of thousands of cases diagnosed in a year or as the second leading cause of death. Viewing the disease in terms of its statistics makes it much too easy to distance ourselves from the faces behind each number; the reality that every number is someone’s child, brother, sister, mother, father, grandparent, or friend.

How better to serve these people, than to prevent them from ever having to experience the anguish that is a diagnosis of cancer.

The surest way to cure a cancer is to prevent it from ever occurring.

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HOW DO WE PREVENT CANCER?

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Cancer Prevention and Control Leaders John Groopman and Elizabeth Platz

AN OUNCE OF PREVENTION IS WORTH POUND OF CURE

PREVENTING CANCER Though cancer is a genetic disease, experts point out, that most of the gene mutations that characterize the disease are acquired, not inherited. Where do these bad genes come from? Often, says cancer prevention and control expert John Groopman, it is through our own behaviors. Cigarette smoking, obesity, poor and unbalanced diets, virus exposure, and sunburns are a few of the most common culprits, he says.

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“THE SOCIETAL BURDEN is lopsided toward

behavioral issues when it comes to cancer,” says Kimmel Cancer Center Director William Nelson. “Most of the genetic mutations we look at in cancers in the general population are caused by lifestyle, not by heredity.”

Nelson says that most major cancers are caused by things that can be avoided or changed—smoking, obesity, and poor diet—or prevented, like HPV infection (by vaccination) and chronic inflammation. As a result, there are many opportunities to derail the cancer process.

The care of heart disease was revolutionized with drugs that manage the underlying causes of the disease, like cholesterol, says Nelson. “We need to harvest this impact for cancer,” he says.

Adverse studies like those of Vioxx, the arthritis drug that was believed to have colon cancer prevention properties, almost caused the demise of pharmaceutical giant Merck when some study participants suffered heart attacks attributed to the drug. As a result, Nelson says, pharmaceutical companies are not in play when it comes to cancer prevention, so we have to look for other options.

Where better to look then to natural products that are safe and found in foods, says Groopman. “We need to use the science to develop targets for prevention, but we must find products that are certain to do no harm.” Our team has found that sulforaphane, a compound found in broccoli and other cruciferous vegetables may fit the bill.

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sulforaphane activates a gene signaling pathway and enzymes that protect us from cancer. In mouse models, sulforaphane reduced inflammation of the lungs caused by cigarette smoke and other environmental pollutants. Investigators are evaluating its cancer prevention properties in a number of cancers including, liver, breast, prostate, stomach, and skin cancers.

To bolster sulforaphane’s cancer preventing capabilities, researchers have learned how to specially grow broccoli plants to produce large amounts of the compound and get its cancer protective benefits by eating just a handful of broccoli sprouts.

In liver cancer research, the research team showed that sulforaphane reduced DNA damage. “This has to be good,” says Groopman. “If it reduces DNA damage, it has to lead to a reduction in the genetic alterations that cause cancer.”

Another natural approach is being investigated in colon cancer. Infectious diseases expert Cynthia Sears sought out the ideas of Kimmel Cancer Center experts when she began to explore the possibility of preventing colon cancer by manipulating the bacteria in the colon.

There are ten times as many organisms in our bodies as cells, and while most of the time they aid in good health, Sears wondered if a bug gone awry could be linked to cancer.

To test her hypothesis, she went straight to the top, seeking the input of world renowned cancer genetics and colon cancer expert Bert Vogelstein and cancer immunologist Drew Pardoll. Vogelstein’s pioneering

“The goal of prevention research is to put off a diagnosis of cancer to as late in life as possible.

Cancer is a disease of aging, so as the average lifespan increases, so does the risk for cancer.

But, if we use prevention to delay the development of cancer until people are in their 80s or 90s, then I think cancer prevention becomes as good as a cancer cure.”

It is not the first bacteria to be linked to cancer.

H. pylori, the bacterial culprit in the development of ulcers was found to cause an inflammatory state in the stomach that could lead to cancer. Experts found that by treating the infection, they could reduce the risk of cancer.

