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.”



‘A Welcome New Addition’ to Field: Dr. Juan Palazzo Authors Breast Pathology Book

Juan P. Palazzo, M.D., an anatomic/surgical pathologist at Thomas Jefferson University Hospital and the Jefferson Breast Care Center, has authored a book that tackles the hard cases in breast disease pathology faced by many clinicians in the healthcare world today.

According to Amazon, Difficult Diagnoses in Breast Pathology (Demos Medical) provides a highly visual presentation of the major problems and questions that a pathologist is likely to encounter in the evaluation of common and uncommon breast diseases.

Addressing real-world diagnostic problems faced in daily practice, the book includes needle core biopsy interpretation, diagnosis of precursor lesions, early stage disease, and recognition of neoplastic mimics and other misleading variants.

Each chapter is authored by a recognizePathologist Dr. Juan P. Palazzod expert in the area, and includes hundreds of high-quality images.

“This is a welcome new addition to this field and it delivers with concise, clear writing, ample illustrations, and appropriate comments on ancillary techniques. This latest addition to the field of histomorphology of (surgical) breast disease compares favorably with many more extensive books,” writes Doody’s Reviews.

Dr. Palazzo is pathologist with over 25 years experience and has been named a U.S. News & World Report “Top Doctor.”

The book is available here.



Brachytherapy reduced death rates in high-risk prostate cancer patients, study finds

Xinglei Shen, M.D., a resident in Jefferson’s Department of Radiation Oncology and a part-time master’s degree student in the Jefferson School of Population Health

Brachytherapy for high-risk prostate cancers patients has historically been considered a less effective modality, but a new study from radiation oncologists at the Kimmel Cancer Center at Jefferson suggests otherwise. A population-based analysis looking at almost 13,000 cases revealed that men who received brachytherapy alone or in combination with external beam radiation therapy (EBRT) had significantly reduced mortality rates.

Their findings are reported online January 23 in the International Journal of Radiation Oncology,Biology,Physics.

Brachytherapy involves the precise placement of radiation sources directly at the site of a tumor and is typically used to treat low and intermediate risk prostate cancers. However, brachytherapy treatment for high-risk patients is less common and controversial, given in part to early retrospective studies that found it to be associated with lower cure rates compared to EBRT.

Many experts believe that these early series were limited by poor brachytherapy technique, and that high-quality contemporary brachytherapy may be an effective tool against high-risk prostate cancer.

“The study contradicts traditional policies of using brachytherapy in just low and intermediate risk patients by suggesting there may instead be an improvement in prostate cancer survival for high-risk patients,” said co-author Timothy Showalter, M.D., assistant professor in the Department of Radiation Oncology at Thomas Jefferson University Hospital, and associate research member of Jefferson’s Kimmel Cancer Center. “Although studies like this cannot prove an advantage for brachytherapy, our report does suggest that brachytherapy is no less effective than EBRT and should be considered for some men with high-risk prostate cancer.”

Researchers identified 12,745 Surveillance, Epidemiology and End Results database patients diagnosed from 1988 to 2002 with high-grade prostate cancer of poorly differentiated grade and treated with brachytherapy (7.1 percent), EBRT alone (73.5 percent) or brachytherapy plus EBRT (19.1 percent). The team used multivariate models to examine patient and tumor characteristics associated with the likelihood of treatment with each radiation modality and the effect of radiation modality on prostate cancer-specific mortality.

Treatment with brachytherapy alone or brachytherapy in combination with EBRT, the researchers found, was associated with significant reduction in prostate cancer-specific mortality rates compared to EBRT alone.

Significant predictors of use of brachytherapy or brachytherapy plus EBRT were younger age, later year of diagnosis, urban residence and earlier T-stage.

According to the researchers, including lead author Xinglei Shen, M.D., a resident in Jefferson’s Department of Radiation Oncology and a part-time master’s degree student in the Jefferson School of Population Health, the study’s findings provide ample evidence to further study brachytherapy as part of an effective treatment strategy for men with high-grade prostate cancer.

“Today, for the most part, brachytherapy is not being used for these high-risk patients or even recommended,” Dr. Shen said. “But if you look at the biology and theory behind it, it makes sense: you can really give a lot more dose with brachytherapy than with EBRT alone to the prostate. And this presents an opportunity for high-risk patients.”



