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T E M P LE U N I V ER S IT Y S C H O O L O F M EDI CI NE

TRANSFORMATIONS IN HEALTH H I G H L I G H T S O F BA S I C A N D C L I N I C A L R E S E A RC H

2014

Innovations In Science


“ At Temple, our science is on a mission to improve

TABLE OF CONTENTS

human health.” LARRY R. KAISER, MD Senior Executive Vice President for Health Sciences, Temple University Dean and Professor of Surgery,

INTRODUCTION

02-05

TARGET No. 1

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06-19

Temple University School of Medicine President and CEO, Temple University Health System

TARGET No. 2

CANCER 26-35

TARGET No. 3

NEUROSCIENCES

38-45

PIONEERS

46-49

RESEARCH DATA

50-51

“ There is a new level of momentum and purpose among our basic and clinical scientists. We’re doing something special here.” ARTHUR M. FELDMAN, MD, PhD Executive Dean, Temple University School of Medicine Chief Academic Officer, Temple University Health System

LEFT Guided by their own research experiences and

excited by the multiple trajectories of scientific discovery, Dr. Kaiser (left) and Dr. Feldman (right) are leading Temple’s aggressive yet highly focused and opportunistic strategy to find novel treatments for serious diseases.


BUILDING ON THE HUMAN BACKBONE OF RESEARCH

The story of research has a human arc. Biological evolution may lack a human purpose, but not biological research. At Temple Health, we believe research has a very clear end goal: better human health. That’s what drives us. In all our research, from our most basic cell studies to our multicenter clinical trials, we’re always building toward that goal: Helping patients beat disease and regain health.


What is the Human Element of Research? The pace of discovery in biomedical research is astonishing. Each fresh detail about the molecular underpinnings of disease sparks new lines of research. More experiments are run. More results are published. The universe of biomolecular knowledge expands. Translating these mounting scientific discoveries into therapies that improve human health is the mission of researchers at Temple Health. This is the human element of research, and it informs everything we do at Temple. Not just in the lab, but also in caring for patients and educating the next generation of clinicians and scientists, we are always seeking to bend science in a new way that improves human lives—here in our own community and all across America. At Temple, the human element gives our research a direction and an edge. This explicit goal does not restrict our ideas or limit our ambitions. Far from it. This is science with a purpose. This is how energy gets focused. This is how big discoveries get made. This is science on a mission.


ABOVE A trained community member visits with a patient two days after his hospital discharge to assist with medications, tests, and

advice. A goal of these home visits in the Grand Aides Program is for culturally trusted partners to reduce readmissions by 30% to 40%.


HOW CAN WE TRANSFORM THE RESEARCH ENTERPRISE? The need for translational medicine is clear. Every day, the scientific knowledge base spins off opportunities for breakthrough medicine. But finding footholds for the long climb from discovery to preclinical tests and clinical trials is a challenge. The familar problems: too much information, ultra-fast change, finite resources. At Temple Health, to meet this challenge, we are transforming our research enterprise by:

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INTRODUCTION


OUR RESEARCH TELLS THE STORY We have taken bold steps. Invested strategically. And our progress is plain to see. From new state-of-the-art labs... to research-driven leaders at the helm of Temple Health... to top

WHERE INSTITUTIONAL STRENGTHS MEET PATIENT NEEDS

researchers recruited here from other institutions... to our national NIH rankings. All these indicators tell part of the story. But we believe our vision for translational research is best illustrated by the research itself—its quality, its potential human impact, and its sheer innovation, exuberance, and diversity. In this report, we highlight several dozen of the most powerful and promising lines of Temple translational research. As you will see, Temple researchers are exploring dozens of novel disease pathways. At every turn—with computers and test tubes, with animal models and human trials—we are hunting for new treatment targets. In many projects, we have already hit these targets—with small molecules, biologicals, and cell- and gene-based therapy— to validate mechanisms and, again, push the science closer to the clinic and improved human health. Even a brief review of our research portfolio reveals the quality of our work—and shows why many peers now say Temple’s research is world-class.

TEMPLE’S PATIENT-FIRST COMMITMENT:

High Outpatient/Inpatient Volumes | Clinical Trials/Registries | Strong Record

of Diversity in Patient Recruitment for Research | Rural Health Programs | Community Partnerships | Outcomes Research Healthcare Disparity/Literacy Initiatives | Public Policy Dialogue | Care for Underserved Communities | Education | Surveys

INTRODUCTION

5


How can we help patients faster?

What can I do that has not been done?

How can we find the root causes — and radically new cures — for heart and lung diseases?

Stem cells, shown here, could revolutionize treatments for heart attack and heart failure. Temple researchers recently proved in animal studies that stem cells—including, surprisingly, cortical bone-derived stem cells —can repair the heart by secreting healing factors and engrafting as new myocardial cells.

{ Why not } B ORROW T OOLS AN D MODELS F ROM OT HER DISEAS ES AN D DISCIP LIN ES?


Target No. 1

HEART | LUNG Many Temple researchers focus on the cellular and molecular mechanisms of heart disease. Their insights into the biology of the heart are opening doors for more targeted treatments—from novel pharmaceuticals and biologicals to therapies with genes, RNA interference, stem cells, and devices. Our faculty based at the Cardiovascular Research Center, the Center for Translational Medicine, the Thrombosis Research Center, and the Center for Metabolic Disease pursue research in heart muscle disease, vascular biology, transplant immunology, drug cardiotoxicity, venous thrombosis, hemorrhagic and inflammatory diseases, tumor angiogenesis, personalized medicine, and long-term disease management. Our pulmonary researchers, working out of the Center for Inflammation, Translational, and Clinical Lung Research, specialize in deciphering the inflammatory and immune aspects of chronic and acute lung diseases. Their goal is to develop novel therapeutics and interventions to slow or reverse diseases such as chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary fibrosis, and pulmonary hypertension. The Temple Lung Center, one of the country’s top pulmonary referral and research centers, works closely with researchers at Temple and at other institutions to offer dozens of clinical trial opportunities to patients every year. Today, over 100 faculty, fellows, and graduate students are engaged in translational cardiovascular or pulmonary research at Temple Health. Our primary lines of research are sketched on the following pages.

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7


HOW CAN WE REDUCE INJURY AND PROMOTE REPAIR IN THE DAMAGED HEART? Two Rays of Hope for the Injured Myocardium In the natural course of recovery after myocardial infarction (MI), downstream areas of the heart muscle inevitably die. Scars form. Heart walls thin. Patients worsen. Temple researchers want to intervene much earlier—while the patient is still in the cath lab —to prevent this post-MI remodeling and heart failure. In one line of research, Steven R. Houser, PhD, and his colleagues are testing growth factors, bone-marrow derived stem cells, genes, and special biomaterials that might protect the post-MI heart or help regenerate myocardial growth. They hope to inject these agents near the damaged area via a NOGA-guided catheter system immediately after revascularization. ABOVE Cortical bone stem cells may

work better than marrow- or cardiac-derived cells for repairing the heart; transdifferentiation and paracrine signaling are key mechanisms in improving cardiac function and survival with bone-derived stem cells.

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In another major line of heart failure research, Dr. Houser’s group discovered a hidden calcium channel that activates cardiac hypertrophy in stressed myocardial cells but—uniquely—does not reduce cardiac contractility. By blocking this rare calveolin-3 L-type Ca2+ channel his lab hopes to halt harmful remodeling while preserving pumping strength.