Unlike H. pylori, there currently is no diagnostic test for B. fragilis, but Sears and team are working to develop tools to identify people who carry it so she can explore eliminating the organism as a way to prevent cancer.

The prospects are exciting,” says Nelson. “Can you imagine preventing colon cancer simply by the changing the bacteria in the colon?”

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Investigators believe inflammation could also be a target for prostate cancer prevention and the work represents another interdepartmental collaboration.

When looking at microscope slides of prostate tissue, pathologist Angelo M. De Marzo observed a lot of inflammation but could not find anything written about what he was seeing in scientific literature. So, he mentioned it to Nelson, a prostate cancer expert, wondering if it could be an underlying cause of prostate cancer. Nelson confirmed that cancer researchers wondered the same thing, noting that men with more inflammation tend to have more cancer.

De Marzo began looking for the underlying causes of the inflammation, exploring dietary and infectious links. Charred meats, those cooked over flames, he found released a chemical compound called PhIP. In animal studies, rats fed PhIP had more gene mutations and precancerous prostate lesions than rats not fed the compound.

There is mounting evidence that a so-called “western” diet increases the risk for prostate cancer.

De Marzo notes that Asian men do not develop prostate cancer until they westernize their diets.

De Marzo is convinced that inflammation brought on by environmental insults caused by diet, infection, and potentially other factors, conspire to bring on the early stages of prostate cancer. He says, figuring out what is causing the inflammation and intervening to stop it may prevent prostate cancer.

Elizabeth Platz also is focused on prostate cancer prevention. Her work is based in epidemiology or observing trends and then working with scientists to find out if they make sense and if they can figure out the biological process in the laboratory. Her recent work links cholesterol-lowering drugs called statins to holding prostate cancer in check. In a large, 10-year comparative study of 30,000 men, Platz found men taking statins were far less likely to develop advanced prostate cancer. It did not affect their risk of developing the disease, but slashed in half the risk of advanced cancers.

“The goal of prevention research is to put off a diagnosis of cancer to as late in life as possible,” says Groopman. “Cancer is a disease of aging, so as the average lifespan increases, so does the risk for cancer.

But, if we use prevention to delay the development of cancer until people are in their 80s or 90s, then I think cancer prevention becomes as good as a cancer cure.”

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breakthrough linked specific genetic mutations to the development of colon cancer and Pardoll helped develop the first cancer vaccines. Sears wondered if an underlying condition such as colon colonization carrying particular bacteria could lead to chronic inflammation, setting in the motion the genetic changes that lead to colon cancer. If we could stop the process, could we stop colon cancer?

“That is the great thing about the Kimmel Cancer Center,” says Sears. “The ability and willingness to share ideas and knowledge across scientific and medical disciplines allows us to accomplish so much more.

I went to them for help with my work, and they did not hesitate.”

Sears is particularly interested in an organism called Bacteroides fragilis. Toxin-secreting strains of B. fragilis are known to promote inflammation. When tested in mouse models, it causes lots of colon tumors, Sears says. She wants to find out if treating the bacteria could help prevent colon cancer.

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2008 Natural Cures Kala Visvanathan, M.B.B.S., 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, Visvanathan 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.

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"Broccoli sprouts are cheap, safe, oral, natural, inexpensive and high in a celldetoxifying agent called sulforaphane".

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 sprouts 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.

Similar broccoli sprouts studies are being explored in lung, prostate, liver, and skin cancers.

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New Findings on Polyps and Colorectal Cancer Young adults without a family history of bowel disease are unlikely to develop adenomas, the colorectal polyps most likely to lead to cancer, according to new research directed by Francis Giardiello, M.D. The finding supports current cancer screening guidelines recommending adults in general undergo screening colonoscopies starting at age 50. The study also showed that white patients more often had adenomas on the left side of the colon, whereas African Americans had lesions more often on the right side.

The take-home lesson, Giardiello says, is that screening and diagnostic evaluations of African Americans should include a colonoscopy rather than a sigmoidoscopy, because the latter evaluates only part of the colon.