KCC To Host Melanoma Research Foundation Symposium

Melanoma Research Foundation

http://www.melanoma.org

CURE OM has announced the inaugural Eyes on a Cure: Patient and Caregiver Symposium to be held on June 16th and 17th, 2012.  The meeting will be held one month after the first CURE OM Scientific Meeting (for physicians and researchers) with the goal of bringing the latest news from the ocular melanoma scientific community directly to patients and their loved ones.  Eyes on a Cure will bring patients, caregivers and researchers from around the world together to offer educational sessions, support groups led by oncology social workers, sessions on complementary therapies, as well as informal time for networking.

This first patient and caregiver symposium will be held in Philadelphia at the Kimmel Cancer Center of Thomas Jefferson University.  Confirmed speakers include: Carol Shields, Takami Sato, David Eschelman, Carin Gonsalves, and James Pingpank.

For more information about the symposium go to the MRF Symposium Announcement



High Dose Vitamin C for Advanced Pancreatic Cancer

By Josh Goldstein, The Daily Dose @Jefferson

A small phase I clinical trial at Jefferson University Hospitals of high-dose, intravenous vitamin C in combination with chemotherapy medications show that this treatment is safe and may have promise for patients with advanced pancreatic cancer.

The study published in the open access online journal PLoS ONE tested the use of intravenous ascorbic acid (vitamin C) three times a week over an eight week cycle in nine patients with metastatic stage IV pancreatic cancer in addition to standard gemcitabine and erlotinib chemotherapy regimens.

“These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients,” wrote the team of researchers from the Kimmel Cancer Center at Jefferson as well as the National Institutes of Health (NIH). “This combination with the observed response to treatment suggests the need for a phase II study of longer duration.”

The research was conducted at Jefferson by a multidisciplinary team from the Jefferson-Myrna Brind Center of Integrative Medicine, Jefferson’s Department of Medical Oncology, Department of Surgery, Department of Radiology, and National Institute of Diabetes and Digestive and Kidney Diseases of the NIH.

Daniel A. Monti, MD, Executive and Medical Director of the Jefferson-Myrna Brind Center of Integrative Medicine and lead author of the study said, “We are pleased and encouraged by these results.”

Dr. Monti added, “it is a Jefferson priority to study promising therapies for pancreatic cancer. It is crucial to explore anything that might feasibly give these patients an edge. We are now actively enrolling eligible patients into the Phase II trial.”



New Clinical Trial: Cabazitaxel with Radiation and Hormone Therapy May Improve Prostate Cancer Survival

Jefferson’s Kimmel Cancer Center has started a Phase I clinical trial investigating the latest prostate cancer chemotherapy drug to extend survival, Cabazitaxel, in combination with radiation and hormone therapy. This first-of-its-kind multimodality approach could improve disease control and eventually survival for locally advanced prostate cancer patients.

The single-center, open-label, non-randomized Phase I study of weekly Cabazitaxel with concurrent intensity modulated radiation therapy (IMRT) and androgen deprivation therapy will test its safety and the tolerable maximum dosing.

Cabazitaxel was approved in the U.S. for second-line use in advanced hormone-refractory prostate cancer in men in 2010, and has been described as a major advance in chemotherapy for advanced prostate cancer. It extended overall survival by 2.4 months when compared with mitoxantrone in patients who were previously treated with docetaxel. However, a multimodality approach with the drug has never been studied.

“We know the drug is effective in prostate cancer, but there is no study with radiation and hormone therapy yet,” said principal investigator Jianqing Lin, M.D., an assistant professor of medical oncology at Thomas Jefferson University Hospital. “Concurrent radiation may have a better control for localized disease, and better long-term survival for these high-risk patients.”

IMRT is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor; androgen deprivation therapy is a treatment to suppress or block the production or action of male hormones. Enrolled men will receive weekly treatments of the chemotherapy drug and hormone therapy and then every three months until two years after completion of IMRT.

For the clinical trial, Dr. Lin is partnering with co-investigator Timothy Showalter, M.D., an assistant professor in the Department of Radiation Oncology at Thomas Jefferson University Hospital.

