Dr. Gomella elected to the Clinical Society of Genitourinary Surgeons

Dr. Leonard Gomella

Dr. Leonard Gomella

Leonard G. Gomella, MD, The Bernard W. Godwin Professor of Prostate Cancer, Chairman, Department of Urology, Associate Director, Jefferson Kimmel Cancer Center, Clinical Director Jefferson Kimmel Cancer Center Network, Editor-in-Chief, Canadian Journal of Urology has been elected to the Clinical Society of Genitourinary Surgeons. This is considered one of the most prestigious societies in the field with active membership limited to 25 of the top academic urologists in the US.



Jefferon’s Kimmel Cancer Center Holds 5th Annual Men’s Event

Jefferson’s Kimmel Cancer Center hosted its 5th Annual Men’s Event to benefit prostate cancer research and awareness at the Prime Rib Restaurant on November 14.

Below are some photos of the night, award ceremony and entertainment provided by Comedy Central’s “100 Greatest Stand-Ups of All Time,” Jim Breuer of Saturday Night Live.


“Spirit of Caring” Awardee:

Wm. Kevin Kelly, D.O.

Professor, Medical Oncology and Urology,
Director, Division of Solid Tumor Oncology

The “Spirit of Caring Award” is presented to an individual to recognize outstanding leadership in cancer research and the hope they hold for improving the quality of life in every community.

“Spirit of Courage” Awardee:
Anthony DiPrimio, PhD

Author, Prostate Cancer: What Men Need to Know About this Disease and Its Treatment

The “Spirit of Courage Award” is presented to an individual who has demonstrated great personal courage, strength and dignity while battling cancer and supporting others in their fight against cancer.

“Spirit of Commitment” Awardee:
Neal Rodin

President, International Financial Company, LLC

The “Spirit of Commitment Award” is presented to an individual to recognize outstanding commitment to supporting the work of the Kimmel Cancer Center through personal and professional contributions dedicated to finding a cure.

“Spirit of Innovation” Awardee:
Dendreon:
The company applies its expertise in antigen identification, engineering and cell processing to produce active cellular immunotherapy (ACI) product candidates designed to stimulate an immune response. They pioneered a novel, first in class autologous immunotherapy first approved for the treatment of advanced prostate cancer. Dendreon is headquartered in Seattle with corporate operations based locally in the Delaware Valley and manufacturing plants in Georgia and California.

The “Spirit of Innovation” Award is presented to an organization whose innovation in cancer measurably improves business and/or clinical processes that impact product development, prevention programs, research, or patient care.



ACS-IRG Pilot Projects Awarded for 2013

Left to Right: Dr. Jordan Winter, Dr. Lara Weinstein, Dr. Aejaz Sayeed, Dr. Richard Pestell, Dr. Tali Gidalevitz, Larry Slagle, Ruth Ann Dailey, Dr. Marja Nevalainen

The Jefferson Kimmel Cancer Center hosted the Annual ACS-IRG Luncheon on September 17th to announce the 2013 Pilot Project award recipients from Thomas Jefferson University. Awardees include Sheikh Aejaz Sayeed, PhD from the Department of Cancer Biology; Jordan Winter, MD, from the Department of Surgery; Yaron Moshel, MD, PhD from the Department of Neurological Surgery; Tiffany Avery, MD, MPH from the Department of Medical Oncology; Lara Carson Weinstein, MD, MPH from the Department of Family & Community Medicine and from Drexel University,  Tali Gidalevitz, PhD from the Department of Biology. Each Awardee briefly explained their research projects to Ruth Ann Dailey, Vice President, Corporate and Distinguished Partners and Larry Slagle, Distinguished Giving Director, of the East Central Division of the American Cancer Society. Ms. Dailey and Mr. Slagle explained the ACS mission and offered ways in which the Pilot Project recipients would be able to assist them in that mission.



A Link between Hormones and DNA Repair Provide New Clues to Treat Advanced Prostate Cancer

Karen Knudsen, Ph.D.

For advanced prostate cancers, new strategies for therapeutic intervention are urgently needed, and require a better understanding of how tumor cells go from slow growth to aggressive behaviors that threaten patient lives.

A new study, published by Thomas Jefferson University’s Kimmel Cancer Center researchers in the September 11th online edition of the journal Cancer Discovery, showed that hormones promote DNA repair, and that this process is critical for prostate tumor cell survival. The research also revealed a new therapeutic target that has potential for improving management for patients with advanced disease.

“We’ve known for decades that in prostate cancer, disease development and progression are dependent on the action of androgens (testosterone), but the means by which androgens promote these events remain poorly defined,” says lead author Karen Knudsen Ph.D., Professor of Cancer Biology at Thomas Jefferson University and the Deputy Director for Basic Science at Jefferson’s Kimmel Cancer Center. “The concept that androgens assist cancer cells in repairing DNA damage helps to explain how tumors evade therapeutic intervention. The good news is that these discoveries may point toward a new way to treat patients with aggressive disease.”

Inhibiting androgens is the first line of treatment for advanced prostate cancers, but this therapeutic strategy is only transiently effective, generally because tumors develop “rescue” pathways to restore androgen action. To try and understand the implications of this process, and to find means for treating such advanced disease, the researchers identified new molecular pathways involved in relaying messages from the androgen receptor to DNA repair genes. They found that androgens enhanced DNA repair by turning on the gene for a powerful DNA repair enzyme called DNAPK.

When the researchers inhibited DNAPK, they saw a reduction in tumor cell growth, and using disease models, observed that standard therapies were more effective. By acting on a more selective target in the androgen pathway, the researchers hope to improve androgen inhibition strategies and to help patients who no longer respond to androgen-inhibition-based therapies.

“These findings give us new insight into how tumors can evade existing therapies. Most importantly, the fact that prostate cancer cells use androgens and DNAPK to survive therapeutic intervention unveiled an Achilles heel for advanced tumors that we can capitalize on,” said Dr. Knudsen.

The researchers discovered that pharmacologic agents, some of which are already in clinical trials for other malignancies, can be used to suppress DNAPK activity. “The next step for us is to translate these findings into the clinical setting. Luckily, our prostate group is highly collaborative, and we are already in the midst of designing clinical trials to fast-track DNAPK inhibitors into the clinic”, said Dr. Knudsen. “There are always challenges in introducing new therapeutic targets, but if we are correct, there is every reason to believe that DNAPK inhibitors can be used to improve outcomes for patients with advanced disease.”