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New Information on HPV-Related Head and Neck Cancer Head and neck cancer experts at the Kimmel Cancer Center have 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. Center experts were the first to link the human papillomavirus (HPV) to oral cancer, identifying 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.

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NanoPill Could Prevent Pancreatic Cancer With survival rates of less than fiver percent, pancreatic cancer is among the most feared of all cancers. Standing as a roadblock between surviving pancreatic cancer, or not, is the lack of warning signs. It is a cancer that exhibits few symptoms until it is already well advanced. Prevention offers the best opportunity to improve the bleak survival rates, says pancreatic cancer researcher Anirban Maitra, Ph.D. Joining together the principles of nanoscience with the Indian spice curcumin, he believes he may be heading in that direction.

Maitra 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.

Nanoscience involves the extension of the existing sciences into the study of ultra-tiny structures, materials, and devices. 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.

The engineered nanocurcumin could be given intravenously or orally, like a vitamin pill.

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2007 C and the Big “C”: How Vitamin C Stops Cancer Nearly 30 years after Nobel laureate Linus Pauling famously and controversially suggested that vitamin C supplements can prevent cancer, a team of Johns Hopkins scientists has shown that in mice at least, vitamin C—and potentially other antioxidants— can indeed inhibit the growth of some tumors—just not in the manner suggested by years of investigation.

The conventional wisdom of how antioxidants, such as vitamin C, help prevent cancer growth is that they grab up volatile oxygen free radical molecules and Dang prevent the damage they are known to do to our delicate DNA. The Hopkins study, led by Chi Dang, M.D., Ph.D., unexpectedly found that the antioxidant’s actual role may be to destabilize a tumor’s ability to grow under oxygen-starved conditions. “The potential anticancer benefits of antioxidants have been the driving force for many clinical and preclinical studies,” says Dang. “By uncovering the mechanism behind antioxidants, we are now better suited to maximize their therapeutic use.”

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Good Nutrition Can Prevent Cancer Experts report that 20 to 50 percent of fatal cancers are attributable to poor diet. Since dietary patterns are established early in life, there are many opportunities for intervention. Ann Klassen, Ph.D., has established a lifespan approach to reducing cancer-related dietary risk in low-income families. Using data sources from 1,300 infants, children, adolescents and

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Stop Smoking, Stop Cancer Smoking is the single most preventable cause for death and disease in the United States. It increases the risk for lung and other cancers, not to mention cardiovascular and respiratory diseases. A nurse-run program, led by Robin Newhouse, Ph.D., R.N., is aimed at reducing lung cancer incidence and death rates by improving the success of smoking cessation. The study focuses on patients already in the hospital and tests a nurse-run, smoking cessation counseling program.

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2006 Grilling Out May Be Bad for the Prostate Kimmel Cancer Center scientists warn that grilling of meats may cause the formation of a compound that can lead to prostate cancer—namely 2-amino1-methyl- 6-phenylimidazo[4,5-b]pyridine, or PhIP. The compound forms in meats cooked at very high temperatures, such as those cooked over flames.

Previous animal studies showed that rats fed food mixed with PhIP had more gene mutations and precancerous lesions in the ventral lobe located in the front of the prostate gland than rats not fed the compound.

New data shows inflammation (a known contributor to development of many types of cancer) was also noted in the ventral lobes of the PhIP-fed rats, says lead investigator Angelo De Marzo, M.D., Ph.D. “For humans, the biggest problem is that it’s extremely difficult to tell how much PhIP you’ve ingested, since different amounts are formed depending on cooking conditions,” says co-investigator William Nelson, M.D., Ph.D. “As a result, it has been difficult to fully determine how many human prostate or other cancers might be caused by PhIP.”

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2005 Statins Lower Risk of Prostate Cancer Use of the cholesterol-lowering medications known as statins appear to lower a man’s risk of developing advanced prostate cancer, data from more than 30,000 men followed for 10 years has revealed by Elizabeth Platz, Sc.D. Platz related men’s self-reported use of cholesterol lowering medications, which included statins, to their future risk of prostate cancer and found there was a notable reduction in risk for advanced prostate cancer.