For further information, please contact the Kimmel Cancer Center at Jefferson’s Clinical Research Management Office at 215-955-1661.



KCC’s Brain Tumor Center’s New Immunotherapy Clinical Trial Featured in Several News Outlets

Led by Dr. David Andrews, co-director of the Brain Tumor Center of the Kimmel Cancer Center, a new immunotherapy clinical trial at Jefferson will harvest cells from brain tumors for use in treatment.

In an interview with KYW Newsradio, Dr. Andrews explains that the first step of the trial will be a surgical procedure to take cells from the brain tumor. He adds, ”We then take the tumor cells and treat them with a drug that will induce cell death. The drug itself actually interacts with the immune system.”

Afterwards, the cells are placed in the stomach to work with the immune system to attack the malignant tumor.

Learn more by reading “In Battle Against Cancer, New Trial Fights Fire with Fire“ from KYW Newsradio and ”Immunotherapy Tested on Brain Tumors” from the Philadelphia Tribune.

Information about this upcoming trial was also mentioned on CBS 3.



Dr. Gomella Talks To 6 ABC About New Light Cystscopy To Better Detect Bladder Cancer

Each year, approximately 70,000 Americans are diagnosed with bladder cancer. In the past, detecting tumors on the bladder wall has been a challenge but a new procedure at Jefferson, blue light cystoscopy, allows doctors to better see where the tumors are located.

In an interview with 6 ABC, Dr. Leonard Gomella, chair of Jefferson’s Department of Urology, explains, “About 20 to 30% of the time, it will find high-grade, or more aggressive cancer that we will miss with the naked eye.”

He adds, ”I think this is going to make a tremendous difference to many patients.”

Read “Healthcheck: New cancer detecting tool” on 6abc.com.



Marja Nevalainen Talks to ‘Cancer Discovery’ About Science Careers

In a Dec. 1 news article  published in the American Association for Cancer Research journal Cancer Discovery,  Marja Nevalainen, M.D., Ph.D., an associate professor of cancer biology, medical oncology, and urology, offers up her insight for a story focusing on the challenges and opportunities postdocs face in an increasingly tight job market.

KCC's Dr. Marja Nevalainen

“Typically, postdoctoral training is overseen by one mentor,” says Nevalainen, who also oversees junior faculty and graduate education at the KCC. Nevalainen suggests an advisory committee of 2 or 3

members for each postdoctoral trainee, especially if the postdoc is supported by an institutional training grant (T32).

In addition, “If you have a strong basic scientist as one mentor, input from a physician–scientist may facilitate thinking about research designs in the lab that have translational applications such as therapy and biomarker development.”

Read the full article here:

“Jobs Wanted: Cancer Research”



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.



Russell J. Schilder, M.D., Joins Jefferson as Director of Gynecologic Medical Oncology

Russell Schilder, M.D.

PHILADELPHIA—Russell J. Schilder, M.D., recently joined Thomas Jefferson University Hospital as Director of the Gynecologic Medical Oncology Program at the Kimmel Cancer Center at Jefferson.

Prior to his arrival at Jefferson, Dr. Schilder served as a professor in the Department of Medical Oncology and Chief of Gynecologic Medical Oncology at Fox Chase Cancer Center.

“It’s an honor to be a part of this outstanding team of highly-skilled clinicians at Jefferson,” Dr. Schilder said. “This hospital has a great reputation, particularly with their approach to individualized patient care, the latest, cutting-edge technology and research, and a much-appreciated sense of community. I’m looking forward to my time here as the director of Gynecologic Medical Oncology.”

A graduate of Rutgers University, Dr. Schilder received both his M.S. and medical degree from the University of Miami. Dr. Schilder’s postgraduate training began at Temple University Hospital with an internship and residency in Internal Medicine. In 1989, he completed a joint hematology and oncology fellowship at Temple University Hospital and Fox Chase Cancer Center.

Board-certified in internal medicine, hematology and oncology, Dr. Schilder’s research in gynecologic oncology has been published extensively in academic journals, including the Journal of Clinical Oncology and the Clinical Cancer Research. Additionally, he serves as a reviewer for academic oncology journals, including Cancer Research.