The study from Dr. Knudsen’s laboratory was a result of an inter-institutional team effort, including contributions of the first author and graduate student Jonathan F. Goodwin, key collaborators from the Thomas Jefferson University Department of Radiation Oncology, Dr. Adam P. Dicker, and Dr. Robert B. Den, and from the University of Michigan, Dr. Felix Y. Feng.

The authors declare that they have no conflicts of interest.

Media Only Contact:
Edyta Zielinska
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 9/11/2013



KCC Researchers Awarded $480,000 from Breast Cancer Research Foundation

Richard Pestell, MD, PhD and Andrew Quong, PhD

The Breast Cancer Research Foundation recently announced that Dr. Richard Pestell and Dr. Andrew Quong received unanimous approval for studies in breast cancer, the second most prevalent cancer-related cause of death in women in the United States.

Beginning October 1, 2013, Dr. Pestell will receive $240,000 to continue the “Molecular Genetic determinants of Breast Cancer Stem Cells” study and Dr. Quong will receive $240,000 to continue the “Clinical Proteomics for Breast Cancer Diagnostics” study.

Dr. Pestell’s study will focus on basal breast cancer including triple negative breast cancer, defined by the absence of three receptors (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [HER2]). Triple negative breast cancer is prominent among African-American women, and currently no targeted therapies for this type of breast cancer exist. Within human breast cancer a subset of cells have characteristics of stem cells (BTIC), which may contribute to recurrence and therapeutic resistance. The mechanism by which the gene DACH1 inhibits BTIC is being determined as a new approach to enhance therapeutic responsiveness. Dr. Pestell’s findings over the last year that DACH1 binds to and enhances function of the p53 tumor suppressor, but fails to bind mutations of p53 identified in human breast cancer, adds further weight to the original hypothesis that DACH1 is a breast tumor suppressor. Dr. Pestell’s studies in 2012-2013 will continue to define the role of endogenous DACH1 as a breast cancer suppressor.

Support from BCRF has also allowed Dr. Quong to complete his studies examining changes in protein levels in breast tumors. From these observed changes, Dr. Quong’s team found changes in the metabolism of tumor cells that are related to the local microenvironment of the tumor. These changes in metabolism can potentially be exploited for both imaging and drug development. In addition, Dr. Quong has continued his work identifying markers that are indicators of toxicity and response to therapy.

In 2012-2013, the goal of Dr. Quong’s research is to determine new strategies for patient treatment that include radiation therapy. By measuring the protein and gene expression in tumors, his will use this information for choosing treatment and also monitoring the patients’ response to treatment both for effectiveness and adverse side effects.



Researchers Find New Clues to Treat Rare and Aggressive Inflammatory Breast Cancer

Massimo Cristofanilli, M.D.

A study led by investigators from Thomas Jefferson University’s Kimmel Cancer Center has discovered molecular clues that may help physicians therapeutically target inflammatory breast cancer (IBC), a highly aggressive form of breast cancer.

Their study, reported in the June 21 online issue of Breast Cancer Research and Treatment, identified two molecules (ALK and FAK1) involved in the IBC cancer pathway. Drugs already exist that inhibit both of these two cancer-promoting proteins at the same time, which the researchers are now testing in animal preclinical studies.

“Women diagnosed with inflammatory breast cancer are in great need of therapies that are tailored to this aggressive form of breast cancer. Survival rates are much lower than for other forms of breast cancer,” says the study’s lead author Sandra V. Fernandez, Ph.D., Assistant Professor in the Medical Oncology department at Jefferson.

IBC is a particularly aggressive and highly metastatic form of breast cancer characterized by very rapid onset of progression— weeks to a few months — and metastasis that spreads quickly to the brain, bones, and soft tissues. The three-year survival rate is 40 percent for IBC patients compared with 85 percent in other forms of breast cancer. Additionally, IBC patients are younger when diagnosed.

The disease is also difficult to diagnose because it appears as redness and swelling of the breast. There are no classic tumor masses.

“Because of how this cancer looks, physicians often think it is dermatitis, or inflammation, or an infection, such as mastitis. I know of many patients who were misdiagnosed from the start, and by the time they were referred to an oncologist, their cancer had progressed,” says the study’s senior investigator, Massimo Cristofanilli, MD, FACP, Professor of Medical Oncology and Director of the Jefferson Breast Care Center.

“We need to improve both diagnosis and treatment of this cancer, which is on the rise for reasons that are not understood,” he says.

The advances reported in the study were possible because the research team developed a new animal model of IBC, derived from tumor  cells from a patient with metastatic triple negative (estrogen receptor-negative, progesterone receptor-negative, Her2-negative) inflammatory breast cancer under an IRB-approved study. At the present, there are few animal models to study this particular disease.

In addition to identifying some of the pathways involved in IBC, the researchers were able to characterize the pattern of spread of the disease, which moved quickly to organs and the brain. They found that clumps of the cancer — not tumor masses — obstruct lymphatic channels in the breast, causing the swelling of breast tissues.

“This animal model is a really important tool to use to study IBC progression and metastasis, and to test potentially beneficial drugs,” says Dr. Fernandez.

Researchers from the University of Texas M D Anderson Cancer Center and Fox Chase Cancer Center contributed to the research.

The study was supported by the American Airlines-Komen for the Cure Foundation Promise Grant KGO81287, NIH NCI 1R01 CA 138239, and the Inflammatory Breast Cancer Foundation.

The authors declare that they have no conflicts of interest.

For more information, contact Jackie Kozloski, 215-955-5296, jackie.kozloski@jefferson.edu.



Protein in Blood Exerts Natural Anti-Cancer Protection

Renato V. Iozzo, M.D.

Researchers from Thomas Jefferson University’s Kimmel Cancer Center have discovered that decorin, a naturally occurring protein that circulates in the blood, acts as a potent inhibitor of tumor growth modulating the tumor microenvironment.

The study, published June 24 online in the Proceedings of the National Academy of Sciences (http://www.pnas.org/content/early/2013/06/19/1305732110.abstract), suggests it may be possible to harness the power of this naturally occurring anticancer agent as a way to treat cancer, including metastases.