GRK2 INHIBITION —WILL IT REVERSE HEART FAILURE? Knocking on New Doors in the Diseased Heart Abnormal beta-adrenergic receptor (βAR) signaling dampens the heart’s contractile and rate responses to inotropic simulation—hallmark signs of distress in the injured or failing heart. A team led by Walter J. Koch, PhD, discovered that the G-protein coupled receptor kinase 2 (GRK2), when upregulated in heart failure, acts on the βAR to trigger those classic maladaptive responses. Dr. Koch’s lab has now tested cardiac gene therapy—in animal models and cultured human myocytes—with viral vectors carrying the gene for βARKct, a novel peptide that inhibits GRK2. Their studies indicate βARKct may halt or even reverse post-ischemic heart failure. The actions appear to be additive, or even synergistic, to old-fashioned current therapy with βAR blockade. The team is now on a fast track to test anti-GRK2 gene therapy in humans, partnering with Temple cardiac gene therapy specialists such as Joseph E. Rabinowitz, PhD, to construct the best viral delivery capsule. Temple’s viral vector team has already succeeded in delivering the gene for an anti-GRK2 peptide, creating an array of re-engineered adeno-associated virus (AAV) vector serotypes capable of targeting not only cardiomyocytes but also adrenal and endothelial ABOVE Adeno-associated viral (AAV) gene

transport vectors can be targeted to the heart—and away from the liver­—with the integration of special elements such as cardiac-biased promoters and Mir122 binding sites. Here, bioluminescence shows decreased vector-associated luciferase signal in the upper abdominal region of Balb/c mice receiving AAV9 with Mir122 binding sites (+Mir122 BS).

tissues—all now being evaluated in animal models. In related research, Dr. Koch’s group is working with Temple heart failure specialists and surgeons to find the best intracoronary delivery route for direct βARKct administration. They have also identified several non-βAR actions of GRK2. In the adrenal gland, for example, hyperexpression of this kinase drives sympathetic nervous system hyperactivity—another telltale sign of heart failure.

HEART | LUNG

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Iso:

0 min

2 min

30 min

SAME RECEPTOR … DIFFERENT RESULTS? Probing the Jekyll-and-Hyde-Like Functional Selectivity of Cardiac Receptors Douglas G. Tilley, PhD, was a researcher at Duke University when the concept of functional selectivity originated. This new view of cardiac receptors explained how, for example, one ligand may stimulate cardiac G protein-coupled receptors (GPCRs) to trigger maladaptive signaling after cardiac stress, while a different ligand may induce cardioprotective signaling. Today at Temple, Dr. Tilley explores one particularly intriguing alternate personality of the β1-adrenergic receptor (β1-AR). While the classic G-protein-dependent pathway of β1-AR is well known—its deleterious effects are targeted by β1-blockers—Dr. Tilley’s lab is exploring a G-protein independent pathway through β-arrestin that leads to transactivation of the epithelial growth factor receptor (EGFR) and cardioprotective ABOVE Stimulation of feline

cardiomyocytes with isoproterenol (ISO) shows that ß1-adrenergic receptor (red) and ß-arrestin 2 (green) rapidly associate at plasma membrane (arrowheads) and in t-tubule striations (arrows), with lingering interactions still seen at 30 minutes.

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outcomes. Similarly beneficial alternate pathways of other GPCRs, including the angiotensin II type 1 receptor have been found. Understanding the molecular mechanisms and functional outcomes of such split-personality signaling through cardiac GPCRs will aid in the rational development of “biased ligands”—agents that simultaneously promote cardioprotective signaling and block maladaptive events— for the treatment of heart failure, hypertension, and coronary artery disease.


WHAT’S THROWING FUEL ON THE FAILING HEART? Altered Energy Metabolism, Oxidative Stress, and Heart Failure Employing a range of customized animal models and ex vivo measurements, Fabio Recchia, MD, PhD, has traced a pathophysiological chain reaction of heart failure mechanisms leading from altered energy substrate selection to sustained functional damage. The ground-breaking central hypothesis of Dr. Recchia et al. is that the decompensated heart switches from free fatty acid oxidation to enhanced glycolysis and glucose oxidation. This, in turn, boosts NADPH supply to superoxide-generating enzymes and accelerates oxidative stress and myocardial damage.

ABOVE Novel experimental models of

heart failure, when probed with exacting hemodynamic and echocardiographic assessments, reveal molecular pathways that may lead to new therapeutic approaches.

In other work, Dr. Recchia’s lab is exploring the cytoprotective and antiapoptotic (but minimally angiogenic) actions of the little-studied vascular endothelial growth factor B (VEGF-B). They are testing the VEGF-B receptor (VEGFR-1) as a potential on/off switch in human cardiomyopathy—an approach that may open a completely new front on the war against heart failure.

HEART | LUNG

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WHAT COMBINATION OF CELL SIGNALS UNLOCKS THE DOOR TO INFLAMMATION? Cross-Talk Between Receptors Chemokine and opioid receptors help regulate many inflammatory and immune responses. Precisely how these and other G-protein coupled receptors (GPCR) operate in these supremely complex processes is a mystery. At Temple, Thomas J. Rogers, PhD, and his colleagues have focused on how cross-talk between receptors either ramps up or inhibits inflammation and also how receptor cross-regulation leads to heterologous desensitization—a newly recognized process wherein activation of one GPCR type turns off a second GPCR type. ABOVE In certain inflammatory diseases,

macrophages become activated and fuse to form large multi-nucleated giant cells. Here, a giant cell (blue) has been activated in an immune response to HIV (green).

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HEART | LUNG

These receptor mechanisms are active in many disease states and that is why Dr. Rogers’ work spans the Temple research spectrum—from studies of disease pathogenesis, immune modulation, or biomarker identification to the development of therapies for inflammatory conditions, cancer, HIV/AIDS, and other infections.


“ Temple has one of the most active pulmonary research programs in the country. All this research creates deeper levels of care and new hope for our patients with debilitating lung disease.” – GERARD J. CRINER, MD

FROM CYTOKINE SUPPRESSION TO SMARTPHONE REMINDERS —WHAT HELPS THE PATIENT? Lung Research that Reflects Patient Needs Over the past decade, Temple has been a national leader in clinical and basic science research projects related to chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, and other serious lung conditions. From analyses of diaphragm function and respiratory muscle recruitment to national studies of new drugs, biologicals, devices, and smartphone-based telemedicine, this team’s wide-angled clinical research agenda reflects the technical competencies as well as the entrepreneurial energies of Temple’s pulmonary faculty. In all this work, Gerard J. Criner, MD, and his pulmonary team have stressed inclusion of patients who reflect the racial/ethnic diversity of the surrounding community. In basic research, Dr. Criner and his team focus on underlying mechanisms of major lung diseases. They possess particular expertise in endothelial cell biology, inflammatory cytokines, mucin expression, and immunoregulatory activity. Many of their studies have drawn correlations between novel biomarkers and disease phenotype, progression, or treatment effects.

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“ In many pulmonary diseases there is a paucity of data on

Control (Sham Surgery)

pathophysiology in racial minorities. Our diverse community is helping us fill this gap.” – STEVEN G. KELSEN, MD

Sepsis

Sepsis + PKCδ Inhibitor

ATHEROSCLEROSIS CAUSES HEART DISEASE. WHAT CAUSES PULMONARY DISEASE? Dissecting Mechanisms of Lung Disease Several Temple researchers are investigating inflammatory, immune, or infectious processes in the lung. From biochemistry to epidemiology, Temple scientists are leaders in the worldwide movement to better understand the root causes of lung disease and develop novel treatment approaches.