Dr. Schilder is the principal investigator for many clinical trials that study the treatment of persistent or recurrent ovarian cancer. He is also the co-principal investigator for many other clinical trials within the Gynecologic Oncology Group.

A member of several professional societies including the American Society of Clinical Oncology, American Association of Cancer Research and the International Gynecologic Cancer Society, Dr. Schilder serves on the advisory boards of several pharmaceutical companies and has presented his oncology research at national and international scientific meetings.

His research interests include evaluating new treatments for gynecologic malignancies and conducting phase I trials for new drug development. He has written more than 150 book chapters, articles, and abstracts.

“Dr. Schilder is an incredible addition to our medical oncology team,” said William Kevin Kelly, DO, Director, Division of Solid Tumor Oncology, at Thomas Jefferson University. “The hospital and university staff and our patients will greatly benefit from his wealth of knowledge, compassion and decades of medical experience in the fields of cancer and gynecology.”



Loss of RB in Triple Negative Breast Cancer Associated with Favorable Clinical Outcome

Researchers at the Thomas Jefferson University Hospital and Kimmel Cancer Center at Jefferson have shown that loss of the retinoblastoma tumor suppressor gene (RB) in triple negative breast cancer patients is associated with better clinical outcomes. This is a new marker to identify the subset of these patients who may respond positively to chemotherapy.

Today, no such marker is applied in care of triple negative breast cancer, and as a result, patients are all treated the same.

Agnieszka Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and Erik Knudsen, Ph.D., Professor of Cancer Biology and Deputy Director of Basic Science at Jefferson’s Kimmel Cancer Center, presented the findings at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium during a poster discussion on Dec. 9.

“This is a step in trying to better direct treatment for patients with triple negative breast cancer,” Dr. Knudsen said.

In general for cancer, loss of tumor suppressor genes is associated with poor clinical outcome. However, loss of RB in triple negative breast cancer patients appears to be a predictor of favorable clinical outcomes.  This is because it changes the way tumor cells respond to therapy such that they end up becoming more sensitive to chemotherapy.

The researchers retrospectively evaluated the RB status and clinical outcome of a cohort of 220 patients diagnosed and treated at Thomas Jefferson University Hospital with chemotherapy.  RB loss, they found, was associated with a longer overall survival. In contrast, patients with RB had worse survival.

“Triple negative breast cancer is the most deadly of breast cancers, with fast-growing tumors, that affects younger women,” said Dr. Witkiewicz. “This work allowed us to identify a marker that could lead to better treatment for patients. It’s about female personalized medicine.”

Edith Mitchell, M.D., Professor of Medical Oncology at Jefferson, and Adam Ertel, Ph.D., a research instructor in the Department of Cancer Biology, were also involved in the study.

The next step for the researchers is a clinical trial at Jefferson to confirm their findings. Tumors of newly-diagnosed patients with triple negative breast cancer will be tested for the RB gene before they receive chemotherapy. After treatment, the data will be evaluated to determine the efficacy of directing future patient care.

This study represents one important example of personalized medicine being performed at the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University and the Kimmel Cancer Center to improve patient care.



Dr. Bo Lu to Lead the Radiation Therapy Oncology Group’s Lung Cancer Translational Research Program

The Radiation Therapy Oncology Group (RTOG) announced that Bo Lu, M.D., Ph.D., of Thomas Jefferson University and the Kimmel Cancer Center at Jefferson, has been appointed chair of the group’s Translational Research Program (TRP) Committee’s Lung Cancer Subcommittee. The RTOG TRP Committee supports the integration of new scientific discoveries into the design of multi-center clinical trials.

Bo Lu, M.D., Ph.D., of Thomas Jefferson University Hospital and the Kimmel Cancer Center at Jefferson

Dr. Lu is professor in the Department of Radiation Oncology at Jefferson, where he also serves as director of the department’s Division of Molecular Radiation Biology.  Prior to joining Jefferson in early 2011, Dr. Lu was associate professor in the Departments of Radiation Oncology and Cancer Biology at Vanderbilt University School of Medicine and director of the Department of Radiation Oncology’s translational research program.  He is also a visiting professor of radiation oncology at Tianjin Medical University Cancer Hospital, in Tianjing, China.