Platz says it’s still far too early to recommend routine statin use in order to avoid developing advanced prostate cancer, but evidence is mounting that statins may be helpful in reducing the incidence of several conditions in which inflammation is thought to play a role.

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Solving the Mystery of the Disappearing Cervical Precancers New research sheds light on why cervical precancers disappear in some women and not in others, and helps pinpoint which women would benefit from a cervical cancer vaccine developed at the Kimmel Cancer Center.

The strain of HPV and the genetic characteristics of a woman’s immune system seem to be the key. The lifetime risk of becoming infected with a high-risk strain of HPV, at least once, is over 80 percent, but only a small percentage of these infections progress to full-blown cancers. In her study of 100 women with high-grade STORIES OF RESEARCH

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precancerous lesions, Connie Trimble, M.D., found that the immune systems of women infected with a specific viral Trimble strain, called HPV16, had the most trouble in clearing the cervical lesions. Among women with non-HPV16 lesions, those carrying an immune-system-related gene called HLA*A201 were three times less likely to have their immune systems resolve their lesions. “Understanding the characteristics of these lesions will help us determine women who may best benefit from our vaccine,” she says. “Some lesions are on the brink of resolving, but may need the vaccine to make it happen.”

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Prevent Prostate Cancer with Antioxidants Oxidation of cells is a normal part of human metabolism but is a known contributor to aging and the cancer development process. Theodore DeWeese, M.D., identified a molecular pathway in mice that makes prostate cells vulnerable to cancer-causing oxygen damage. Studying this pathway may help investigators determine whether antioxidants, such as vitamins, can prevent prostate cancer in humans.

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Prevent Inflammation, Prevent Prostate Cancer The earliest stages of prostate cancer probably begin in areas of chronic inflammation that could be reversible with anti-inflammatory drugs and dietary supplements, say researchers William Isaacs, Ph.D., and Angelo De Marzo, M.D., Ph.D. They believe agents that inhibit the inflammatory response may decrease prostate cancer risk and are testing their theory in animal studies.

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Detoxifying Prostate Cells William Nelson, M.D., Ph.D., and Angelo De Marzo, M.D., Ph.D., are studying an enzyme called GSTP1 that may protect prostate cells against environmental damage from smoke and other chemicals. The enzyme was found to play a key role in preventing precancerous prostate lesions from turning into cancer. In people with prostate cancer, the investigators found that the gene may be deactivated. They are exploring the potential of using a drug to restore or compensate for missing or low levels of the enzyme.

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adults to identify diets and behaviors associated with cancer risk. Her team will keep track of what study participants eat and look for risk factors for being overweight and rapid weight gain.

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COMMUNITY OUTREACH AS AN AFRICAN AMERICAN man, Rodney Scruggs knows the importance of being screened for prostate cancer. He has even been screened before. When it was again time for his regular screening, however, he did not call his doctor because he had been laid off from his job and had no insurance.

Fortunately, he heard about the Johns Hopkins-Maryland Cigarette Restitution Fund prostate cancer screening program on a talk radio station and made an appointment. It turned out that Rodney had prostate cancer. Because his cancer was detected early enough through screening, his story has a happy ending. The Johns Hopkins surgeon that operated on him in 2004 believes he got all the cancer.

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With the combined strength of the worldrenowned Johns Hopkins medicine, engineering, physics, and business programs and the support of Mr. Sidney Kimmel, there is no single place in the world as capable of translating these discoveries into clinical cancer care as rapidly and adeptly as the Johns Hopkins Kimmel Cancer Center, an internationally recognized engine for discovery cancer research and innovative clinical research.

With the combined strength of the worldrenowned Johns Hopkins medicine, engineering, physics, and business programs and the support of donors like Mr. Sidney Kimmel, there is no single place in the world as capable of translating these discoveries into clinical cancer care as rapidly and adeptly as the Johns Hopkins Kimmel Cancer Center, an internationally recognized engine for discovery cancer research and innovative clinical research.