> Steven G. Kelsen, MD, focuses on chronic obstructive pulmonary disease (chronic

bronchitis and emphysema) and on the impact of specific stressors like cigarette

smoke on alveolar, airway epithelial, and immune cell function. Dr. Kelsen uses

a variety of proteomic, cellular, and molecular techniques to study cells and tissues

obtained from at-risk or diseased individuals. Results are correlated with patient

genotype or phenotype, pharmaceutical treatment, and population factors such as

racial/ethnic background. Dr. Kelsen has two main goals: to determine the cellular

and molecular mechanisms that underpin lung damage and to identify the individual

susceptibility factors that confer lung risk.

> How neutrophils flip from host defender to inflammatory instigator in the lung ABOVE PKC kinases are signaling transducers for diverse biological functions; inhibitors of specific PKC isoforms can regulate inflammatory responses as shown in this animal experiment where a novel PKCδ inhibitor protected against sepsis-induced acute respiratory distress syndrome.

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—as in acute respiratory distress syndrome—is the question being asked by

Laurie Kilpatrick, PhD. Her laboratory is investigating the signaling pathways that

control neutrophil migration and release of toxic oxygen radicals and proteases.

One such pathway involving Protein Kinase C delta (PKCδ) is now targeted in

preclinical studies with novel PKCδ inhibitors. The goal is to protect the lung

from neutrophil-mediated inflammatory diseases.


WHAT HAPPENS AT THE LUNG-AIR INTERFACE? The Elements of Oxygen Exchange Temple’s research expertise in the physiology of airway and alveolar surface structures has contributed directly to many clinical advances in treating respiratory failure and other advanced lung diseases.

> To prevent long-term lung damage in preterm infants or mature injured lungs,

Marla R. Wolfson, PhD, and Thomas H. Shaffer, PhD, have pioneered the use of

perfluorochemical liquids to inflate and oxygenate the at-risk lung. With liquid

instead of gas ventilation, the lung gains protection from mechanical pressure,

biotrauma, and inflammation. Dr. Wolfson’s team is defining the impacts of the

liquid-liquid interface on lung morphology and inflammation, and also exploring

its potential to enhance intrapulmonary delivery of anti-inflammatory or anti-oxidant

drugs, proteins, or genes. Her laboratory is also exploring the novel use of

intranasal perfluorochemicals for hypothermic brain neuroprotection and

developing aerosolized peptide-containing synthetic surfactants for non-invasive

delivery during nasal continuous positive airway pressure.

> Airway surfaces rely on mucus to trap and clear bacteria, viruses, and other airborne ABOVE An array of new molecular

structures have biomedical applications, including a unique perfluorochemical nanocrystal formulation with promise in improving pulmonary drug delivery.

particles. Kwang Chul Kim, PhD, has discovered that mucin 1 (MUC1), a glycoprotein

made by the underlying epithelial cells, acts via toll-like receptors to reduce

inflammation in the aftermath of respiratory infections. Dr. Kim’s team is developing

drugs to boost MUC1 function and to prevent mucus hypersecretion as a way to

control diseases such as chronic obstructive pulmonary disease and cystic fibrosis.

HEART | LUNG

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Control

HHcy

HHcy + Hcy-lowering

HOW DOES HYPERHOMOCYSTEINEMIA TRIGGER ENDOTHELIAL DYSFUNCTION? A Risk Factor that Rivals Smoking and Hyperlipidemia Hong Wang, MD, PhD, and her Temple group are national leaders in the search for a cure for hyperhomocysteinemia (HHcy), an amino acid metabolic disorder that is a potent independent risk factor for cardiovascular disease. Dr. Wang’s team discovered a unique biochemical mechanism by which HHcy causes DNA methylation suppression selectively in endothelial cells—an action that delays post-injury endothelial repair and contributes to vascular remodeling and spontaneous atherosclerosis. Dr. Wang’s laboratory also described a mechanism by which HHcy causes potassium channel dysfunction and impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation of resistance arterioles. They have made the case that inhibition of small- or intermediate conductance Ca2+ may trigger the EDHF-mediated responses that presage at herothrombic disease. Recently, they reported that HHcy causes systemic and vessel wall inflammation via promoter inflammatory monocyte subset differentiation.

ABOVE Atherosclerotic fatty plaque

thickening (bright red) in the aortas of hyperhomocysteinemia (HHcy) mice is effectively reversed using Hcy-lowering vitamin therapy (HHcy+).

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Ongoing studies with a novel array of models (e.g., metabolic, epigenetic, transgenic mouse) and advanced molecular techniques are aimed at verifying the exact risk triggers of HHcy—and then blocking them to elicit protective vascular effects. Impaired insulin receptor signaling is also being probed in HHcy and other high-risk vascular states.


OW HF Control

12W HF

WHAT SPARKS FORMATION OF ATHEROSCLEROTIC LESIONS? An Immune Angle on Vascular Inflammation T cell regulation, homeostasis, and apoptosis play critical roles in regulating cancer and autoimmune disease. Xiao-Feng Yang, MD, PhD, believes immune mechanisms also govern the early stages of vascular inflammation induced by metabolic stresses such as hyperlipidemia, hyperglycemia, hyperhomocysteinemia, uremia, and obesity. Using database mining and other novel tools, the team has discovered molecular events involving alternative splicing, micro-RNA suppression, immune regulatory cytokines, and caspase-1 activation.

ABOVE In an atherogenic mouse model, a high-fat (HF) diet produces atherosclerotic plaque in the aortic artery at 12 weeks. This gene-deficient model is speeding characterization of immune gene function in chronic inflammatory pathology.

IS PHOSPHOLEMMAN A POTENTIAL LEVER IN TREATING MULTIPLE DISEASES? A Gatekeeper of Ion Transport Phospholemman (PLM) is highly expressed in the heart. Joseph Y. Cheung, MD, PhD, and his research partners examine the overlapping and complex interactions between PLM and Na+-K+ ATPase, the Na+/Ca+ exchanger, and the L-type Ca2+ channel. Their novel genetic models have shed light on physiological roles for PLM in regulation of cardiac ABOVE Molecular interactions between

FXYD proteins such as phospholemman and sodium pump subunits determine the function and tissue specificity of these ion transport regulators.

contractility. In particular, this group has proposed that PLM preserves inotropy while reducing arrhythmia risks during stress. As these and other mechanisms are clarified, opportunities for novel rational therapies have emerged窶馬ot only in cardiac disease but also in neurological and renal diseases.

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Case Studies in Vascular & Cardiovascular

INNOVATION AT TEMPLE


CELL THERAPY FOR CRITICAL LIMB ISCHEMIA Eric T. Choi, MD, is a vascular surgeon who performs endovascular interventions for diabetic patients with limb-threatening ischemia or infection. Preventing amputations is his goal. For patients not eligible for revascularization, Dr. Choi is researching novel nonsurgical therapies to stimulate vessel, bone, and tissue repair. In one Temple clinical trial, Dr. Choi offers patients autologous bone marrow therapy—basically extracting the patients’ own bone marrow cells and directly injecting these cells into the ischemic tissue to help increase circulation and increase amputation-free survival.

BENDING THE TECHNOLOGY TO FIT THE PATIENT Howard A. Cohen, MD, is an interventional cardiologist responsible for several advances in percutaneous coronary intervention. Of particular note: his pioneering efforts in radial (wrist) artery access for angioplasty and his participation in the development of cannulation of the TandemHeart™, a percutaneous left ventricular assist device that supports the heart during complex coronary interventions. His newest lines of research at Temple— including “hybrid” catheter-plus-minimally invasive surgical techniques, percutaneous partial left heart bypass, gene therapy, and percutaneous methods for valve repair and replacement—promise further gains in coronary care, especially for high-risk patients such as the elderly, those in cardiogenic shock or with acute MI, or those with comorbidities or complex coronary blockages.