“As a member of RTOG’s Translation Research Program Committee since 2009, it has been exciting to be part of research efforts incorporating novel cancer treatment strategies into the design of early phase, multicenter clinical trials,” says Dr. Lu. Among Dr. Lu’s basic science research interests are the development of drugs that cause tumor cells to be more sensitive to radiation therapy and that target lung cancer stem cells.

“Dr. Lu is internationally renowned for his work in translational radiation oncology, and I am enthusiastic about his leadership role with regard to guiding the RTOG’s translational research agenda in lung cancer,” says Adam Dicker, M.D., Ph.D, Professor and Chairman of Radiation O­ncology at Thomas Jefferson University and RTOG’s Translational Research Program Chair. “He has demonstrated talent for applying findings from the laboratory into clinical research,” remarks Dr. Dicker.

“Dr. Lu’s extensive basic science background and insight about promising new agents will be a tremendous asset to RTOG’s Lung Cancer Committee,” says committee chair and radiation oncologist Jeffrey Bradley, M.D., Associate Professor of Radiation Oncology at Washington School of Medicine. Dr. Bradley adds, “I anticipate an exciting and productive collaboration.”

“The opportunity to work with RTOG colleagues to advance new treatment options and improve clinical care for lung cancer patients is very rewarding,” says Dr. Lu, “and I am pleased to assume an expanded role within a research organization that promotes the robust evaluation of new therapeutic approaches in radiation oncology.”

Dr. Lu received his Ph.D. in cell and molecular biology from Baylor School of Medicine and his doctorate in medicine from Shanghai Medical University in China. He completed his residency in radiation oncology at the University of Southern California. Dr. succeeds Quynh Le, M.D., Ph.D. from Stanford University who recently was named chair of RTOG’s Head and Neck Cancer Committee.

“An important goal at the Kimmel Cancer Center is to foster translational medicine—taking basic science research and moving it closer to clinical practice,” said Richard Pestell, M.D., Ph.D., FACP, Director of the Kimmel Cancer Center at Jefferson. “With his lab investigations focusing on just that, and now this appointment to RTOG’s lung cancer subcommittee, Dr. Lu will no doubt help us discover safer and more effective treatments for patients suffering from this disease.”

For more information about RTOG and the group’s Translational Research Program: www.rtog.org

# # #

The Radiation Therapy Oncology Group (RTOG) is administered by the American College of Radiology (ACR), and located in the ACR Center for Clinical Research in Philadelphia, PA. RTOG is a multi-institutional international clinical cooperative group funded primarily by National Cancer Institute grants CA21661, CA32115 and CA37422. RTOG has 40 years of experience in conducting clinical trials and is comprised of over 300 major research institutions in the United States, Canada, and internationally. The group currently is currently accruing to 40 studies that involve radiation therapy alone or in conjunction with surgery and/or chemotherapeutic drugs or which investigate quality of life issues and their effects on the cancer patient.

The American College of Radiology (ACR) is a national professional organization serving more than 32,000 radiologists, radiation oncologists, interventional radiologists and medical physicists with programs focusing on the practice of radiology and the delivery of comprehensive health care services.



New “Achilles’ Heel” in Breast Cancer: Tumor Cell Mitochondria

Researchers at the Kimmel Cancer Center at Jefferson have identified cancer cell mitochondria as the unsuspecting powerhouse and “Achilles’ heel” of tumor growth, opening up the door for new therapeutic targets in breast cancer and other tumor types.

Reporting in the online Dec.1 issue of Cell Cycle, Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Thomas Jefferson University, and colleagues provide the first in vivo evidence that breast cancer cells perform enhanced mitochondrial oxidative phosphorylation (OXPHOS) to produce high amounts of energy.

“We and others have now shown that cancer is a ‘parasitic disease’ that steals energy from the host—your body,” Dr. Lisanti said, “but this is the first time we’ve shown in human breast tissue that cancer cell mitochondria are calling the shots and could ultimately be manipulated in our favor.”