In several different publications it has been described the ability of decorin to affect a number of biological processes including inflammatory responses, wound healing, and angiogenesis.

In this new article, the study’s senior investigator, Renato Iozzo, M.D., Ph.D., has labeled decorin a “soluble tumor repressor” — the first to be found that specifically targets new blood vessels, which are pushed to grow by the cancer, and forces the vessel cells to “eat” their internal components. This reduces their potential to feed the cancer overall causing an inhibition of tumor progression.

“The tumor suppressors we all know are genes inside tumors that a cancer deletes or silences in order to continue growing. I call decorin a tumor repressor because its anti-tumor activity comes from the body, outside the cancer,” says Dr. Iozzo, Professor of Pathology & Cell Biology, Biochemistry & Molecular Biology at Kimmel Cancer Center.

“Decorin is a soluble compound that we found has a powerful, natural protective effect against cancer — an exciting finding that we believe will open up a new avenue for both basic research and clinical application,” Dr. Iozzo says. “Acting from the outside of the cells, decorin is able to modify the behavior of the cancer cells and of the normal cells in order to slow down the progression of the tumor. For this reason, decorin acts as a guardian of the matrix, the complicated structure built around the cells in our body.”

Absence of decorin promotes tumor growth

Decorin has long been known to be involved in human development. It is so named because deposits of decorin “decorate” collagen fibrils after the human body forms.

A second pool of decorin has been found circulating in blood after production by connective tissue throughout the body. This connective tissue is part of the extracellular matrix, which provides both structural support and biological regulation of tissue cells.

But no one has understood the biological function of this second pool of decorin, according to Dr. Iozzo.
The research team, including the two co-first authors, Simone Buraschi, Ph.D., and Thomas Neill, a graduate student, who work in the laboratory of Dr. Iozzo, decoded the function of soluble decorin. They found that addition of exogenous decorin to the tumor microenvironment induces autophagy, a mechanism by which cells discard unnecessary or damaged intracellular structures. “This process regulates a lot of cellular activities,” says Dr. Iozzo.

The researchers specifically found that decorin evoked autophagy in both microvascular and macrovascular endothelial cells — cells that line the interior surface of blood vessels.

“This matters because autophagy can exert a potential oncosupressive function by acting to discard critical cell components that would otherwise be involved in promotion of tumor growth through angiogenesis, the production of new blood vessels that can provide nutrition to the tumor,” Dr. Iozzo says. “In contrast, absence of decorin permits tumor growth.”

Therefore, the presence of decorin in the surroundings of the tumor is essential to control tumorigenesis and formation of new blood vessels, he says. Moreover, Dr. Iozzo’s laboratory has characterized for the first time Peg3, a known tumor-suppressor gene, as a master player in the autophagy process induced by decorin. “This discovery is important as it opens up to the study of new unexplored genes and signaling pathways in the field of autophagy,” he says.

“Circulating decorin represents a fundamental cellular process that acts to combat tumor angiogenesis,” Dr. Iozzo says. “Treatment based on systemic delivery of decorin may represent a genuine advance in our ongoing war against cancer.”

The study was funded by the National Institutes of Health grants R01 CA39481, R01 CA47282, and R01 CA120975.

Collaborating researchers from LifeCell Corporation, in Branchburg, New Jersey, and Goethe University in Frankfurt, Germany, also contributed to the study.

For more information, contact Jackie Kozloski, 215-955-5296, jackie.kozloski@jefferson.edu.



Researchers Discover Molecule That Drives Aggressive Breast Cancer

Richard G. Pestell, M.D., Ph.D.

Recent studies by researchers at Thomas Jefferson University’s Kimmel Cancer Center have shown a gene known to coordinate initial development of the eye (EYA1) is a powerful breast tumor promoter in mice. The gene EYA1 was also shown to be overexpressed in a genetic breast cancer subtype called luminal B.

The scientists found that excess activity of this gene —EYA1 — also enhances development of breast cancer stem cells that promote resistance to cancer therapy, recurrence, and poor survival.

Because EYA1 is an enzyme, the scientists are now working to identify a natural compound that could shut down EYA1 activity, says Richard Pestell, M.D., Ph.D., Director of Kimmel Cancer Center.

“It was known that EYA1 is over-expressed in some breast cancers, but no one knew what that meant,” he says. “Our studies have shown the enzyme drives luminal B breast tumor growth in animals and the enzyme activity is required for tumor growth.”

In a mouse model of aggressive breast cancer, the research team targeted a single amino acid on the EYA1 phosphatase activity. They found that inactivating the phosphatase activity of EYA1 stopped aggressive human tumors from growing.

“We are excited about the potential of drug treatment, because it is much easier to develop a drug that targets a phosphatase enzyme like EYA1, than it is to target a gene directly,” he says.

Tracing how EYA1 leads to poor outcomes

The study, which was published in the May 1 issue of Cancer Research, examined 2,154 breast cancer samples for the presence of EYA1. The researchers then linked those findings to patient outcomes. They found a direct relationship between increased level of EYA1 and cyclin D1 to poor survival.

They then chose one form of breast cancer —luminal B — and traced the bimolecular pathway of how EYA1 with cyclin D1 increases cancer aggressiveness. Luminal B breast cancer, one of five different breast cancer subtypes, is a hormone receptor-positive form that accounts for about 20 percent of human breast cancer. It is more aggressive than luminal A tumors, a hormone receptor-positive cancer that is the most common form of breast cancer.

Their work delineated a string of genes and proteins that are affected by EYA1, and they also discovered that EYA1 pushes an increase in formation of mammospheres, which are a measure of breast cancer stem cells.

“Within every breast cancer are breast cancer stem cells, which give rise to anti-cancer therapy resistance, recurrence and metastases,” Dr. Pestell says. “We demonstrated in laboratory experiments that EYA1 expression increase the number of mammospheres and other markers of breast cancer stem cells.”

“As the EYA1 phosphatase activity drove breast cancer stem cell expansion, this activity may contribute to worse survival,” he says.