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The Home-Field

ADVANTAGE IN RESEARCH

To beat diseases like heart failure and cancer you need every possible edge. Where you do your research —the actual built environment of facilities—can really make a difference. Temple’s magnificent Medical Education and Research Building (MERB) provides a vibrant interdisciplinary hub for team science. This building provides all the lab space, equipment, and support needed for comprehensive state-of-the-art research. This 11-story structure is now filled with Temple researchers. To a scientist’s eye, the utter functionality of the MERB research space only enhances the building’s striking physical beauty. The building’s research-centric design and advanced technologies make it highly conducive to sustained experimentation and rapid scale-up. Abundant light and open-air adjoining laboratories encourage cross-project interactions. Just a few years old, our research building has already created a home-field advantage that has helped convince many researchers and students to join the Temple research team.

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Hotbeds

OF RESEARCH

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Most researchers maintain a base within one of our Temple Research Centers. While these centers support the efforts of faculty, graduate students, and postdoctoral fellows, their boundaries are porous by design. Faculty usually hold appointments in both basic science and clinical departments and consult regularly with colleagues in other centers, at other universities, and with clinicians at Temple University Hospital and affiliated clinical centers. Where lines of research intersect we have also created shared resources —technology cores, service centers, administrative support, and community outreach teams—that eliminate duplication and build research quality and efficiency. Research Centers at Temple University School of Medicine: > Cardiovascular Research Center > Center for Bioethics, Urban Health and Policy > Center for Inflammation, Translational and Clinical Lung Research > Center for Neurovirology > Center for Obesity Research and Education > Center for Substance Abuse Research > Center for Translational Medicine > Comprehensive NeuroAIDS Center > Fels Institute for Cancer Research & Molecular Biology > Fox Chase Cancer Center > Shriners Hospitals Pediatric Research Center > Sol Sherry Thrombosis Research Center > Temple Autoimmunity Center > Center for Bioengineering Research LEFT Research is a team activity, and Temple is a team environment.

The network of Dr. Walter Koch illustrates the collaborative and interdisciplinary nature of research today. Partnering with colleagues from Temple, Dr. Koch can easily share resources and equipment, trade insights, and complement skills and knowledge across disciplines. Project-driven work with other universities, government agencies, and industry are also common. Temple’s size, focus, organization, and leadership foster such complex and nimble networks. 23


We see the

HUMAN FACE OF RESEARCH

ABOVE Studying the slight epigenetic differences between monozygotic (identical) twins allows Temple cancer researchers like Nora Engel, PhD, to determine how DNA is modified during development and over the course of a lifetime by factors such as pesticide exposure and delayed reproduction. Insights into epigenetics are being exploited to develop more personalized medicine.

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Research evolves. Knowledge expands. Treatment becomes more individualized, safer, more effective. By including more diverse populations in our studies and by using genomics, expression analysis, and information sciences, we are inching closer to an era of custom therapies for patients. At Temple, we are partnering with our patient community and using the full toolkit of modern research to speed development of personalized medicine.

SECTION | SECTION

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MAKE EXISTING CANCER TREATMENTS

Which cell signal is the ideal target?

MORE EFFECTIVE?

Why does animal DNA repair differ from human DNA repair?

HOW CAN WE

When is my hypothesis ready for first-in-human testing?

Philadelphia chromosome. The vast majority of patients with chronic myelogenous leukemia have a distinctive abnormal swapping of chromosomal segments (between chromosomes 9 and 22). This “Philadelphia chromosome” was co-discovered by researchers at Fox Chase Cancer Center, a breakthrough that prompted development of highly effective targeted treatments. note: This is a corrected copy. The original report inaccurately linked the awarding of a Nobel Prize for work done by Fox Chase Cancer Center researchers in 30the co-discovery SECTION | SECTION of the “Philadelphia chromosome.” We apologize for that error.

{ What } COMES AF T ER T HE H U MAN GENOME P RO JECT ?

Why is that one gene turned on in cancer?


Target No. 2

CANCER Cancer researchers at Fox Chase Cancer Center and Fels Institute for Cancer Research & Molecular Biology aim to understand the etiology and pathogenesis of cancer and to translate their findings into targeted anti-cancer therapies. One of only 41 National Cancer Institute-designated Comprehensive Cancer Centers in the U.S., Fox Chase has long been at the forefront of scientific discovery. In 2012, Fox Chase became part of Temple University Health System, opening the door to a range of new collaborations. Researchers at Fox Chase can now, for example, capitalize on unique technical capabilities residing within the Temple Proteomics Facility and Temple School of Pharmacy’s Moulder Center for Drug Development Research. New collaborations among Temple’s cancer researchers are already far advanced in the critically important field of epigenetics. To jump-start more collaborations— in areas such as cancer signaling, synthetic lethality, and personalized medicine— Temple leadership recently created a $1 million venture fund to seed the most promising ideas.

CANCER

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“ Fox Chase has a tremendous history of contributions to the fight against cancer. In partnering with Temple, we have created a model of the modern integrated approach needed for translational, and truly transformative, cancer research. Today, many of our more than 130 cancer researchers stand on the threshold of human testing with novel therapies.” – RICHARD I. FISHER, MD

President and CEO, Fox Chase Cancer Center – Temple Health

Senior Associate Dean, Temple University School of Medicine


EPIGENETIC DRUG

WHAT IF WE REWRITE EPIGENETIC TAGS IN CANCER CELLS? Exploiting Bookmarks in the Genetic Code At the Fels Institute and Fox Chase, more than 30 Temple researchers are working together to understand how epigenetic changes that block or boost gene expression can lead to cancer, aging, and age- or environmental-related conditions such as diabetes and neurodegeneration. This is now one of the major epigenetic programs in the country. The Temple Epigenetic Cancer Drug Discovery group led by Jean-Pierre Issa, MD, has already identified epigenetic molecules and pathways that can be targeted to treat cancer. Dr. Issa’s work helped lead to FDA approval of decitabine (which affects DNA methylation) as a standard of care in myelodysplastic syndrome. Temple is providing certain services (and conducting a clinical study) for a pharmaceutical company regarding a novel DNA methylation inhibitor called SGI-110 that is being developed for use in acute myeloid leukemia. The group is also exploring the epigenetic correlates of aging, environmental and nutritional exposures, and developmental factors. Nora I. Engel, PhD, at the Fels Institute along with Alexei V. Tulin, PhD, Alfonso Bellacosa, MD, PhD, and others at Fox Chase also study how specific genes are regulated, imprinted, mutated, and repaired in ways that affect development of cancer.

> Dr. Engel’s group uses a gamut of in silico, in vitro, and in vivo techniques to

explore the precise biomolecular mechanisms that dictate epigenetic modifications.

> Dr. Tulin and his team want to know how the nuclear enzymes PARP1 and

TOP Cancer cells use epigenetics to turn off an artificial gene that makes them glow green. BOTTOM Epigenetic drugs edit the bookmarks and restore the green color.

PARG act on chromatin and heterochromatin, respectively, to activate or silence

transcription of specific genes—a line of research that is uncovering new therapeutic

targets amenable to small molecule inhibition or gene reprogramming.

> Dr. Bellacosa and his partners focus on the role of the DNA repair enzymes TDG

and MBD4 in removing epigenetic marks represented by DNA methylation and other

DNA modifications. They are studying how abnormal persistence of these epigenetic

marks leads to profound developmental defects and is involved in turning off

hundreds of cancer-blocking genes.