Mitochondria are the energy-producing power-plants in normal cells. However, cancer cells have amplified this energy-producing mechanism, with at least five times as much energy-producing capacity, compared with normal cells.  Simply put, mitochondria are the powerhouse of cancer cells and they fuel tumor growth and metastasis.

The research presented in the study further supports the idea that blocking this activity with a mitochondrial inhibitor—for instance, an off-patent generic drug used to treat diabetes known as Metformin—can reverse tumor growth and chemotherapy resistance. This new concept could radically change how we treat cancer patients, and stimulate new metabolic strategies for cancer prevention and therapy.

Investigating the Powerhouse

Whether cancer cells have functional mitochondria has been a hotly debated topic for the past 85 years. It was argued that cancer cells don’t use mitochondria, but instead use glycolysis exclusively; this is known as the Warburg Effect. But researchers at the Jefferson’s KCC have shown that this inefficient method of producing energy actually takes place in the surrounding host stromal cells, rather then in epithelial cancer cells.  This process then provides abundant mitochondrial fuel for cancer cells. They’ve coined this the “Reverse Warburg Effect,” the opposite or reverse of the existing paradigm.

To study mitochondria’s role directly, the researchers, including co-author and collaborator Federica Sotgia, Assistant Professor in the Department of Cancer Biology, looked at mitochondrial function using COX activity staining in human breast cancer samples. Previously, this simple stain was only applied to muscle tissue, a mitochondrial-rich tissue.

Researchers found that human breast cancer epithelial cells showed amplified levels of mitochondrial activity. In contrast, adjacent stromal tissues showed little or no mitochondrial oxidative capacity, consistent with the new paradigm.  These findings were further validated using a computer-based informatics approach with gene profiles from over 2,000 human breast cancer samples.

It is now clear that cancer cell mitochondria play a key role in “parasitic” energy transfer between normal fibroblasts and cancer cells, fueling tumor growth and metastasis.

“We have presented new evidence that cancer cell mitochondria are at the heart of tumor cell growth and metastasis,” Dr. Lisanti said. “Metabolically, the drug Metformin prevents cancer cells from using their mitochondria, induces glycolysis and lactate production, and shifts cancer cells toward the conventional ‘Warburg Effect’.  This effectively starves the cancer cells to death”.

Personalized Treatment

Although COX mitochondrial activity staining had never been applied to cancer tissues, it could now be used routinely to distinguish cancer cells from normal cells, and to establish negative margins during cancer surgery. And this is a very cost-effective test, since it has been used routinely for muscle-tissue for over 50 years, but not for cancer diagnosis.

What’s more, it appears that upregulation of mitochondrial activity is a common feature of human breast cancer cells, and is associated with both estrogen receptor positive (ER+) and negative (ER-) disease. Outcome analysis indicated that this mitochondrial gene signature is also associated with an increased risk of tumor cell metastasis, particularly in ER-negative (ER-) patients.

“Mitochondria are the ‘Achilles’ heel’ of tumor cells,” Dr. Lisanti said. “And we believe that targeting mitochondrial metabolism has broad implications for both cancer diagnostics and therapeutics, and could be exploited in the pursuit of personalized cancer medicine.”



Dr. Iozzo’s Work Chosen as Editor’s Choice in Science

Dr. Renato Iozzo

Dr. Renato Iozzo

A recent Science Signaling article (Science Signaling) (Pubmed Abstract), co-Senior Authored by Dr. Renato Iozzo, entitled “Signaling by the Matrix Proteoglycan Decorin Controls Inflammation and Cancer Through PDCD4 and MicroRNA-21″, was selected in the November 21st issue of Science Magazine as the Editor’s Choice (more info) in the Cell Signalling Category. Dr. Renato Iozzo is a Professor of Pathology & Cell Biology and is a member of the Kimmel Cancer Center’s Cancer Cell Biology and Signaling Research Program.



KCC’s 3rd Annual Men’s Event

Another successful year! The Kimmel Cancer Center hosted its 3rd annual Men’s Event at the Prime Rib in Philadelphia on November 15.