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Special Facility Speeds Development of Cancer Therapies It is one of about a dozen in the country and it helped make the Kimmel Cancer Center’s world-renowned pancreatic cancer and breast cancer vaccines a reality. Known as the Cell and Gene Therapy Facility, it is the unique and highly sophisticated on-site facility where Center experts make cancer vaccines and other biological therapies for cancer patients.

“In order to move from test tube and animal studies to human clinical trials, you need enough product to test,” says facility medical director Elizabeth Jaffee. “Without this facility, we would have to contract with biotech companies, which costs us a significant amount of time and money.”

What makes this laboratory different from others is its technically advanced and controlled environment. It is equipped with filtration and scrubbers that make it the most sterile environment on the medical campus. Jaffee and her team have become experts on quality control and FDA and other federal regulations to ensure the facility complies with the many requirements aimed at patient safety.

“Anything that can be done to manipulate a cell can be

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done in this facility,” says Jaffee. “We can alter gene expression in tumor cells and normal cells, insert missing enzymes, transfer genes into vaccines, or replace missing genes. These new and improved cells can be given to patients in the form of vaccines or other biological therapies.”

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Maryland Establishes Cigarette Restitution Fund: Kimmel Cancer Center Awarded Grants for Cancer Research, Treatment, and Screening In the late 1990s, attorneys from nearly every state in the U.S. brought suit against America’s cigarette manufacturers in an effort to recover costs incurred from smoking-related diseases like cancer. The States prevailed, winning $53 billion in penalties known as the Master Settlement Agreement. In 1999, Maryland’s Governor and the General Assembly were among the first of their lawsuit counterparts to use their award to establish the multi-million dollar Cigarette Restitution Fund (CRF). State leaders have continued to allocate funds throughout our state for smoking-cessation programs and education, crop conversion assistance for tobacco farmers, cancer research, prevention, education, screening, treatment, and other smoking and cancer-related initiatives.

While legislators from other states used their CRF money to patch holes in their state budgets or engaged in lengthy legal battles over how the funds should be allocated, Maryland was held as a national model in the media and at Congressional hearings for quickly investing its funds to fight cancer.

Since the CRF was established Maryland’s cancer death rankings have dropped from 3rd to 19th. While the improvement cannot be solely attributed to the CRF, says Kimmel Cancer Center director William Nelson, observing that the reductions in death rates coincided with the dates and scope of the CRF, he believes it is evident that it played a key role.

State leaders recognized one of the surest ways to impact cancer in our state was to look to Maryland’s two academic health centers—Johns Hopkins and the University of Maryland. In 2000, legislation was passed providing these institutions with grants for public health initiatives and cancer research. Since that time, the CRF provided $2.15 million for nearly 100 research projects, including seed funding for pioneering studies, like the cancer genome blueprints and a cervical cancer vaccine, and helped the Center recruit and retain talented researchers and clinicians.

The CRF also provided Johns Hopkins $1.2 million in

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The Art of Healing The Johns Hopkins Kimmel Cancer Center is not just one of the finest comprehensive cancer centers, it is also a place dedicated to creating an uplifting environment with a sense of hope and optimism for its patients, their families, and the faculty and staff. With its Art of Healing program of artwork and music, Kimmel Cancer Center visionaries added an artistic dimension to the healing process. With the opening of a new clinical cancer facility they wanted an environment with the technology to heal the human body, but one that was nurturing and comforting to heal the human spirit.

With the help of art curator Ted Cohen, Peggy Heller, whose husband had died of lung cancer, and the generous gift of Lorraine Levin, whose husband also lost his life to cancer, the Center became home to a museum-quality art collection of 122 pieces. The collection includes water colors, pastels, prints, etchings, silk screens, quilts, sculpture, and mixed media from a number of Maryland artists. “The artists are as proud to have their work displayed in the Center as we are to have it here,” says Heller. “This is a first-rate collection befitting a first-rate cancer center.”

The Center later added a Young Chang piano, courtesy of Steve Cohen, owner of Jason’s Music, and Young Chang America. The Center hosts a music series as part of its Art of Healing program.