CANCER

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DOESN’T ACHILLES HAVE ANOTHER HEEL? Synthetic Lethality: A Two-Hit Strategy for Crippling Cancer For decades, geneticists have known about synthetic lethality—the condition when two gene mutations are lethal to a cell or organism while the presence of only one or the other mutation does not cause death. At Fox Chase, Igor Astsaturov, MD, PhD, and Erica Golemis, PhD, work with new high-throughput screening approaches to find mutations or signaling networks that allow cancer cells to dodge the effects of anti-cancer therapies. In this manner, they have identified specific enzymes that, if blocked, could synergistically enhance the therapeutic effect of existing agents. Recently the team has focused on improving the anticancer activity of EGFR (epidermal growth factor receptor) inhibitors. Their clinical partners have already speeded ahead with clinical trials to combine existing signal blockers with new agents in patients with esophageal, lung, or head/neck cancer. Even as the clinical trials progress, researchers at Fox Chase continue the hunt for linked mechanisms within cancer cells. Targeting these overlapping signals with combination therapy may not only prevent tumor resistance, it may also open the door to completely new two-hit ABOVE Targeting the epidermal growth

factor receptor (EGFR) on the surface of tumor cells elicits powerful anti-cancer effects, but many cancer cells become resistant. Looking for ways to overcome this resistance, Temple researchers have studied the movement of EGFR receptors (shown in green) after drug binding and found that some remain on the cell surface while others are engulfed inside the cell via bubble-like endosomes.

strategies for our most difficult-to-treat cancers.

BUT HOW DOES IT WORK? From Genome to Proteome… to 3-D Structure Knowledge of the amino acid sequences of proteins has exploded, greatly outpacing the progress of structural biologists in determining the associated three-dimensional shapes that dictate the precise action of proteins and protein complexes within the cell. Roland L. Dunbrack, Jr., PhD, is a molecular modeler whose new computational tools ABOVE Insulin-like growth factor 1 (IGF1) receptor, implicated in several cancers, acts by passing a phosphate group between its own subunits (“autophosphorylation”), a key step in kinase activation that is depicted in this molecular model.

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CANCER

are breaking this backlog. Dr. Dunbrack’s team at Fox Chase has created an array of methods for homology modeling, fold recognition, molecular dynamic simulations, and protein data base analysis. Their new libraries, maps, and software tools are helping scientists envision the finest-scale biological interactions of kinases, antibodies, cell-surface receptors, and other proteins and their complexes.


“ We are examining the genomic and cellular signaling perturbations in select human cancers —and our goal is to identify suitable targets for intervention in cancer.” – JONATHAN CHERNOFF, MD, PhD

HOW DOES TWEAKED PHOSPHORYLATION LEAD TO NEOPLASTIC TRANSFORMATION? Oncogenic Signals: A Trail of Clues in the Cell To solve crimes, detectives follow the money. To cure cancer, researchers follow the protein kinases. These enzymes transmit signals inside cells—their currency is phosphorylation—and they often become hyperactive in cancer. Acting on orders from GTPases like Cdc42 and Rac, they regulate downstream molecules to alter cell motility, proliferation, or survival. In the labs of Jonathan Chernoff, MD, PhD, the large family of p21-activated kinases (PAKs) is under surveillance. The goal is to identify the substrates that take the PAK phosphorylation payoff to pull the trigger and disrupt cell function. The Fox Chase group is studying PAK activity in disease models of neurofibromatosis, mesothelioma, breast cancer, and noncancer conditions. They are also exploring the role of protein tyrosine phosphatase 1B in cancer. Jeffery R. Peterson, PhD, takes a wide-lens view of the more than 500 human protein kinases identified thus far. His team has created high-throughput screening techniques and other biochemical, microscopic, and cell and animal models to characterize and catalog the “kinome.” This systems-level analysis has led to identification and testing of drug-like molecules capable of inactivating kinase function that could lead to new cancer therapies. The group led by Joseph R. Testa, PhD, was the first to link AKT kinase to human cancer. Since that seminal finding, Dr. Testa’s laboratory went on to identify genes that overlap and interact with this major AKT oncogenic pathway. They also discovered that specific tumor suppressors elevate the risk of highly invasive malignant mesothelioma. Their recent BAP1 findings prompted development of a test for early detection of mesothelioma and led to recognition of a cancer susceptibility known as BAP1 Syndrome.

CANCER

31


HOW DOES INFLAMMATION FOSTER COLORECTAL CANCER? Immunity, Inflammation, and Cancer As hematopoietic stem cells mature and give rise to distinct blood cell types, genes flash on and off like railyard switches to control the branching direction and ultimate fate of this maturation. Those same genetic switches, as illustrated in Temple work described here, likely regulate the destiny of cancer cells.

> David L. Wiest, PhD, discovered that the strength of T cell receptor signaling

determines the type of T lymphocyte a progenitor will become, and those signals

regulate a ribosomal protein Rpl22, which not only steers normal T cell development,

but also contributes to T cell acute lymphoblastic leukemias.

> Dietmar J. Kappes, PhD, employs unique knockout and transgenic animal models to

study T lymphocyte lineage commitment and effector functions. His group identified the

transcription factor ThPOK as a master regulator of CD4 T lymphocyte commitment.

> Richard R. Hardy, PhD, and colleagues study signaling events that direct B cells

in their highly ordered development from early and transitional stages to the

mature B cell. How the immunoglobulin heavy chain VDJ structure influences

this process is one of their key questions.

ABOVE In a zebrafish model, primary B

cell development is evident in the kidney (red + green = yellow transgene reporter indicating early B and/or T lymphocyte) while T cell development is focused in the thymus (only green indicating mature B cells or reindicating early T cells).

32

CANCER

> Sergei Grivennikov, PhD, explores the functional interactions between immune

cells and cancer cells—and in particular how the resulting inflammatory

microenvironment might promote tumorigenesis (as in colitis-associated neoplasia)

or, in certain settings, actually quell the disease.


IS THIS NEW THERAPY READY FOR HUMAN TESTING? Clinical Trials: Testing the Promise When a new anticancer agent looks promising in preclinical testing, Fox Chase is perfectly positioned to confirm that promise in first-in-human (Phase 1) clinical trials. These critical early milestones are achieved with the help of the Developmental Therapeutics Program and the Phase I Early Drug Development Program (led by Anthony J. Olszanski, MD, RPh) through major collaborative efforts that bring together ABOVE Fox Chase researchers now lead

trials to find biomolecular signatures that will help select patients with head and neck cancer who can benefit from less intensive therapies. The urgency of such efforts to adjust treatment strategies based on the underlying cancer pathobiology and prognosis has been highlighted by the recent wave of oropharynx cancers related to HPV infection (shown here).

basic science researchers and physicians. These groups speed the translation of ideas between laboratory and clinic, while also ensuring the highest standards in IRB-approved study design, safety, and ethics. Today at Fox Chase, nearly 200 clinical trials are underway at any given time. Many of these trials are testing first-in-class agents or novel methods or tests. Early-phase clinical trials are a priority and a strength at Fox Chase—a fact recognized by the National Cancer Institute in its long-standing designation of the institution as a Comprehensive Cancer Center.

CANCER

33


Case Studies in

CANCER PREVENTION RESEARCH

ABOVE Increasingly, cancer therapy is personalized based on an individual’s tumor genetics and—as shown in this pedigree of hereditary breast/ovarian cancer syndrome—family history.


CANCER RISK ASSESSMENT The Risk Assessment Program at Fox Chase helps patients understand the genetic factors that increase cancer risk. Led by Mary B. Daly, MD, PhD, this clinical team of oncologists, nurses, and genetic counselors offers personalized cancer risk assessment and counseling to families and individuals. The group’s first-hand knowledge of the expanding power of genetic risk assessment also informs their basic research and registry-based longitudinal studies, which are aimed at better defining and quantifying the biological, genetic, and environmental factors that increase cancer risk. Special studies on communicating cancer risk and optimizing decision-making are also underway.