This study was supported in part by the NIH grants RO1CA132115, R01CA70896, R01CA75503, R01CA86072 and P30CA56036 (RGP), a grant from the Breast Cancer Research Foundation (RGP), a grant for Dr. Ralph and Marian C. Falk Medical Research Trust (RGP), Margaret Q. Landenberger Research Foundation, the Department of Defense Concept Award W81XWH-11-1-0303.

Study co-authors are, from Kimmel Cancer Center: first author Kongming Wu, Zhaoming Li, Shaoxin Cai, Lifeng Tian, Ke Chen, Jing Wang and Adam Ertel; Junbo Hu, from Huazhong University of Science and Technology, China; and Ye Sun, and Xue Li from Boston Children’s Hospital.

For more information: Jackie Kozloski, 215-955-5296, jackie.kozloski@jefferson.edu.



Need to Analyze Your Next-Generation Sequencing Data? Thomas Jefferson University’s New Web-Based Resource Makes the Task Easy

Isidore Rigoutsos, Ph.D.

In the early 1990s, an international effort was launched by the U.S. Department of Energy and the National Institutes of Health to sequence the human genome. The project took 13 years, involved many scientists in several countries, and cost $2.7 billion (in FY 1991) dollars.

Since then, technological advances and the advent of next generation sequencing have greatly increased the speed at which the genome or the transcriptome of a model organism such as human or mouse can be sequenced. Nowadays, a typical sequencing platform can generateseveral billion bases of DNA or RNA in the course of a few days and can do so at a far lower cost.

However, such an embarrassment of riches poses difficulties for the typical research groups who would like to make use of this technology but are neither accustomed nor equipped to handle the great amounts of data that can now be generated. To help address this problem, Thomas Jefferson University is making available to researchers and clinicians such an analytical capability on the web.

The resource, referred to as HandsFree, is a system that was designed and implemented by the Computational Medicine Center at Thomas Jefferson University. The goal of HandsFree is to provide researchers and clinicians at Thomas Jefferson University and Hospitals with the ability to analyze the large datasets that next generation sequencing platforms generate. And since HandsFree is web-based, scientists at other universities, in the Delaware Valley and elsewhere, could also take advantage of it.

“It is a unique resource to academic research and medicine,” says Isidore Rigoutsos, Ph.D., Director of the Center. “I don’t know of any other research institution or medical center that currently makes a similar system available to their researchers and clinicians.”

How does it work? Dr. Rigoutsos offers as an example a researcher who wants to understand a particular aspect of the biology of Alzheimer’s disease, and who has brain samples taken from a deceased patient, as well as samples from a normal brain. The investigator would give the samples to the sequencing facility at the Kimmel Cancer Center at Jefferson and several days later she will get back data files typically containing 200 million sequences for each sequenced sample, he says.

“This is where HandsFree comes in,” Dr. Rigoutsos says. “The investigator can access HandsFree through her computer browser, securely transfer the sequencing dataset to the HandsFree web-server, and answer a few questions about the type of data and desired analyses. At this point, the data will be placed in a queue with other datasets for analysis by the Computational Medicine Center’s computers. When the dataset reaches the front of the queue, it will be quality-trimmed and preprocessed, then mapped on the corresponding genome followed by a series of analyses that are typical for such data.”

“The system will also generate genomic maps for the investigator to also enable subsequent off-line visual exploration. The generated results and maps are then placed back on the HandsFree web-server and the investigator is notified through email that the output is ready for collection,” he says.

“The whole process is as hands-free as it can get for these kinds of datasets,” Dr. Rigoutsos says. “The investigator still has some work ahead of them but the system does all the ‘heavy lifting’ for them taking the guess-work out and making this kind of analysis easy to harness.”

It took his team one and a half years to put the HandsFree system together. The underlying pipeline uses both publicly available standard tools as well as tools that the team specifically developed to automate the whole process. “HandsFree enables others to access the very same pipeline that we use ourselves for our own basic research. In this regard, the pipeline’s components have already been ‘vetted’ by us,” says Dr. Rigoutsos.

Very importantly, the system handles the data in a secure fashion, he adds. “Any data that the investigator exchanges with HandsFree is encrypted in both directions. Moreover, the processing and analyses of the data are carried out by the Center’s machines in a separate and secure high performance computing facility.”

Currently, the HandsFree system can accommodate DNA and RNA datasets generated by several popular sequencing platforms, from both human and mouse. “For these datasets, the user can carry out a number of standard analyses at the click of a button,” Dr. Rigoutsos says. “A whole host of additional capabilities is in the process of being implemented and will be enabled in HandsFree in the months ahead.”

The system is now available to researchers, and the cost for analyzing these datasets “is very reasonable,” he says. “HandsFree will help advance medical science, and we are very pleased to have it online and available to our researchers and to others.”

The system can be accessed at http://cm.jefferson.edu/HandsFree

For more information, contact: Jackie Kozloski, 215-955-5296 or jackie.kozloski@jefferson.edu.



Dr. Iozzo’s recent PNAS publication shows link between decorin to autophagy in endothelial cells

Renato V. Iozzo, M.D., Ph.D.

Dr. Renato Iozzo, MD, PHD, Professor of Pathology & Cell Biology, Biochemistry & Molecular Biology and Kimmel Cancer Center member, and his group recently published results in the Proceedings of the National Academy of Science (PNAS) which show decorin functions as a tumor suppressor/anti-angiogenesis factor, in part, by inducing the autophagy of endothelial cells. The publication details are below:

Buraschi, S., Neill, T., Goyal, A., Poluzzi,C., Smythies,J., Owens, R.T,  Schaefer, L., Torres,A. and Iozzo, R.V., Decorin causes autophagy in endothelial cells via Peg3.  Proc. Natl. Acad. Sci. USA 110 (28): E2582-E2591, 2013 PMID:23798385

This paper was selected by the faculty of 1000 and highlighted in Science Daily and in Extracellualr Matrix News, 4.27, 2013.

For more information please see the pubmed abstract or the full text at PNAS.



Dr. Karen Knudsen and Dr. Renato Iozzo receive Distinguished Mentor Awards.