“There is no question that the medical staff is most important to recovery, but I see cancer therapy as a mixture of science and art” said Kimmel Cancer Center patient Eleanor Metz. “When I walk into the Center and see the grand piano and beautiful artwork, it pulls me in. I almost forget why I’m here. I look at the art pieces, the rich colors, and the ambiance of the building, and I feel as if I’m wrapped in a warm blanket.”

funding for a public health grant focused on community-based cancer prevention, education, and screening programs.

Hopkins clinicians collaborate with colleagues at University of Maryland, Sinai Hospital, the Baltimore City Health Department, and the Department of Health and Mental Hygiene. The primary focus is on prostate cancer because of high incidence rates in Maryland, particularly among African-American men. In 2009, Johns Hopkins, Sinai Hospital, and the Baltimore City Health Department added a colon cancer component.

Since the CRF was established, Maryland’s cancer death rankings have dropped from 3rd to 19th. While the improvement cannot be solely attributed to the CRF, says Kimmel Cancer Center director William Nelson, observing that the reductions in death rates coincided with the dates and scope of the CRF, he believes it is evident that it played a key role.

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Howard and Hopkins Team Up to Reduce High Minority Cancer Rates In Maryland and Washington, D.C., cancer has emerged as one of the leading health threats to African-Americans. To develop a stronger national cancer program aimed at understanding the reasons behind significant cancer disparities and their impact on minority populations, Howard University Cancer Center in Washington, D.C., and the Johns Hopkins Kimmel Cancer Center formed a partnership earning a collaborative grant from the National Cancer Institute.

The goal of the partnership is to enhance the laboratory and clinical cancer research programs at Howard and provide training opportunities at the Kimmel Cancer Center for Howard faculty and increase the accrual of African Americans in clinical trials. The joint research is expected to help both institutions attract new, independent funding in breast, prostate, lung, and GI cancers.

Joint studies have helped uncover unique genetic characteristics of breast cancer that contribute to poor outcomes for African American women; a better understanding of the H. pylori bacteria, more common in the lining of the stomachs of African Americans and linked to the origination of gastric cancers; and explore a common DNA mistake in colon cancer cells, called microsatellite instability. Many more joint studies are ongoing.

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Pain Control in the Palm of the Hand In this high-tech era, handheld data organizers, commonly known as PDAs (personal digital assistants), have become as common to physicians as their pagers and stethoscopes. Kimmel Cancer Center leading cancer pain expert Stuart Grossman, M.D., taking notice of this trend, instantly recognized the opportunity to use these devices to enhance patient care.

Cancer-related pain remains a top concern to cancer patients. More than 90 percent of patients name it as a real fear accompanying a cancer diagnosis, says Grossman. For more than a decade, he has been an international leader in improving the treatment of cancer pain. His most recent contribution is a computerized program that calculates dosages for all forms and types of pain medications. “If a patient is not getting relief on a particular medication, it is common for his physician to switch him to a stronger pain medication. The problem we were encountering, however, is that when the physicians were converting the patient’s current medication to a more potent pain reliever, calculations were often done incorrectly, and patients frequently ended up receiving less total pain medication than they were getting from the original ineffective drug,” explains Grossman.

Now, physicians throughout Hopkins and the world can make accurate conversions by downloading the program from the Center’s Web site [www.hopkinskimmelcancercenter.org /specialtycenters/hop.cfm] onto their PDA. Called HOP, for Hopkins Opioid Program, this free service includes a complete listing of essentially all pain medications used in hospitals.

Users simply select the name and dose of the medication currently being used and the new medication to which they would like to convert. The program calculates the conversion and provides the correct dosage. The program also has built-in safety features providing a warning to users if they select a medication that is an inappropriate or dangerous choice, as well as a registration system.

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To develop a stronger national cancer program aimed at understanding the reasons behind significant cancer disparities and their impact on minority populations, Howard University Cancer Center in Washington, D.C., and the Johns Hopkins Kimmel Cancer Center formed a partnership earning a collaborative grant from the National Cancer Institute.