About 150 people joined Richard Pestell, M.D., Ph.D., Director, Kimmel Cancer Center at Jefferson, Leonard Gomella, M.D., Chair, Department of Urology at Jefferson and 2011 Men’s Event Co-Chairs Edward Glickman, President of Pennsylvania Real Estate Investment Trust, and Joseph Weiss, Chairman, Electronic Ink, for an evening of cocktails, dinner, entertainment, auctions and friends.

The dinner and auction raised more than $100,000 to build awareness about prostate cancer and benefit research at Jefferson’s National Cancer Institute Designated Cancer Center.

At this year’s event, John W. Buehler, Jr., a prostate cancer survivor and KCC patient, received the “Symbol of Courage” award, and Kenny Boone was recognized for his support of prostate cancer research and awareness with a “Symbol of Caring” award.

Here’s a glimpse of the night.

Dr. Richard Pestell, director of the KCC

Men's Event auction raised over $100,000

Co-chair Joe Weiss

Eagles long snapper Jon Dorenbos emceed the event

Prostate cancer survivor John Buehler received the "Symbol of Courage" award

Drs. Adam Dicker and Neal Flomenberg

Jessica Soens, Guy Galcerno, Ellen Doubet, and Don Seitz






Dr. Timothy Showalter receives 2011 Ben Franklin PCF Young Investigator Award

Timothy Showalter, M.D., of the Department of Radiation Oncology, was one of 24 people to be named a new Young Investigator by the Prostate Cancer Foundation in 2011.

Young Investigator awards are designed to encourage the most innovative minds in cancer research to focus their careers on prostate cancer. These grants provide three years of funding for transformational research focused on prostate cancer treatments and patients.

Timothy Showalter, M.D., 2011 Ben Franklin PCF Young Investigator Award Recipient

With the addition of these grants, the Young Investigators represent a $5.32 million investment in the global cancer research community. Since 2007, PCF has invested more than $16.5 million in Young Investigator grants. Each Young Investigator recipient is awarded $225,000 over a three-year period. Funding is also matched dollar-for-dollar by each recipient’s research institution to protect time or to bridge salary support prior to a first government grant, making the total award worth $450,000.

Dr. Showalter, whose mentors include the Chair of Radiation Oncology, Adam Dicker, M.D., and Theresa Hyslop, PhD, of the Department of Pharmacology & Experimental Therapeutics, received this prestigious award for his ongoing investigation of the benefits of adjuvant radiation therapy (RT) after a radical prostatectomy and physician perceptions of the treatment option.

For prostate cancer patients at higher risk of recurrence after radical prostatectomy (RP), early RT has been shown in randomized trials to improve PSA-relapse free survival, metastasis-free survival and overall survival. Despite evidence to support adjuvant RT, less than 20% of qualifying patients in the U.S. actually receive this treatment. A national survey conducted by Dr. Showalter and colleagues has previously shown that urologist recommendations for adjuvant RT are influenced by perceptions of RT-related toxicity. The evidence to inform these toxicity estimates is lacking. Therefore, it is essential to bridge this difference by elucidating the real-world complication rates of post-prostatectomy RT, and to critically evaluate the significance of RT timing on the risk of complications.

Dr. Showalter’s findings will improve management of high-risk prostate cancer, including the influence of timing after surgery, improve cure rates for these patients, and limit complications for lower risk patients.

“Young Investigators provide the most innovative and ground-breaking ideas in prostate cancer research,” said Howard Soule, PhD, chief science officer and executive vice president of PCF. “With their fresh ideas, the field of prostate cancer research will be heavily impacted and improved, and lives will be saved. We are extremely grateful to our generous donors who support these Young Investigators and have allowed our foundation to award 24 new recipients.”



ACS-IRG Pilot Projects Awarded for 2011

The Kimmel Cancer Center at Jefferson hosted the Annual ACS-IRG Luncheon on October 20. The 2011 Pilot Project recipients are Takemi Tanaka, PhD. of the Department of Pharmaceutical Sciences, Benjamin Leiby, PhD from the department of Pharmacology & Experimental Therapeutics, Timothy Showalter, MD, department of Radiation Oncology, Ayush Dagvadorj, MD, PhD, and A. Kathleen McClendon, PhD, both of the department of Cancer Biology. They briefly explained their research projects to RuthAnn Dailey, Regional Vice-President, and Larry Slagle, Distinguished Giving Director, Southeast Region, 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.

Dr. Ayush Dagvadorg, Dr. Tim Showalter, Dr. Marja Nevalainen, Dr. Katie McClendon, Mr. Larry Slagle, Dr. Takemi Tanaka, MS. RuthAnn Dailey, and Dr. Ben Leiby



Kimmel Cancer Center Hosts Interurban Clinical Club

On Friday, October 28, the Kimmel Cancer Center at Jefferson hosted the 204th meeting of the Interurban Clinical Club at Jefferson Medical College of Thomas Jefferson University.

Drs. Michael Lisanti, Richard Pestell, Carrie Sims and Michael Root at the 204th meeting of the Interurban Clinical Club at the Union League of Philadelphia.

The Interurban Clinical Club is a prestigious club founded by Sir William Osler in 1905 for the purpose of exchanging ideas and fellowship among medical teachers in some of the leading Eastern medical schools.

Several prominent physicians and researchers from institutions in the Philadelphia region presented the latest in their cancer research and other disciplines.

Many KCC researchers spoke at the all-day event, including opening remarks by Richard Pestell, M.D., Ph.D., director of the KCC, Steven McMahon, Ph.D., Erik Knudsen, Ph.D., Michael Lisanti, M.D., Ph.D, and Michael Root, M.D., Ph.D.

That night, a black tie cocktail reception and dinner were held at the Union League of Philadelphia, with a special performance by “The Arrhythmia, a capella group made up of a dozen students in such fields as medicine, pharmacy, and doctoral studies at Jefferson Medical College.

This year, the Sir William Osler Young Investigator Award was given to Jordan Orange, M.D., Ph.D., an Associate Professor of Pediatrics at the University of Pennsylvania School of Medicine.

Dr. Mark Zeidel, the ICC President, also presented Dr. Alfred Knudson, of Fox Chase Cancer Center, with a gift as a “thank you” and in recognition of his extensive accomplishments in cancer research.

There are five to nine active members of the ICC  from each city, including Baltimore, Boston, New Haven, New York and Philadelphia. Existing members of the ICC from the Kimmel Cancer Center at Jefferson include Richard Pestell, M.D., Ph.D., Barry J. Goldstein, M.D., Scott Waldman, M.D., Ph.D, and Michael Lisanti, M.D., Ph.D.

See below for photographs from the event:

The Arrhythmias performing at the Union League of Philadelphia before the dinner and lecture

Dr. Wafik El-Deiry (ICC Secretary/Treasurer), Dr. Michael Levine, Dr. Jordan Orange, Dr. Steven Douglas, Dr. Richard Pestell. Dr. Orange is being presented with the 2011 Sir William Osler Young Investigator Award

Dr. Rochelle Hirschhorn and Dr. Kurt Hirschhorn at the Union League of Philadelphia

Dr. Pestell, Dr. Mark Zeidel (ICC President), and special guest speaker Dr. Alfred Knudson. Dr. Zeidel was presenting Dr. Knudson with a gift as a thank you and in recognition of his extensive accomplishments in cancer research




Gordon Schwartz, M.D., Nominated to National Accreditation Program for Breast Centers Board

Gordon F. Schwartz, MD, MBA, FACS, director of the Jefferson Breast Care Center

Gordon F. Schwartz, MD, MBA, FACS, director of the Jefferson Breast Care Center, will represent the American Society of Breast Disease on the board of the National Accreditation Program for Breast Centers (NAPBC).

The NAPBC is a consortium of national, professional organizations dedicated to the improvement of the quality of care and the monitoring of outcomes for patients with diseases of the breast.

Dr. Schwartz attended his first meeting as a member of the board in San Francisco the week of October 24 during the 2011 Clinical Congress of the American College of Surgeons.

Dr. Schwartz is an internationally renowned expert in breast diseases and a professor of surgery and medical oncology at Thomas Jefferson University Hospital.  His practice has been dedicated to treating breast diseases, both benign and malignant, for more than 30 years.

In 2009, Dr. Schwartz became director of the Jefferson Breast Care Center—one of the first Academic Medical Institutions receiving full accreditation by NAPBC.