On Monday, June 11, 2012, at the Annual Jefferson Postdoctoral Research Symposium, Dr. Karen Knudsen and Dr. Renato Iozzo were honored with The Distinguished Mentor Award. The Distinguished Mentor Award was established to recognize Jefferson faculty members that excel in the mentoring of postdoctoral fellows. The award also serves to highlight the importance of positive and effective mentoring of postdoctoral fellows. A good mentor not only teaches his/her mentees but serves as an advocate, advisor and positive role model during the period of direct training and most often, in the following years. It is our hope that the Distinguished Mentor will serve as a model for the entire university and help to enhance the culture of mentoring at Jefferson.



HIV Drug May Slow Down Metastatic Triple-Negative Breast Cancer

Richard Pestell, M.D., Ph.D, Director of the KCC

Researchers at the Kimmel Cancer Center, led by Dr. Richard G. Pestell have discovered that FDA-approved HIV drugs may stop triple-negative breast cancer from spreading to other organs in pre-clinical models.

These results were originally reported in Cancer Research.

Recent articles about this discovery have also appeared in NewsWise and the Philadelphia Inquirer.




Dr. Jeannie Hoffman-Censits leads Walk for Bladder Cancer

On Saturday, May 5, 2012 Jeannie Hoffman-Censits, M.D. led Team Jefferson from the Kimmel Cancer Center‘s Bluemle Life Sciences Building to Independence Hall. Dr. Hoffman-Censits teamed up with “the first national advocacy organization devoted to bladder cancer,” the Bladder Cancer Advocacy Network, to help raise public awareness of bladder cancer and much needed funding.

Team Jefferson will be walking again on May 4, 2013. For more information, please contact Jessica Soens at Jessica.Soens@JeffersonHospital.org or call 215-955-2054.



Kimmel Cancer Center Founding Directors Portrait Unveiled


Dr. Richard G. Pestell, Martha Mayer Erlebacher, Dr. Carlo M. Croce, Dr. Richard L. Davidson

A portrait of Dr. Carlo Croce, the founding Director of the Jefferson Kimmel Cancer Center, painted by Philadelphia artist Martha Erlebacher, was unveiled on Tuesday, April 10, 2012, at 4:00 PM in the Bluemle Life Sciences Building.

Martha Mayer Erlebacher has been recognized as one of the leading representational figurative and still-life artists in America who has shown her work nationally and internationally. A number of books and periodicals feature her work, much of which “examines the deep metaphorical and social themes of contemporary culture through her painterly and aesthetic images.”

Dr. Croce is world-renowned for his contributions involving the genes and genetic mechanisms implicated in the pathogenesis of human cancer. He is a member of the National Academy of Sciences and Institute of Medicine in the United States and the Accademia Nazionale delle Scienze detta deiXL in Italy. He has earned a plethora of awards in recognition of his hard work and dedication including two Outstanding Investigator awards from the National Cancer Institute and most recently, an Elected Membership to The American Academy of Arts and Sciences.

Dr. Joesph S. Gonnella and Dr. Carlo M. Croce

Dr. Croce is a principal investigator on eleven federal research grants and has more than 950 peer-reviewed, published research papers. A native of Milan, Italy, Dr. Croce earned his medical degree, summa cum laude, in 1969 from the School of Medicine, University of Rome. He began his career in the United States the following year as an associate scientist at the Wistar Institute of Biology and Anatomy in Philadelphia. In 1980, he was named Wistar Professor of Genetics at the University of Pennsylvania and Institute Professor and Associate Director of the Wistar Institute, titles he held until 1988. From 1988-91, he was Director of the Fels Institute for Cancer Research and Molecular Biology at Temple University School of Medicine in Philadelphia.

In 1991 Dr. Croce was named Director of the Kimmel Cancer Institute at Thomas Jefferson University.  While here, Dr. Croce discovered the role of microRNAs in cancer pathogenesis and progression, implicating a new class of genes in cancer causation.  After thirteen years as Director of the Kimmel Cancer Center, Dr. Croce moved to Ohio State University in 2004.  Under his direction at OSU, faculty within the Human Cancer Genetics Program conduct both clinical and basic research.  Basic research projects focus on how genes are activated and inactivated, how cell-growth signals are transmitted and regulated within cells, and how cells interact with the immune system. Clinical research focuses on discovering genes linked to cancer and mutations that predispose people to cancer.



Ovarian, Glioblastoma & Non-Small Cell Lung Cancer: Jefferson Researchers Present at AACR

Several researchers from Jefferson’s Kimmel Cancer Center presented abstracts at the American Association for Cancer Research Annual Meeting 2012 in Chicago. Some of those findings include:

HuR and Ovarian Cancer

Silencing HuR may be a promising therapeutic approach for the treatment of ovarian cancer, according to an abstract presented at AACR by researchers from Thomas Jefferson University, Lankenau Institute for Medical Research, the Geisinger Clinic and the Massachusetts Institute of Technology.

HuR is a RNA-binding protein that post-transcriptionally regulates genes involved in the normal cellular response to cancer-associated stressors, like DNA damage, nutrient depletion and therapeutic agents.  When triggered by stress, HuR translocates from the nucleus to the cytoplasm where it potently influences translation of key tumor promoting mRNAs by mRNA stabilization and direct facilitation of translation.

Previously, it has been shown that HuR expression is a prognostic marker in ovarian cancers. Thus, researchers tested the effects of manipulating HuR expression levels on ovarian tumor growth characteristics and tested the hypothesis that silencing HuR through delivery of an HuR siRNA would be effective in suppressing the growth of ovarian tumors.

Following treatment of ovarian cancer cells in culture with an adenovirus containing the HuR coding sequence, HuR expression was increased by about 40% above control cells.

In the patient cohort, researchers also detected HuR activation (i.e., cytoplasmic HuR positivity) in twenty-four of thirty four patients (71 percent), providing evidence that the majority of patients have activated HuR.

“These data provide evidence that silencing HuR, even as a monotherapeutic strategy, may be a promising therapeutic approach for the treatment of ovarian cancer,” wrote the authors.

Authors of the paper include Janet A. Sawicki and Yu-Hung Huang, of Lankenau Institute for Medical Research, Charles J. Yeo, Agnieszka K. Witkiewicz, Jonathan R. Brody, of Thomas Jefferson University, Radhika P. Gogoi, of Geisinger Clinic, Danville, Pa., and Kevin Love and Daniel G. Anderson, of Massachusetts Institute of Technology, Cambridge, Mass.