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Kimmel Cancer Center Called Cancer Research Powerhouse Scientific journals are researchers’ way of disseminating key findings throughout the medical community. Rather than starting from scratch, investigators build upon published discoveries of others. In cancer research, the “others” are most often five Johns Hopkins Vogelstein Kimmel Cancer Center investigators, according to Science Watch, a newsletter published by Thomson Scientific.

With more than 90,000 references between them, the investigators were named in the newsletter as the most frequently cited in cancer research from 1995 to 2005. “The Kimmel Cancer Center solidifies its stance as a research powerhouse in the field of oncology with its researchers accounting for the top five spots in this category,” reports Science Watch.

Calling cancer researchers Bert Vogelstein, M.D., Kenneth Kinzler, Ph.D. James Herman, M.D., Stephen Baylin, M.D., and David Sidransky, M.D., doctors of the decade, Science Watch editor Christopher King said, “The impressive number of citations these exceptional researchers have received is evidence of their profound influence on modern scientific thought."

Kinzler Science Watch compiled the list by using data from Essential Science Indicators(SM) and evaluating institutions based on papers published and cited in clinical-medicine journals indexed by Thomson Scientific.

Vogelstein and Kinzler, who topped the cancer list with more than 50,000 citations, are the leading experts in molecular genetics and were, in large part, responsible for defining cancer as a disease of genetic mistakes.

They have identified the key genetic mutations Herman involved in the development and progression of colorectal cancer and have invented genetic screening tests for people at high risk of developing the disease. More recently, they have deciphered the genetic blueprint for breast, brain, colon, and pancreatic cancers.

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Herman and Baylin are pioneers in epigenetics, or the study of gene alterations that occur without mutating the DNA. Sidransky Instead of mutating, genes are altered by a cellular mechanism known as methylation. When tumor suppressor genes are hypermethylated, they do not function and stop the growth of cells, which may cause cancers to start. Demonstrating how important these changes are, the FDA has recently approved the first demethylating agent, a drug that reduces methylation in genes and restores their function.

Sidransky studies genetic and epigenetic changes in cancer and is a leader in the study of cancer biomarkers, among the earliest molecular changes in the cancer process. His discoveries have been used to develop screening tests for cancer by identifying early markers of cancer in urine, blood plasma, sputum, and other bodily fluids. Sidransky also was among the first to definitively link cigarettes to cancer by identifying the mutation caused by smoking.

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With more than 90,000 references between them, the investigators were named in Science Watch as the most frequently cited in cancer research from 1995 to 2005. “The Kimmel Cancer Center solidifies its stance as a research powerhouse in the field of oncology with its researchers..."

Top Accolades in Cancer Research In 2009 five cancer researchers at the Johns Hopkins Kimmel Cancer Center won top accolades in their field.

Internationally recognized scientist Stephen B. Baylin, M.D., was awarded the Kirk A. Landon-AACR Prize for basic and translaBaylin tional cancer research, along with his colleague Peter A. Jones, Ph.D., D.Sc., director of the University of Southern California/Norris Comprehensive Cancer Center.

Baylin and Jones were selected for their work in the field of epigenetics. Epigenetics refers to modifications of genes other than those changes made to the DNA sequence itself.

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Epigenetic modifications or “marks” generally turn genes on of off. Because genes carry the blueprints to make proteins in every cell of the body, epigentics play a key role in how our cells behave. Baylin and Jones have established there is a major epigenetic component in the onset and progression of cancer.

The Kirk A. Landon-AACR awards are recognized as among the most prestigious international awards given to cancer researchers by a professional society of their peers.

Victor Velculescu, M.D., Ph.D., won the Outstanding Achievement Award in Cancer Research from the American Association of Cancer Research (AACR). The award recognizes young investigators for their contributions to the field.

Velculescu pinpointed the PIK3CA gene as one of the most frequently mutated genes ever identified in human cancer. He also Velculescu developed a method to rapidly identify disease-related genes and measure gene expression called SAGE (Serial Analysis of Gene Expression) and, with his colleagues, developed the first draft genome sequence of the four human cancer types: breast, colorectal, pancreatic, and an aggressive form of brain cancer, called glioblastoma multiforme.