COLORECTAL CANCER SCREENING AND PREVENTION The Chairman of Medicine at Fox Chase, David S. Weinberg, MD, MSc, leads a far-ranging search for better colorectal cancer screening methods. Only half the U.S. population is appropriately screened by current standards. Dr. Weinberg and his partners have dug deep to find the reasons for this poor screening acceptance and they have also tested new educational strategies—such as spousal support tools and web-based interventions—aimed at boosting screening rates. Looking beyond the current era of colonoscopy-centric screening, the team is also developing and evaluating new molecular and genetic markers as well as stratification tools and emerging technologies that might sharpen estimates of risk especially for individuals considered at average risk of gastrointestinal cancer.

BIOMARKER DISCOVERY AND CHEMOPREVENTION Identifying precancerous alterations as early as possible—and then intervening with chemopreventive agents to halt disease development—is the mission in the laboratories of Margie L. Clapper, PhD. Her group employs genomic and imaging technologies to detect the first molecular inklings of cancer. These molecular changes, they believe, may serve both as early biomarkers of cancer risk and as targets for intervention in the development of cancer, in particular colorectal and lung cancer. In Dr. Clapper’s recent studies, serial monitoring of murine colon tumors by MRI and endoscopy has provided novel insight into how tumors grow and respond to therapy over time. Significant progress has been made in using new bioactivatable fluorescent probes to identify abnormal areas of colon tissue before they are detectable as visible lesions.

CANCER

35


Feel the

HUMAN IMPACT OF RESEARCH

ABOVE Much of the most exciting medical research at Temple today merges new molecular or gene-based approaches with device- or surgeryrelated treatments. Howard Cohen, MD, leads the way in these emerging hybrid techniques and his special coronary interventions are already giving more patients relief and hope without the need for major surgery.

40

SECTION | SECTION


Biomedical research results in new knowledge—and new therapies including drugs, biologicals, cell- and gene-based therapies, devices, or novel radiological, surgical, and interventional procedures. These new therapies directly impact the quality and duration of human life. It is this potential for a powerful human impact that motivates and directs Temple researchers.

SECTION | SECTION

37


Neurogenesis in the adult mouse brain. Dividing neural stem cells are labeled in red/green/light blue.

42

SECTION | SECTION

In Alzheimer’s disease, is amyloid cause or effect?

Do immune cannabinoid receptors modulate inflammation?

Is there a better animal model for Alzheimer’s disease?

CAN PARPS TIGHTEN THE BLOOD BRAIN BARRIER?

{ How } D O H I V- I N F E C T E D M AC RO P H AGE S R E S I ST A N T I R E T ROVI RA L T HE RA PY?


Target No. 3

NEUROSCIENCES Faculty from over 13 basic and clinical science departments at Temple now participate in neuroscience research focused on neurodegeneration, neuroinfection, neuroinflammation, and neurooncology. In these areas, Temple researchers—basic scientists working side by side with clinicians—seek to understand the molecular events that lead to devastating diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, AIDS dementia, cerebral palsy, and pediatric and adult brain tumors. The goal is to create better tests and more effective therapies. The Temple Neurosciences Program first gained international recognition for its pioneering work in neurovirology and especially neuroAIDS. This deep expertise in the pathogenesis of neurotropic viruses has led to important findings in both viral and non-viral associated neurologic disorders. This special focus also played a role in the National Institute of Mental Health recently awarding Temple an $8 million grant for the Comprehensive NeuroAIDS Core Center. Now, as promising treatment leads emerge, this group has attracted additional funding to speed multidisciplinary translation efforts. A new laboratory for the Center for Neurovirology and Department of Neuroscience has been built, additional faculty have been hired, and several joint international research efforts are underway.

NEUROSCIENCES

39


HOW DO VIRUSES CAUSE NEURODEGENERATION? CNS Viruses: Targets and Tools Viruses that inhabit the central nervous system contribute to many neurological diseases. Kamel Khalili, PhD, leads Temple neuroscientists in a quest to understand how these neurotropic viruses, such as HIV-1 and JCV, get into the brain, how they replicate there, and how they trigger their distinctive pathologies. One immediate aim of their work is to improve tests and treatments for the debilitating neurological problems so often seen in HIV/AIDS patients or others with immunodeficiencies. But these viruses are more than targets. Viruses that naturally infect the brain can also be exquisite research tools for probing the tangled molecular and cellular pathways that lead to neurodegeneration, neuroimmune disorders, and neuroproliferative disease. In pursuing these goals, the Temple group draws from several departments and they engage in basic science and animal experiments as well as clinical testing. For example, the work of Jennifer Gordon, PhD, in developing knock-out and transgenic mice has greatly accelerated understanding of how viral reactivation contributes to neuronal proliferation and migration, neurocognition, neurite outgrowth, and tumorigenesis. Based on this neurovirology team’s strong track record of accomplishment, the NIH ABOVE Immunostaining of the mouse

brain shows Pur-alpha in the cytoplasm of neurons within the dentate gyrus.

40

NEUROSCIENCES

recently awarded Temple a major grant to create the Comprehensive NeuroAIDS Core Center—one of only nine such centers in the U.S.—and translational advances have been made on several fronts.


HOW DO VIRUSES GET INTO THE BRAIN AND ALTER IMMUNITY? Hidden HIV Reservoirs in the Brain Thinking about HIV/AIDS, most physicians naturally focus on T cells. But it turns out that HIV also invades the innate immune system in the brain—creating deep-seated reservoirs of infection and contributing to AIDS-induced neuropathogenesis. The laboratory of Jay Rappaport, PhD, at Temple was one of the first to show that perivascular and microglial macrophages are infected by HIV in the central nervous system. Their subsequent findings in this area, recently awarded a patent, prove that a specific monocyte subset expands with unchecked HIV infection, dampening immunity ABOVE Photomicrograph (magnification

400X) of human brain specimen derived from a patient with HIV encephalitis. The formalin-fixed brain section was stained with an antibody to the major HIV-1 viral core protein, p24 (red). Cells (microglia) which are producing virus appear red as a result of the staining process.

and creating pockets of drug resistance throughout the body. The Temple group believes that co-opting of the monocytes/macrophages may be a central survival strategy for HIV as it is for certain tumors. They are now testing compounds which could prevent differentiation of monocytes into the immunosuppressive macrophage subset or block immunosuppressive pathways.

NEUROSCIENCES

41


WHY DOES THE BLOOD BRAIN BARRIER LEAK DURING INFLAMMATION? Tight Junction Dysfunction: The Need for Neuroprotection in the CNS The brain floats in a world of its own. Specialized endothelial cells lining the brain’s capillaries try to keep it that way. It’s the tight junctions between these endothelial cells that prevent chemicals, bacteria, viruses, and other foreign substances from passing into the brain’s extracellular fluid from the blood circulation. For over a decade now, this privileged environment of the brain—and the so-called blood brain barrier (BBB) that protects it—have been the focus of research for Temple’s Yuri Persidsky, MD, PhD. His laboratory was one of the first to elucidate mechanisms of BBB breakdown during alcohol or methamphetamine abuse and also with HIV infection. In recent years, Dr. Persidsky and his colleagues have dissected the contributions of oxidative stress, inflammation, and viral infection to a leaky BBB and they have also tested novel therapies to reverse BBB permeability. Wen-Zhe Ho, MD, MPH, explores a different aspect of CNS neuroprotection: innate TOP Brain microvessels (red) and brain

immunity. Dr. Ho is especially interested in how HIV and HCV escape from host defense

macrophages (green) at rest.

mechanisms (e.g., RIG-I, toll-like receptor TLR-3) and how drugs of abuse abet

BOTTOM Microglial macrophages activated by neuroinflammation.

42

NEUROSCIENCES

virus-induced breaches of CNS neuroprotection. This Temple team is now designing immunity-based treatments for patients infected with HIV and/or HCV.


Control

LentiGFP

Fluorescence

LentiVIP/GFP

HOW IS IL-23 UPREGULATED IN AUTOIMMUNE DISEASES? New Windows on Neuro-Immune Signaling Look closely at diseases with strong inflammatory or autoimmune components and, more often than not, you will see abnormal outbursts of signaling between the neuroendocrine and immune systems. Doina Ganea, PhD, has built a menagerie of animal and cell models to generate these sparks, trace their molecular pathways, and then counter them with disease-targeted therapies. Dr. Ganea recently used a lentiviral vector to insert the gene for vasoactive intestinal peptide (VIP)—a powerful immunosuppressive neuropeptide—into dendritic cells, a first step toward her goal of cell-mediated gene therapy that suppresses immune responses in multiple sclerosis (MS). Dr. Ganea’s team is also testing an agent that blocks the cannabinoid 2 (CB2) receptor to reduce inflammation in MS, stroke, and spinal cord injury. Another major line of Temple research aims to understand the role of N-3/N-6 lipids— such as prostaglandinE2—that spike during inflammation. Temple researchers were ABOVE When dendritic cells engineered

to express vasoactive intestinal peptide (VIP) were injected into mice with experimental autoimmune encephalomyelitis (EAE), symptoms were reduced compared to controls, with lower levels of pro-inflammatory cytokines and higher levels of anti-inflammatory IL10. The results show the promise of VIP-expressing dendritic cells in treating patients with multiple sclerosis.

the first to show that PGE2 boosts dendritic cell production of the pro-inflammatory interleukin-23 and they are now testing a variety of PGE2 inhibitors in models of diabetes, rheumatoid arthritis, and inflammatory bowel disease. Temple researchers including Stefania Gallucci, MD, are performing several other studies related to the breakdown of immunological tolerance and autoimmune disease— research with clinical implications for tolerance induction, vaccine development, transplantation, and immune augmentation in a variety of diseases.

NEUROSCIENCES

43


“ For some, finding better ways to treat substance abuse doesn’t have the appeal of curing cancer or heart disease. But this disease takes a huge toll on our society. By revealing the biological mechanisms of addiction, we get closer to treatments that can turn lives around. We also, inevitably, discover fundamental neurobiological systems that have implications in other human diseases.” – ELLEN UNTERWALD, PhD

HOW DO DRUGS OF ABUSE HIJACK ENDOGENOUS PHYSIOLOGICAL PATHWAYS? The Science of Substance Abuse Addiction to cocaine, opioids, or amphetamines is a brain disease. Ellen Unterwald, PhD, and her research partners at the Center for Substance Abuse Research (CSAR) examine the neuro-pharmacologic basis for the mix of powerful and complex human behaviors that define addiction. The pre-clinical research performed in this P30 Center funded by the National Institute on Drug Abuse is wide ranging. For example:

> Dr. Unterwald has documented that blocking a specific serotonin receptor

reduces anxiety produced by cocaine withdrawal, thereby helping to prevent

relapse to cocaine abuse.

> CSAR studies have shown that specific chemokines released during inflammation

dampen the analgesic effects of morphine—a finding that led Martin W. Adler, PhD,

and Alan Cowan, PhD, to test novel chemokine receptor antagonists as a way to

boost opioid efficacy in the treatment of neuropathic pain and other challenging

clinical situations.

> Research led by Mary E. Abood, PhD, has defined the full diversity of actions of

44

NEUROSCIENCES

the endogenous cannabinoid system in cell physiology, neuronal cell fate and,

specifically, the neurodegenerative disease amyotrophic lateral sclerosis (ALS).

Tests of drugs that act on cannabinoid receptors by Dr. Abood and her Temple

colleagues have demonstrated reductions in inflammation and tissue damage in

animal models of stroke, graph rejection, multiple sclerosis, and ALS.


HOW DO DIET AND STRESS LEAD TO ALZHEIMER’S? New Targets for Neurodegenerative Disease Therapies Diet and long-term stress have long been linked to neurodegenerative diseases. Temple scientists recently outlined the biochemical pathways by which these environmental and behavioral factors, as well as aging, may predispose individuals to cognitive decline. New agents that block these pathways are nearly ready for testing in humans. In one recent breakthrough, Domenico Praticó, MD, and colleagues showed that the 12/15 lipoxygenase (LO) enzyme is an endogenous regulator of beta-secretase (beta site APP-cleaving enzyme, or BACE)—the key enzyme known to create amyloid fragments that clump together to form the hallmark amyloid plaques seen in the brains of Alzheimer’s patients. They have now developed a small molecule capable of passing through the blood brain barrier and blocking 12/15LO in a way that, as shown in animal ABOVE Amyloid plaque deposited

outside neurons and neurofibrillary tangles inside neurons are the signature toxicities found within brains of patients with Alzheimer’s disease.

models, reduces plaque, and improves memory. In related research, Dr. Praticó’s group has shown that 5LO regulates the formation of tau protein, which causes the tangles associated with frontotemporal dementia. The group is now creating potent 5LO inhibitors for patients with this under-appreciated form of neurodegeneration.

NEUROSCIENCES

45


New

PIONEERS AT TEMPLE

A vibrant biomedical research institution requires continual investment in talent. New researchers don’t just sustain existing programs—they tend to produce the most surprising, radically divergent, and occasionally brilliant ideas that can lead to completely new treatments. At Temple today, we recruit many of the nation’s brightest early-stage researchers into our target areas of heart/lung, cancer, and neurosciences. These faculty are the research pioneers of the future. FROM LEFT TO RIGHT Wissam Chatila, MD; John W. Elrod, PhD; Toby Ferguson, MD, PhD; Victor Kim, MD; Madesh Muniswamy, PhD; Richard Pomerantz, PhD; Pamela Roehm, MD, PhD; Jonathan Soboloff, PhD; and Emily J. Tsai, MD.

50

NEUROSCIENCES


1

2

3

4

5

6

7

8

9


1

WISSAM CHATILA, MD

Immune Factors in COPD Pulmonologist Wissam Chatila, MD, was one of the first to win a Temple Faculty Development Award—the Department of Medicine’s two-year $150,000 grant intended to jump-start junior faculty research careers. The grant allowed Dr. Chatila to thrive, creating a balance of clinical and research responsibilities that continues to this day in his K08-funded studies of adaptive immunity in COPD.

2

JOHN W. ELROD, PhD

The Protocols of Dying Heart Cells When cells in the heart are injured, as occurs in heart failure, they do not just spiral into molecular chaos and die a random death. Myocardial cell death on the cellular level is, surprisingly, a much more orderly event than originally thought. John W. Elrod, PhD, Assistant Professor in the Center for Translational Medicine, is deciphering the genetic and molecular scripts that initiate signaling—especially mitochondrial calcium signaling —in the injured heart cell and the resultant physiological processes that culminate in cellular necrosis or cardioprotection.

3

TOBY A. FERGUSON, MD, PhD

Distress Signals at the Axon-Glial Interface Hoping to improve nerve recovery—and patient function—after nervous system injury, Toby Ferguson, MD, PhD, is picking apart the complex axon-glial interactions that mediate peripheral and central nerve loss and regrowth. As part of his K08 award at Shriner’s Hospitals Pediatric Research Center, he is searching for genes involved in axon degeneration and regeneration. Several clear signals of interest have been detected within the cacophony of expression that follows nerve injury, and Dr. Ferguson is now testing these proteins in models of disease and injury.

4

VICTOR KIM, MD

Inflammation and Mucus in COPD Another past winner of the Temple Faculty Development Award, Victor Kim, MD, works within the Center for Inflammation, Translational and Clinical Lung Research to pursue his interests in small airway disease, inflammation, and mucus metaplasia as they relate to COPD. Dr. Kim recently received an NIH K23 award to investigate the role of Th17 cytokines in chronic mucus hypersecretion and chronic bronchitis.

5

MADESH MUNISWAMY, PhD

Calcium in the High-Voltage Mitochondria Preventing calcium overload in mitochondria is an uphill battle. As mitochondria generate ATP they become pools of negative voltage in a vast cytoplasmic sea of positively charged calcium ions. Madesh Muniswamy, PhD, is trying to determine what prevents a damaging crush of positively charged calcium ions from flooding into the mitochondria. His group recently found that loss of MCUR1 protein shuts off calcium uptake into the mitrochondria while ablation of another MICU1 protein influenced mitochondrial Ca2+ overload during resting conditions. Dr. Muniswamy’s team is exploring how therapeutic manipulation of mitochondrial calcium channel activators might prevent cell damage and disease.


6

RICHARD POMERANTZ, PhD

Hardware for DNA Restoration In human cancer cells, DNA repair mechanisms are often broken. Richard Pomerantz, PhD, leads efforts to understand the role of DNA repair machinery in both normal genome maintenance and cancer pathogenesis. His K99-funded work is searching for drugs that inhibit DNA polymerase theta, a repair protein that is upregulated in most breast cancer cells. Dr. Pomerantz’s team aims to develop drugs that target cancers cells for personalized medicine.

7

PAMELA ROEHM, MD, PhD

A Virus Hidden in the Nerves Vestibular neuritis is a common cause of vertigo, Bell’s palsy, and certain forms of hearing loss. It is often triggered by reactivation of a dormant infection with herpes simplex virus (HSV) type 1. Pamela C. Roehm, MD, PhD, created one of the first laboratory models capable of emulating the HSV1 eruptive lytic infection. In her K08 research, Dr. Roehm is exploring how neurotrophins may trigger viral reactivation.

8

JONATHAN SOBOLOFF, PhD

A STIMulis for the Cell’s Economy Stromal interaction molecules (STIM) are critical in maintaining a proper concentration of intracellular calcium—acting as a kind of central bank to release internal supplies of the ion and, when needed, tapping extracellular stores. These fluxes in calcium mediate a vast range of both short-term (contraction, secretion) and long-term (mitogenesis, differentiation, and survival) cellular events. Recent investigations by Jonathan Soboloff, PhD, Associate Professor in the Department of Biochemistry and at the Fels Institute for Cancer Research and Molecular Biology are providing new insights into STIM’s modulation of the physiological economy of the cell and its potential therapeutic role in cancer, arthritis, and immune diseases.

9

EMILY J. TSAI, MD

The Middlemen in Intracellular Signaling Emily J. Tsai, MD, Assistant Professor of Medicine and Physiology, is a researcher in the Cardiovascular Research Center. She studies regulation of cyclic GMP, a second messenger in the myocardium where it regulates contractility, hypertrophy, and cell death. Dr. Tsai’s team is finding targetable points in the cGMP signaling cascade to disrupt cardiovascular disease. Exploring a link between beta-adrenergic blockade and specific cGMP compartments, Dr. Tsai won the 2012 Jay N. Cohn New Investigator Award in Basic Sciences from the Heart Failure Society of America (HFSA).


TEMPLE UNIVERSITY SCHOOL OF MEDICINE FY’13 RESEARCH DATA*

90.7

MILLION DOLLARS NIH FUNDS GRANTED

334

16

207

NIH RESEARCH GRANTS

CORE RESEARCH CENTERS

PRINCIPAL INVESTIGATORS

316

FULL-TIME FACULTY

* Includes Temple University School of Medicine and its affiliated hospitals (Fox Chase Cancer Center, Weis Center for Research - Geisinger Clinic and Allegheny-Singer Research Institute- West Penn Allegheny Health System).

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RESEARCH DATA


TEMPLE UNIVERSITY SCHOOL OF MEDICINE RANKINGS

NEUROSCIENCE DEPARTMENT RANKS**

PHYSIOLOGY DEPARTMENT RANKS**

18th

20th

in the nation for total neuroscience research grant funding awarded by the NIH

in the nation for total physiology research grant funding awarded by the NIH

PHARMACOLOGY DEPARTMENT RANKS**

TEMPLE UNIVERSITY SCHOOL OF MEDICINE RANKS

24th

54th

in the nation for total pharmacology research grant funding awarded by the NIH

as the best research-oriented medical school in the nation for 2015 per U.S. News and World Report

** Source: Blue Ridge Institute for Medical Research. Blue Ridge is a non-profit group based in North Carolina that ranks academic departments of U.S. medical schools according to the amount of federal grant funding they attract.


Temple University School of Medicine

LEADERSHIP ADMINISTRATION

DEPARTMENT CHAIRS

Larry R. Kaiser, MD

Anatomy and Cell Biology | Steven N. Popoff, PhD

Senior Executive Vice President for Health Sciences Temple University

Anesthesiology | Rodger Barnette, MD Biochemistry | Dianne R. Soprano, PhD (Interim)

Dean and Professor of Surgery Temple University School of Medicine

Clinical Sciences | Susan Fisher, MS, PhD

President and CEO Temple University Health System

Emergency Medicine | Robert McNamara, MD

Dermatology | Gil Yosipovitch, MD

Family and Community Medicine | Stephen Permut, MD, JD Arthur M. Feldman, MD, PhD Executive Dean Temple University School of Medicine Chief Academic Officer Temple University Health System

Medicine | Joseph Y. Cheung, MD, PhD Microbiology and Immunology | Doina Ganea, PhD Neurology | S. Ausim Azizi, MD, PhD Neuroscience | Kamel Khalili, PhD Neurosurgery | Michael Weaver, MD Obstetrics, Gynecology and Reproductive Sciences | Enrique Hernandez, MD Ophthalmology | Jeffrey D. Henderer, MD

Verdi J. DiSesa, MD, MBA

Orthopaedic Surgery and Sports Medicine | Pekka Mooar, MD (Interim)

Vice Dean for Clinical Affairs and Professor of Surgery Temple University School of Medicine

Otolaryngology - Head and Neck Surgery | John H. Krouse, MD, PhD

Chief Operating Officer Temple University Health System

Pathology and Laboratory Medicine | Yuri Persidsky, MD, PhD Pediatrics | Stephen C. Aronoff, MD, MBA Pharmacology | Walter J. Koch, PhD Physical Medicine and Rehabilitation | Ian Maitin, MD, MBA Physiology | Steven R. Houser, PhD

Richard I. Fisher, MD

Psychiatry and Behavioral Science | William R. Dubin, MD

President and CEO Fox Chase Cancer Center – Temple Health

Radiology | Charles A. Jungreis, MD

Senior Associate Dean Temple University School of Medicine

52

LEADERSHIP

Radiation Oncology | Curtis Miyamoto, MD Surgery | Selwyn O. Rogers, Jr., MD, MPH Urology | Jack Mydlo, MD


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of purpose, our supporters are speeding progress in hundreds of research projects that aim to transform lives here at home and around the world.

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Temple University School of Medicine - Highlights of Basic and Clinical Research - 2014