This work was supported by the Marsha Rivkin Center for Ovarian Cancer Research.

Radiotherapy and Glioblastoma

Radiotherapy’s effect on glioblastoma (GBM) is enhanced in the presence of a heat shock protein and a P13K inhibitor, researchers from the Department of Radiation Oncology reported at AACR.

Glioblastoma tumors frequently contain mutations in the tumor suppressor gene, PTEN, leading to loss of PTEN activity, which causes overactivation of the PI3K pathway, inducing inhibition of apoptosis and radioresistance.

Heat-shock protein 90 (HSP90) is a molecular chaperone that is over-expressed in GBM and that has among its client proteins, PI3K and Akt.

It was hypothesized that dual inhibition of HSP90 and PI3K signaling would additively or synergistically radiosensitize GBM through inhibition of radiation-induced PI3K/Akt signaling, leading to enhanced apoptosis.

Confirming their theory, the researchers found that the response of glioblastoma to radiotherapy was enhanced in the presence of BKM120 and HSP990. Enhanced apoptosis also contributed to the mechanism of cell death.

Authors of the study include Phyllis Rachelle Wachsberger, Yi Liu, Barbara Andersen, and Adam P. Dicker, of the Department of Radiation Oncology at Thomas Jefferson University Hospital and Richard Y. Lawrence, of Jefferson and the Sheba Medical Center, Tel Hashomer, Israel.

This work was supported by a grant from Novartis Pharmaceuticals.

Non-Small Lung Cancer and DACH1

Researchers from the Kimmel Cancer Center at Jefferson have identified a protein relationship that may be an ideal treatment target for non-small cell lung cancer (NSCLC).  They presented their findings at AACR.

DACH1, a cell fate determination factor protein, appears to be a binding partner to p53, a known tumor suppressor, which inhibits NSCLC cellular proliferation.

As cancer develops and becomes more invasive, the expression of DACH1 decreases. Clinical studies have demonstrated a reduced expression of the DACH1 in breast, prostate and endometrial cancer.

In a previous study of more than 2,000 breast cancer patients, Jefferson researchers found that a lack of DACH1 expression was associated with a poor prognosis in breast cancer patients. Patients who did express DACH1 lived an average of 40 months longer.

Genetic studies have identified several oncogenes activated in lung cancer, including K-Ras and EGFR. Given the importance of the EGFR in human lung cancer, researchers examined the role of DACH1 in lung cancer cellular growth, migration and DNA damage response.

For this study, endogenous DACH1 was reduced in human NSCLC, with expression levels of DACH1 correlating inversely with clinical stage and pathological grade.

Re-expression of DACH1 also  reduced lung cancer cell colony formation and cellular migration. Cell cycle analyses demonstrated that G2/M block by ectopic expression of DACH1 occurs synergistically with p53.

Fluorescent microscopy demonstrated co-localization of DACH1 with p53, and immunoprecipitation and western blot assay showed DACH1 association with p53.

“DACH1 enhanced the cytotoxcity of cisplatin and doxorubicin, two commonly used drugs for NSCLC,” the authors write in the abstract. “Together, our studies demonstrate that p53 is a DACH1 binding partner that inhibits NSCLC cellular proliferation.”

Authors of the study include Ke Chen, Kongming Wu, Wei Zhang, Jie Zhou, Timothy Stanek, Zhiping Li, Chenguang Wang, L. Andrew Shirley, Hallgeir Rui, Steven McMahon, Richard G. Pestell, of  Thomas Jefferson University, Kimmel Cancer Center and Huazhong University of Science and Technology, Wuhan, China.



Biomarker Links Clinical Outcome with New Model of Lethal Tumor Metabolism

Researchers at the Kimmel Cancer Center at Jefferson have demonstrated for the first time that the metabolic biomarker MCT4 directly links clinical outcomes with a new model of tumor metabolism that has patients “feeding” their cancer cells.  Their findings were published online March 15 in Cell Cycle.

To validate the prognostic value of the biomarker, a research team led by Agnieszka K. Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson, analyzed samples of patients with triple negative breast cancer, one of the most deadly of breast cancers, with fast-growing tumors that often affect younger women.

A retrospective analysis of over 180 women revealed that high levels of the biomarker MCT4, or monocarboxylate transporter 4, were strictly correlated with a loss of caveolin-1 (Cav-1), a known marker of early tumor recurrence and metastasis in several cancers, including prostate and breast.

“The whole idea is that MCT4 is a metabolic marker for a new model of tumor metabolism and that patients with this type of metabolism are feeding their cancer cells. It is lethal and resistant to current therapy,” Dr. Lisanti said. “The importance of this discovery is that MCT4, for the first time, directly links clinical outcome with tumor metabolism, allowing us to develop new more effective anti-cancer drugs.”

Analyzing the human breast cancer samples, the team found that women with high levels of stromal MCT4 and a loss of stromal Cav-1 had poorer overall survival, consistent with a higher risk for recurrence and metastasis, and treatment failure.

Applying to a Triple Threat

Today, no such markers are applied in care of triple negative breast cancer, and as a result, patients are all treated the same. Identifying patients who are at high risk of failing standard chemotherapy and poorer outcomes could help direct them sooner to clinical trials exploring new treatments, which could ultimately improve survival.

“The idea is to combine these two biomarkers, and stratify this patient population to provide better personalized cancer care,” said Dr. Witkiewicz

The findings suggest that when used in conjunction with the stromal Cav-1 biomarker, which the authors point out has been independently validated by six other groups worldwide, MCT4 can further stratify the intermediate-risk group into high and low risk.

Since MCT4 is a new druggable target, researchers also suggest that MCT4 inhibitors should be developed for treatment of aggressive breast cancers, and possibly other types.  Targeting patients with an MCT4 inhibitor, or even simple antioxidants, may help treat high-risk patients, who otherwise may not respond positively to conventional treatment, the researchers suggest.

Paradigm Shift

But the work stems beyond triple negative breast cancer, challenging an 85-year-old theory about cancer growth and progression.

This paper is the missing clinical proof for the paradigm shift from the “old cancer theory” to the “new cancer theory,” known as the “Reverse Warburg Effect,” said Dr. Lisanti. The new theory being that aerobic glycolysis actually takes place in tumor associated fibroblasts, and not in cancer cells, as the old theory posits.

“The results by Witkiewicz et al. have prominent conceptual and therapeutic implications,” wrote Lorenzo Galluzzi, Ph.D., Oliver Kepp, Ph.D., and Guido Kroemer, M.D., Ph.D. of the French National Institute of Health and Medical Research and Institut Gustave Roussy, in an accompanying editorial. “First, they strengthen the notion that cancer is not a cell-autonomous disease, as they unravel that alterations of the tumor stroma may constitute clinically useful biomarkers”.

“Second, they provide deep insights into a metabolic crosstalk between tumor cells and their stroma that may be targeted by a new class of anticancer agents.”

Dr. Kroemer entitled his commentary “Reverse Warburg: Straight to Cancer” to emphasize that the connective tissue cells (fibroblasts) are directly “feeding” cancer cells, giving them a clear growth  and survival advantage.  New personalized therapies would cut off the “fuel supply” to cancer cells, halting tumor growth and metastasis.



PCF Young Investigator Award Goes to Jefferson Researcher

Heather Montie, Ph.D., a post-doctoral research fellow in the Department of Biochemistry and Molecular Biology, has received a Prostate Cancer Foundation Young Investigator Award for her work with androgen receptor (AR) acetylation and its role in castration-resistant prostate cancer.

Young Investigator awards are designed to promote long-term careers in the field of prostate cancer by providing three year grants for transformational research focused on prostate cancer treatments to improve patient outcomes. Since 2007, PCF has invested more than $20 million in Young Investigator grants.

“PCF-supported young investigators have changed the scope of prostate cancer research, advancing treatment sciences and improving the lives of patients worldwide,” said Howard Soule, PhD, chief science officer and executive vice president of PCF. “It is with great pride and appreciation that PCF can now announce our young investigator program spans across six countries and 42 research institutes.”

Prostate cancer is driven by the male hormones, androgens which mediate their activity through the androgen receptor. Unfortunately most prostate cancerous tumors progressively become resistant to the preferred treatment modality, androgen deprivation therapy. One of the mechanisms proposed to enhance the activity of androgen receptors in castration-resistant prostate cancer, even in the absence of androgens, is the addition of a small chemical group/moiety to the AR protein. This modification of AR is termed ‘acetylation’ and is proposed to convert the protein to a ‘super AR.’

However, there is currently no experimental data to show that AR acetylation directly enhances AR-dependent prostate cancer cell viability.

Dr. Montie proposes to evaluate the role of AR acetylation in the enhanced AR functional activity central to CRPC. She will study the precise mechanisms by which this modification of AR enhances its cancer-promoting activity. Dr. Montie will also validate the potential of AR acetylation as a therapeutic target for castrate-resistant prostate cancer.

A total of 15 competitive research grants have been awarded to-date in 2012, bringing the total of young investigators awarded to 89.

Each Young Investigator recipient is awarded $225,000 over a three-year period.

Dr. Montie received the 2012 John A. Moran PCF Young Investigator Award. 

Visit here for more on the Young Investigator awards.



Stronger Intestinal Barrier May Prevent Cancer in the Rest of the Body, New Study Suggests

Scott Waldman, M.D., Ph.D., chair of the Department of Pharmacology and Experimental Therapeutics at Jefferson and director of the Gastrointestinal Cancer Program at Jefferson’s Kimmel Cancer Center

A leaky gut may be the root of some cancers forming in the rest of the body, a new study published online Feb. 21 in PLoS ONE by Thomas Jefferson University researchers suggests.

It appears that the hormone receptor guanylyl cyclase C (GC-C)—a previously identified tumor suppressor that exists in the intestinal tract—plays a key role in strengthening the body’s intestinal barrier, which helps separate the gut world from the rest of the body, and possibly keeps cancer at bay. Without the receptor, that barrier weakens.

A team led by Scott Waldman, M.D., Ph.D., chair of the Department of Pharmacology and Experimental Therapeutics at Jefferson and director of the Gastrointestinal Cancer Program at Jefferson’s Kimmel Cancer Center, discovered in a pre-clinical study that silencing GC-C in mice compromised the integrity of the intestinal barrier.  It allowed inflammation to occur and cancer-causing agents to seep out into the body, damaging DNA and forming cancer outside the intestine, including in the liver, lung and lymph nodes.

Conversely, stimulating GC-C in intestines in mice strengthened the intestinal barrier opposing these pathological changes.

A weakened intestinal barrier has been linked to many diseases, like inflammatory bowel disease, asthma and food allergies, but this study provides fresh evidence that GC-C plays a role in the integrity of the intestine.  Strengthening it, the team says, could potentially protect people against inflammation and cancer in the rest of the body.

“If the intestinal barrier breaks down, it becomes a portal for stuff in the outside world to leak into the inside world,” said Dr. Waldman. “When these worlds collide, it can cause many diseases, like inflammation and cancer.”

The role of GC-C outside the gut has remained largely elusive. Dr. Waldman and his team have previously shown its role as a tumor suppressor and biomarker that reveals occult metastases in lymph nodes. They’ve used to it better predict cancer risk, and have even shown a possible correlation with obesity.

Reporting in the Journal of Clinical Investigation, Dr. Waldman colleagues found that silencing GC-C affected appetite in mice, disrupting satiation and inducing obesity. Conversely, mice who expressed the hormone receptor knew when to call it quits at mealtime.

However, its role in intestinal barrier integrity, inflammation, and cancer outside the intestine is new territory in the field.

A new drug containing GC-C is now on the verge of hitting the market, but its intended prescribed purpose is to treat constipation.

This study helps lays the groundwork, Dr. Waldman said, for future pre-clinical and clinical studies investigating GC-C’s abilities beyond those treatments in humans, including prevention and treatment of inflammatory bowel disease and cancer.

“We’ve shown that when you pull away GC-C in animals, you disrupt the intestinal barrier, putting them at risk for getting inflammatory bowel disease and cancer.  And when you treat them with hormones that activate GC-C it helps strengthen the integrity of the intestinal barrier,” Dr. Waldman said.  “Now, if you want to prevent inflammation or cancer in humans, then we need to start thinking about feeding people hormones that activate GC-C to tighten up the barrier.”



Drugs targeting chromosomal instability may fight a particular breast cancer subtype

Richard Pestell, M.D., Ph.D, Director of the KCC

Another layer in breast cancer genetics has been peeled back.

A team of researchers at Jefferson’s Kimmel Cancer Center (KCC) led by Richard G. Pestell, M.D., PhD., FACP, Director of the KCC and Chair of the Department of Cancer Biology, have shown in a study published online Feb. 6 in the Journal of Clinical Investigation that the oncogene cyclin D1 may promote a genetic breakdown known as chromosomal instability (CIN). CIN is a known, yet poorly understood culprit in tumor progression.

The researchers used various in vitro and in vivo model systems to show that elevated levels of cyclin D1 promotes CIN and correlate with CIN in the luminal B breast cancer subtype. Cyclin D1 protein is elevated in breast, prostate, lung and gastrointestinal malignancies.

The findings suggest that shifting towards drugs targeting CIN may improve outcomes for patients diagnosed with luminal B subtype. Luminal B breast cancer has high proliferation rates and is considered a high grade malignancy.

Estrogen or progesterone receptor positive and HER2 positive cancers indicate luminal B, and about 10 percent of patients are diagnosed with it every year, though many do not respond well to treatment. The identification of CIN in luminal B provides a new therapeutic opportunity for these patients.

“Cyclin D1 has a well defined role in cell proliferation through promoting DNA replication,” says Dr. Pestell. “My team was the first to discover that cyclin D1 also has alternate functions, which include regulating gene transcription at the level of DNA. We were interested in discovering the function of DNA associated cyclin D1.”

To help answer this, the researchers, including lead author Mathew C. Casimiro, Ph.D., of the Department of Cancer Biology at Thomas Jefferson University, first needed to directly access cyclin D1′s role in gene regulation.

They applied an analysis known as ChIP sequencing to study the protein’s interactions with genes that comprise the entire mouse genome, and found it occupied the regulatory region of genes governing chromosomal stability with high incidence.

They went on to show cyclin D1 promoted aneuploidy and chromosomal rearrangements typically found in cancers.

Faulty chromosomes—either too many or too few, or even ones that are the wrong shape or size—have been shown to be the crux of many cancers. However, a major question of cancer genetics is the mechanisms of CIN. What causes the breakdown in chromosomal stability?

As cyclin D1 expression is increased in the early phases of tumorigenesis, cyclin D1 may be an important inducer of CIN in tumors.

To analyze the association between CIN and cyclin D1 expression in the context of breast cancer, the team aligned an expression of a 70-gene set with the highest CIN score against over 2,000 breast cancer samples. They stratified the samples based on previously described subtypes and aligned them with cyclin D1 expression profiled across the dataset.

A significant correlation among CIN, cyclin D1 and the luminal B subtype was identified, and it was apparent that the relationship between these levels was subtype specific.

“Interestingly, previous studies have presented contradictory results,” Dr. Pestell says. “Many studies have suggested a positive correlation between cyclin D1 expression and outcomes, while others have shown reduced survival. Here, we’ve dug deep, using a genome-wide analysis, and found that overexpression of the protein appears to be directly associated with the genes involved in CIN and this correlates with the luminal B subtype.”

Drugs targeting chromosomal instability for cancer therapy have been explored, but a sub-stratification rationale for the luminal B subtype has not been established. The research presented in this study suggests such a target is worthy of further investigation.

“There is a big drive towards using targeting therapies for stratified breast cancers,” says Dr. Casimiro. “What we are thinking is that there are a growing number of drugs that target aneuploidy, like AICAR and 17-AAG, that may be used as an adjuvant therapy in patients with luminal B breast cancer.”



Richard Pestell Named AAAS Fellow

Richard Pestell, M.D., Ph.D., FACP, Director of the Kimmel Cancer Center at Jefferson (KCC), has been named a 2011 Fellow of the American Association for the Advancement of Science (AAAS).

As part of the Section on Medical Sciences, Dr. Pestell was elected as an AAAS Fellow for his distinguished contributions to cancer care as director of two National Cancer Institute cancer centers, including the KCC and Lombardi Cancer Center at the Georgetown University Medical Center, and research identifying new molecular targets (cyclins, acetylation) and light activated gene therapy.

Richard Pestell, M.D., Ph.D., FACP, Director of the Kimmel Cancer Center at Jefferson

Dr. Pestell is an internationally renowned expert in oncology and endocrinology, who also currently serves as Chairman of the Department of Cancer Biology, Associate Dean of Cancer Programs at Jefferson Medical College (JMC), and Vice President of Oncology Services at Thomas Jefferson University Hospital.

Election as a AAAS Fellow is an honor bestowed upon AAAS members by their peers.

Dr. Pestell, who was named Director of the KCC in November 2005, is a highly respected researcher and clinician whose current work is focused on developing new cancer therapies that specifically target tumors, and reduce the side effects that are associated with commonly used cancer treatments such as chemotherapy and radiation.

He has made significant contributions to our understanding of cell cycle regulation and the disturbances that can lead to the malignant transformation of cells. Dr. Pestell has particular expertise in hormonally-responsive tumors, such as those of the breast and prostate, and his work is directed toward the eventual discovery of novel therapies for these cancers.

This year 539 members have been awarded this honor by AAAS because of their scientifically or socially distinguished efforts to advance science or its applications. New Fellows will be presented with an official certificate and a gold and blue (representing science and engineering, respectively) rosette pin on Saturday, February 18 at the AAAS Fellows Forum during the 2012 AAAS Annual Meeting in Vancouver, B.C., Canada.

This year’s AAAS Fellows will be formally announced in the AAAS News & Notes section of the journal Science on Dec. 23.

Also, as part of the Section on Medical Sciences, Hideko Kaji, Ph.D., of the Department of Biochemistry and Molecular Biology of Thomas Jefferson University, was named a AAAS fellow for her distinguished contributions to biology by discovering specific tRNA binding to mRNA-ribosome complexes, N-terminal protein modification by arginine, and ribosome recycling, the last step of protein synthesis.

Fellows elected in previous years include Eric Wickstrom, Ph.D., a Professor of Biochemistry and Molecular Biology at JMC and member of the KCC, and Charlene J. Williams, Ph.D., of the Department of Medicine at JMC.