Childhood cancer specialist Donald Small, M.D., Ph.D., received the Frank A. Oski Award from the American Society of Pediatric Hematology/Oncology. The award honors clinicians and basic science investigators in pediatric hematology and oncology who have made significant research contributions to the field.

Small and his team were the first to clone the human FLT3 receptor gene, which is the most frequently mutated gene in acute myelogenous leukemia (AML).

The FLT3 mutation is a predictor of poor survival for Small patients with this mutation.

Discovering that the gene contributes to turning normal hematopoietic blood cells into leukemic cells, From there, Small found small molecules capable of inhibiting the receptor and showed that these drugs would kill leukemia cells with the FLT3 mutation, while leaving normal blood cells unharmed leading to a new targeted therapy for acute leukemia.

Small led the design of clinical trials using one of these drugs, first as a monotherapy and later in combination with chemotherapy for adults with AML. Most recently, the drug has entered clinical trials through the Children’s

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Oncology Group for children with FLT3 mutant AML and infants with acute lymphocytic leukemia (ALL).

The annual Frank A. Oski Memorial Award and Lecture is named for Frank Oski, M.D., an internationally recognized expert in children's blood disorders and nutrition, an outspoken advocate for breast feeding, and a social activist.

As part of his award, Small will deliver the Frank A. Oski Memorial Lecture entitled “FLT3: Biology and Targeting in Leukemia.”

Breast cancer expert Leisha Emens, M.D., Ph.D., earned the Great Baltimore Area YWCA President’s Award for her work in developing a Emens breast cancer vaccine. The award recognizes women who exemplify the YWCA’s tradition of leadership—combining professional excellence with a personal commitment to helping others.

The award was presented to Emens at the YWCA’s 2009 Leader Lunch. This event pays tribute to extraordinary women leaders in the Baltimore metropolitan area, selected for their accomplishments in business, education, and civic life.

Emens began clinical trials on a vaccine to treat breast cancer in 2004, and continues further work in this area today. Recently, her efforts were the basis for a series in the Baltimore Sun titled “Trial of Their Lives,” which chronicled the experiences of four patients.

Bert Vogelstein, M.D., whose published studies of cancer genetics are the most highly cited works in the field, received the American Society of Clinical Oncology “Science of Oncology” Award.

Vogelstein was selected for his role in discovering the specific genes and mutations responsible for colorectal cancer and for establishing a genetic model that explains how most solid tumors form and progress. In addition to discovering these genes, Vogelstein and his team have developed blood tests which are now used to identify patients with inherited mutations in the genes linked to colorectal cancer. They are currently working on the development of non-invasive methods to detect individuals who have early, curable colorectal tumors and to design therapies based on the new understanding of the molecular basis of cancer.

Vogelstein and colleagues recently mapped the complete genetic blueprints for pancreatic brain, breast, and colon cancers.

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PATIENT AND FAMILY PAVILION

Hackerman-Patz

The Hackerman-Patz Patient and Family Pavilion is a home-away-from-home for cancer patients and their families who travel to the Kimmel Cancer Center for treatment.

WHILE COPING with the complex demands of treatment, patients and their families may be away from their homes and away from their social network of support for extended periods. The Pavilion offers a welcoming environment that actively supports medical care while also providing for the practical, psychological, spiritual, and social needs of patients and families.

Through the vision and generosity of Mr. Willard Hackerman and Mr. Sidney Kimmel, the Pavilion has been designed to support patients and their families in coping with these psychosocial demands.

It is located directly across the street from the clinical facilities of the Kimmel Cancer Center and provides affordable lodging for 39 patients and families in specially-designed suites and apartments. Spacious central kitchens and family rooms located throughout the Pavilion provide patients with comfortable spaces to relax and gather with other patients and families.

A library, meditation space, and garden provide private space for quiet reflection. Services such as complementary and integrative medicine, interactive patient and family education, and support groups also are offered at the Pavilion. •

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

Š The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins