Doubling up on Advanced Prostate Cancer with PARP Inhibitors

A newly discovered function of PARP-1 could be the key to more effective therapeutics to treat advanced prostate cancer patients, a recent preclinical study published in Cancer Discovery by Jefferson’s Kimmel Cancer Center researchers suggests.

Karen E. Knudsen, Ph.D., Professor in the Departments of Cancer Biology, Urology, & Radiation Oncology

The team, led by Karen E. Knudsen, Ph.D., Professor in the Departments of Cancer Biology, Urology, & Radiation Oncology at Thomas Jefferson University, found that functions of PARP-1 not only include DNA damage repair but also androgen receptor (AR) regulation in advanced prostate cancer growth and progression.  PARP inhibition in various models was found to suppress AR activity, which fuels prostate growth.

Researchers believe that the dual functions of PARP-1—as both a regulator of AR as well as critical for DNA damage repair—could be leveraged for therapeutic benefit.  PARP inhibitors could slow down advanced-stage prostate cancer and shrink tumors, the team surmises.

“We hope to capitalize on this previously unknown function in PARP-1 in prostate cancer,” said Dr. Knudsen. “Our data show that PARP-1 plays a major role in controlling AR function and that, when suppressed with inhibitors, enhanced anti-tumor effects of castration and delayed onset to castration resistance. “

“This is the basis to support a clinical trial investigating PARP-1 inhibitors in patients with advanced disease,” she added.

Today, PARP-1 is seen as a valuable target because of its involvement in DNA damage repair for cancer cells. The therapy has been successful when combined with DNA-damaging drugs because it heightens the apoptotic activity of these drugs. In other words, it helps halt tumor growth by stopping DNA repair in various cancers.

Prostate cancer is dependent on AR activity for growth and survival, and is largely resistant to standard chemotherapy. AR-directed therapies are the first-line intervention for patients with advanced disease; however, recurrent tumors arise when AR is reactivated, a common occurrence in the castrate-resistant stage of the disease.

Therefore, there is a dire need to develop means to suppress the AR function in these patients. With this new role defined, PARP inhibitors targeting both functions could sensitize prostate cancer cells to DNA damage, and potentially improve the efficacy of AR-directed therapies in these patients, the researchers suggest in the paper.

Almost 40 percent of men with prostate cancer progress into an advanced stage, termed castrate-resistant prostate cancer, where chemotherapy and other therapies have little to no effect.

Using various in vitro and in vivo model systems, the researchers found that PARP-1 activity is required for AR function and is increased in castrate-resistant prostate cancer.  Additionally, inhibiting PARP-1 suppressed proliferation of cultured, primary human tumor specimens in a state-of-the-art system.

“These findings introduce a paradigm shift with regard to PARP-1 in prostate cancer,” said Dr. Knudsen, “and provide the basis for new therapies that could help a whole population of cancer patients who have little options.”

Dr. Knudsen recently received a two-year Challenge Award worth $1 million from the Prostate Cancer Foundation (PCF) for her work with PARP-1 and prostate cancer, and attended PCF’s 10th annual fundraiser in Philadelphia.

The study from Dr. Knudsen’s laboratory was a result of an inter-institutional team effort, including the contributions of lead author and postdoctoral fellow Dr. Matthew Schiewer, of the Department of Cancer Biology at Thomas Jefferson University, as well as key collaborators: Dr. Felix Feng (University of Michigan), Drs. Wayne Tilley and Lisa Butler (University of Adelaide), Dr. Ganesh Raj (UT Southwestern), Dr. Peter McCue, Dr. Leonard Gomella, Dr. Adam Dicker, Dr. Jonathan Brody, and Dr. John Pascal of Thomas Jefferson University.

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This work was supported by NIH grants (R01 CA099996-09, and R01 ES016675-11), the Commonwealth of Pennsylvania grant, a Prostate Cancer Foundation Creativity award, a Prostate Cancer Foundation Young Investigator Award grants from the National Health and Medical Research Council of Australia, a Cancer Council of South Australia Senior Research Fellowship, and Pre-doctoral Fellowships from the DOD.



KCC’s New Magazine “Milestones” is Now Available

Jefferson’s Kimmel Cancer Center announces its first issue of “Milestones,” an online magazine covering breakthrough research, faculty, clinical updates, events and all things KCC.

This issue’s cover story delves into the latest advances in cancer genomics and how researchers are transforming cancer treatment with focused genomics.

“The work of Dr. Paolo Fortina and the staff in the Cancer Genomics Shared Facility allow the cancer center to provide the highest quality genomic analysis using Next Generation Sequencing (NGS). The technology allows us to determine the molecular drivers of an individual patient’s tumor. With NGS, we will provide more specific therapy, targeting the molecular mechanisms driving an individual patient’s tumor. In this way, we will provide the most specific and least toxic therapies for all patients who come to our door,” writes Richard G. Pestll, M.D., Ph.D., Director of the KCC, in this issue’s “Director’s Perspective.”

Look for Q&A sections on researchers and clinical staff, the latest in melanoma and breast cancer research, the phase I clinical trial program, and past and future events, including November’s Men’s Event with comedian Jay Mohr.

To read the online version of the 2012 Fall/Winter “Milestones” magazine, please visit
http://www.kimmelcancercenter.org/about/Fall-Winter-2012-Milestones.pdf



Tissue around tumor holds key to fighting triple negative breast cancer

Renato V. Iozzo, M.D., Professor of Pathology, Anatomy and Cell Biology, at Thomas Jefferson University

A natural substance found in the surrounding tissue of a tumor may be a promising weapon to stop triple negative breast cancer from metastasizing.

A preclinical study published in PLOS ONE September 19 by Thomas Jefferson University researchers found that decorin, a well-studied protein known to help halt tumor growth, induces a series of tumor suppressor genes in the surrounding tissue of triple negative breast cancer tumors that help stop metastasis.

“These findings provide a new paradigm for decorin, with great implications for curbing tumor growth by inducing new tumor suppressor genes within the tumor microenvironment, and for the discovery of novel gene signatures that could eventually help clinical assessment and prognosis,” said senior author Renato V. Iozzo, M.D., Professor of Pathology, Anatomy and Cell Biology, at Thomas Jefferson University.

Triple negative breast cancer is the most deadly of breast cancers, with fast-growing tumors, that disproportionately affect younger and African-American women. Today, no such marker is applied in care of triple negative breast cancer, and as a result, patients are all treated the same.

“Originally, we thought that decorin was affecting the tumor, but, surprisingly, decorin affects the so-called tumor microenvironment, where malignant cells grow and invade, igniting genes to stop such growth,” said Dr. Iozzo, who is also a member of Jefferson’s Kimmel Cancer Center. “Absence of decorin in the microenvironment could explain metastasis in some patients, where higher levels of the protein may keep cancer from spreading.”

In the study, 357 genes were found to be induced by the increased presence of decorin, but more interestingly, the researchers discovered that three of these genes, which were previously unlinked to triple negative breast cancer, were tumor suppressor genes affecting the tumor microenvironment, including Bmp2K, Zc3hav1, and PEG3.

Decorin is a naturally occurring substance in the connective tissue where, among other roles, it helps regulate cell growth by interacting with growth factors and collagen. A decade ago, Dr. Iozzo and his team discovered that decorin, a cell protein, and specifically, a proteoglycan, is increased in the matrix surrounding tumor cells. They also discovered that decorin causes production of a protein, p21, which also can arrest cell growth. However, decorin’s role in breast cancer and the mechanism behind its anti-tumor properties remained elusive.

For this study, researchers aimed to investigate the impact of decorin in triple negative breast cancer tumors using human cell lines in mice, as well analyze gene expression activity in the tumor microenvironment.

Tumors treated with decorin were found to have a decreased volume of up to 50 percent after 23 days. Using a sophisticated microarray technique, the researchers then analyzed the mouse tumor microenvironment, finding increased expression of 357 genes, three of which are the tumor suppressor genes of interest.

These results demonstrate a novel role for decorin in reduction or prevention of tumor metastases that could eventually lead to improved therapeutics for metastatic breast cancer.

“Here, we have a molecule that can turn a tumor microenvironment from a bad neighborhood to a clean neighborhood by inducing genes in that neighborhood to stop growth and prevent the tumor from metastasizing,” said Dr. Iozzo.



Jefferson and the Eagles Team Up for Prostate Health and Cancer Awareness

Eagles player Jason Avant and Dr. Leonard Gomella, Chair of Urology at Jefferson

September is Prostate Cancer Awareness month, and Thomas Jefferson University Hospitals has again teamed up with the Philadelphia Eagles to educate fans and others about prostate health and to raise cancer awareness.

To help kick off the campaign, Jefferson will serve as the presenting partner at the Sunday, September 16 game versus the Baltimore Ravens, with Edouard Trabulsi, M.D., Director of Multidisciplinary Genitourinary Oncology Center of the Kimmel Cancer Center at Jefferson (KCC),  and David P. McQuaid, FACHE, President, Thomas Jefferson University Hospitals, Inc., receiving Eagles jerseys on the field before kickoff.

“The KCC and our Departments of Urology, Medical Oncology and Radiation Oncology are deeply honored and grateful to once again have the Eagles as our partners,” said Leonard Gomella, MD, chair of the Department of Urology at Thomas Jefferson University Hospitals and director of clinical affairs at the KCC. “Prostate cancer is the second leading cause of cancer death among men, and over 200,000 will be diagnosed this year alone.  That’s why it’s so important for men to take their prostate health seriously.”

Prostate cancer is the most common type of cancer among men, with one in six men being diagnosed in his lifetime, and most treatable if caught early.

“In the months ahead, Jefferson and the Eagles look forward to more victories on the field and in raising prostate cancer awareness,” Dr. Gomella said.

Eagles wide receiver Jason Avant is also joining forces with Jefferson to help spread prostate health awareness, participating in several community events and a public service announcement with Dr. Gomella on the importance of prostate health and screening.

For the 23rd consecutive year, Jefferson Hospitals will also offer free prostate health and cancer screenings on September 19 and 25 from 9 a.m. to 3 p.m. (registration required). Call 1-800-JEFF-NOW to make an appointment.



KCC Becomes Provisional ECOG Member

In August, The Eastern Cooperative Oncology Group (ECOG) voted to approve Jefferson’s Kimmel Cancer Center and Thomas Jefferson University Hospital as a Provisional Member.

ECOG is one of the largest clinical cancer research organizations in the United States, and conducts clinical trials in all types of adult cancers. It constitutes a large network of private and public medical institutions that work toward developing various protocols for effective cancer treatments.

It was established in 1955 as one of the first cooperative groups launched to perform multi-center cancer clinical trials.

Funded primarily by the National Cancer Institute (NCI), ECOG has evolved from a five member consortium of institutions on the East Coast to one of the largest clinical cancer research organizations in the U.S. with almost 6000 physicians, nurses, pharmacists, statisticians, and clinical research associates (CRAs) from the U.S., Canada, and South Africa.

Institutional members include universities, medical centers, Community Clinical Oncology Programs (CCOPs), and Cooperative Group Outreach Programs (CGOPs). These institutions work toward the common goal of controlling, effectively treating, and ultimately curing cancer. Research results are provided to the worldwide medical community through scientific publications and professional meetings.

Currently, ECOG has more than 90 active clinical trials in all types of adult malignancies. Annual accrual is 6,000 patients, with more than 20,000 patients in follow-up.

For more information, please visit http://www.ecog.org/



Dr. Karen Knudsen Led Group Receives Million Dollar Prostate Cancer Foundation Award

Karen Knudsen, Ph.D.

A group of investigators led by Dr. Karen Knudsen was awarded a 2-year challenge grant of one million dollars by the Prostate Cancer Foundation.  The details of this award (from the PCF web site) are:

2012 Movember-PCF Challenge Award

Lead Investigator:
Karen Knudsen, PhD
Thomas Jefferson University

Title
Interrogation of Aberrant DNA Repair in Sporadic Prostate Cancer

Co-investigators: Johann De Bono, MD, PhD, Royal Marsden Hospital; Felix Feng, MD, University of Michigan; Mark Rubin, MD, Weill Cornell Medical College.

What this means to patients: Understanding the extent and impact of alterations in DNA Damage Response pathways in prostate cancer patients will target specific DNA repair problems and allow effective Precision Medicine (tailored treatment regimens) based on molecular subtyping of patient DDR alterations matched to drug therapy.

Synopsis: DNA Damage Response (DDR) pathway alterations are changes in DNA repair mechanisms that promote genomic instability and have been associated with local and advanced prostate cancer. Dr. Knudsen and team will identify and comprehensively determine the frequency of abiraterone in DDR pathways at different stages of prostate cancer progression. They will determine the clinical relevance of these DNA repair defects in prostate cancer patients and their role in the development and progression of treatment-resistant prostate cancer. Previous studies showed that the DNA repair protein PARP1 is elevated in tumors of advanced prostate cancer patients. PARP1 is recruited to sites of androgen receptor function and is required for AR activity in both hormone-dependent and treatment refractory disease. PARP inhibition therefore has dual effects on cancerous cells; 1) impairs DNA repair in tumors and, 2) suppresses AR signaling—halting cancer progression. Dr. Knudsen and colleagues will evaluate effects of combination therapy with PARP inhibitors and next generation anti-androgens in treatment-resistant prostate cancer patients.



Dr. Onder Alpdogan and Dr. Jianqing Lin Granted ACS-IRG Awards

Congratulations to Dr. Onder Alpdogan and Dr. Jianqing Lin for each being selected recipients of an ACS-IRG award.

The American Cancer Society-Institutional Research Grants (ACS-IRG) are designed to provide seed money to support junior faculty members with an interest in cancer research. The ACS defines junior faculty as investigators at the rank of assistant professor or equivalent who are eligible to apply as a principal investigator for grant support from national agencies.

Jianqing Lin, M.D., assistant professor of medical oncology


Dr. Lin’s Research Overview
The current proposal is a continuation of the concept that digoxin is an inhibitor of HIF-1a that will subsequently slow the growth of prostate cancer progression. Since the drug has minimal toxicity, it would be an ideal therapy to explore in other disease states in prostate cancer. With the awareness of over-treatment and treatment related complications in men with low-risk localized prostate cancer patients are willing to be on active surveillance. This current proposal is to examine the effects of digoxin to delay or reverse prostate cancer progression, with significant effort on tissue acquisition and to understand the molecular pathway affected with the treatment of digoxin. This study will shed light on the effects of future HIF-1a inhibitors for the treatment of prostate cancer and the foundation for future NIH funding.

Dr. Alpdogan’s Research Overview

Onder Alpdogan, M.D., assistant professor of medical oncology

Use of haploidentical HSCT in the treatment of advanced/relapsed RCC is a novel idea and has never been studied in preclinical models. We believe that haploidentical transplant model is a better platform to develop immunotherapy to solid tumors specificall renal cell carcinoma. Immunological response would be faster than other transplant models because of MHC disparity. This innovative new approach might give us an opportunity to develop new treatment strategies for patients with resistant/relapsed RCC after exhausting standard therapy including cytokine (IL-2) and Tyrosine Kinase Inhibitors (TKIs). These studies will not only generate new information about clinically relevant treatment strategies, but also provide substantial new findings about stem cell biology and transplantation.



Voichita Bar-Ad, M.D., Named Residency Program Director in Jefferson’s Radiation Oncology Department

Voichita Bar-Ad, M.D., an associate professor in the Department of Radiation Oncology at Thomas Jefferson University Hospital

Voichita Bar-Ad, M.D., an associate professor in the Department of Radiation Oncology at Thomas Jefferson University Hospital and Jefferson’s Kimmel Cancer Center, has been named Residency Program Director.

Dr. Bar-Ad is a board-certified radiation oncologist who treats primarily head and neck and gastrointestinal cancer cases. Her research focuses on treatment-related side effects and toxicities, patient quality of life and symptom management. She has paid specific attention to radiation-induced oral mucositis for head and neck cancer patients treated with radiotherapy or concurrent chemoradiotherapy, using the intensity- modulated radiation therapy technique.

“I am devoted to my patients and immersed in my research projects, but teaching is my joy, my passion,” Dr. Bar-Ad said last fall when she was named an “Educator of the Year” by the Association of Residents in Radiation Oncology (ARRO).

“This new role as Program Director enables me to continue what I love to do, guiding and teaching residents,” said Dr. Bar-Ad. “I’m greatly honored, and feel fortunate to lead a program that trains the radiation oncologists of tomorrow to have excellent clinical and research skills.”

Radiation oncology residency at Jefferson is a four-year training program, with resident having already completed one year of post-graduate training in medicine, surgery, or a transitional program.

The residency in radiation oncology trains residents broadly in cancer management and emphasizes interdisciplinary care.  Faculty members provide instruction in all modes of radiation oncology:  megavoltage photon- and electron-beam therapy, interstitial and intracavitary radioactive-source implantations, stereotactic radiosurgery and radiotherapy, intensity modulated radiation therapy and the diagnostic and therapeutic uses of radioactive isotopes.

In addition to the residents unanimously selecting Dr. Bar Ad for the ARRO 2011 Teacher of the Year Award, they also selected her to receive the 2012 Department of Radiation Oncology’s “Teacher of the Year Award,” an honor bestowed every June by the residents to the one faculty member who has helped them the most in their educational experience.

Jefferson’s Residency Program became accredited in 1973, but has been in existence since 1960.  The first resident, Dr. Carl Mansfield, went on to become a Chair of the Department, a position he maintained until May 1995, when he went to the National Cancer Institute to serve as a director of the Radiation Research Program

“Thomas Jefferson University Hospital has created one of the nation’s most outstanding residency programs in radiation oncology, and it is with great honor to have such a distinguished physician, researcher and teacher help continue that tradition,” said Adam P. Dicker, M.D., Ph.D., Chair of the Department of Radiation Oncology. “A strong residency program is essential for the successes of an academic medical center, and I look forward to having Dr. Bar-Ad’s leadership bring significant benefits to our residents and patients.”



Nicole Simone, M.D., Receives ASTRO Research Award

Nicole L. Simone, M.D., Department of Radiation Oncology

The American Society for Radiation Oncology (ASTRO) has awarded five physicians with research grants to promote the continued advancement of radiation therapy.

One of this year’s recipient for the Junior Faculty Career Research Training Award is Nicole L. Simone, M.D., of the Department of Radiation Oncology at Thomas Jefferson University Hospital.

The Junior Faculty Award provides $100,000 annually for two years to help develop the careers of promising junior faculty by allowing them dedicated time to work on research relevant to radiation oncology and cancer treatment.

It is presented each year to board-eligible physicians or physicists in radiation oncology or radiobiologists who are within the first three years of their junior faculty appointment.

The Residents/Fellows in Radiation Oncology Research Seed Grant Award was established to support residents or fellows who are planning a career focused on basic science or clinical research to support a pilot project related to radiation therapy. The grants are awarded each year for a one-year project and are in the amount of $25,000 each.

Recipients were selected by ASTRO’s Research Evaluation Committee.

‘Providing these leaders of tomorrow with the necessary funding for their valuable research is essential for the radiation oncology field,” said Leonard L. Gunderson, MD, MS, FASTRO, chairman of the ASTRO Board of Directors, said in a release. “It is very rewarding to know that these grants are going to physicians whose research will make a lasting impact on our field.”

For more on the ASTRO awards, visit https://www.astro.org/News-and-Media/News-Releases/2012/ASTRO-awards-five-research-grants.aspx



Breast Cancer Patients Who Lack RB Gene Respond Better to Neoadjuvant Chemotherapy

Breast cancer patients whose tumors lacked the retinoblastoma tumor suppressor gene (RB) had an improved pathological response to neoadjuvant chemotherapy, researchers at Thomas Jefferson University Hospital and the Kimmel Cancer Center at Jefferson report in a retrospective study published in a recent online issue of Clinical Cancer Research.

Many breast cancer patients undergo neoadjuvant therapy to reduce the size or extent of the cancer before surgical intervention.   Complete response of the tumor to such treatment signifies an improved overall prognosis.  Today, no marker is applied to identify tumors which will respond to such treatment, and as a result, only a subset of patients exhibit benefit from it.

“We found that loss of RB was associated with better pathological response rates in breast cancer patients—at various stages and representing multiple molecular subtypes—who were administered neoadjuvant chemotherapy,” said Agnieszka Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University.

Erik Knudsen, Ph.D, Professor of Cancer Biology and the Hilary Koprowski Chair in Cancer Biology, was excited that discoveries from his life-long research on the RB-pathway were making their way into the clinic. “This represents a potential new biomarker that could be used to tailor treatment plans for women considering neoadjuvant therapy and is a testament to the importance of cancer research,” he said.

For the study, researchers, including Gordon Schwartz, M.D., Director of the Jefferson Breast Care Center and Adam Ertel, Ph.D., Bioinformatics Specialist, Department of Cancer Biology, performed a combination of gene expression profiling to identify those with RB loss and direct histological analysis in over 1,000 breast cancer patients who had undergone neoadjuvant therapy.   These patients represented distinct subtypes of breast cancer and were treated with multiple different therapeutic regimens.

RB loss was associated, the team found, with an improved response to all the neoadjuvant regimens investigated in the major subtypes of breast cancer.

“Together, these data indicate that the loss of RB, which occurs relatively frequently in locally advanced disease, could be a useful tool for defining patients who experience an improved response to neoadjuvant chemotherapy,” said Dr. Witkiewicz. “Based on these findings, we have initiated a prospective clinical trial at Jefferson, evaluating the association of RB and another marker, PTEN, with the response to neoadjuvant chemotherapy.”

The clinical trial is open to patients who have a diagnosis of triple negative breast cancer and are eligible for neoadjuvant chemotherapy. (clinicaltrials.gov/ct2/show/NCT01514565).



Thomas Jefferson University Hospital Ranked Among Best for Cancer by U.S. News & World Report

Thomas Jefferson University Hospital has again been ranked as one of the nation’s best hospitals for cancer care by the U.S. News & World Report, coming in at No. 20 in the 2012 Best Hospitals survey.

Last year, Jefferson ranked 31st in the nation for cancer.

In addition, the hospital was ranked number three in the state of Pennsylvania and number two in the Philadelphia metro area.

This year, the institution ranked among the best in the nation in 11 specialty areas, including cancer. What’s more, there was a dramatic improvement in nine of those 11 ranked specialties.

U.S. News & World Report this year named Thomas Jefferson University Hospital 7th in the nation in orthopedics, 12th in pulmonology, and 14th for rehabilitation medicine.  Jefferson was also nationally ranked in diabetes and endocrinology (25), ear nose and throat (16), gastroenterology (22), geriatrics (31), gynecology (40), nephrology (39), and urology (27).

The urology ranking is 21 places higher than last year.

“Jefferson University Hospital is again honored to be among the top hospitals across so many specialties.  This recognition is a reflection of our commitment to our patients and providing a standard of care that is among the very best in the nation and the region.  Our clinicians and staff work tirelessly to move us forward and provide the high-quality care the community has come to expect from Jefferson,” said David P. McQuaid, FACHE, President, Thomas Jefferson University Hospitals, Inc.

Since its establishment in 1825, this academic medical center has provided nationally recognized care intended to improve the health of all the communities it serves. Jefferson accomplishes its mission in partnership with Thomas Jefferson University and as a member of the Jefferson Health System.



ATP: From Bystander to Actor in Kinase Regulation

Tung O. Chan, Ph.D.

A new function of ATP—beyond its passive roles as an energy source and a phosphate donor for phosphorylation reactions—was unraveled by Jefferson researchers.

Their studies revealed a new model of kinase regulation, whereby ATP modulates an “on-off-switch” mechanism in Akt by inducing conformational changes in the Akt kinase domain.

The three members of the Akt protein kinase family play key roles in multiple cellular processes, including glucose metabolism, cell survival and proliferation, and cell migration. The Jefferson team’s data was reported in the Proceedings of the National Academy of Sciences (PNAS) and was the subject of a perspective in Science Signaling in their May issue, entitled “Uncaging Akt.”

Jefferson paper’s senior author Tung O. Chan, Ph.D., assistant professor at Jefferson’s Center for Translational Medicine and Ulrich Rodeck, M.D., Ph.D., professor at the Department of Dermatology and Cutaneous Biology, indicate that their work, together with a complimentary study by Genentech researchers, describes a new mechanism with high translational appeal.

Ulrich Rodeck, M.D., Ph.D.

A molecular switch that affects the activation state of specific Akt isoforms may be exploited to modulate Akt signal strength in malignant diseases, as well as in diabetes and diseases of the heart and the central nervous system.

The Jefferson studies were conducted by a team of investigators at the Center for Translational Medicine, Department of Medicine and Kimmel Cancer Center, in collaboration with colleagues in the Departments of Dermatology and Cutaneous Biology, Radiation Oncology, Molecular Biology and Biochemistry, and Pharmaceutical Sciences.



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.



How Aging Normal Cells Fuel Tumor Growth and Metastasis

It has long been known that cancer is a disease of aging, but a molecular link between the two has remained elusive.

Now, researchers at the Kimmel Cancer Center at Jefferson (KCC) have shown that senescence (aging cells which lose their ability to divide) and autophagy (self-eating or self-cannibalism) in the surrounding normal cells of a tumor are essentially two sides of the same coin, acting as “food” to fuel cancer cell growth and metastasis.

Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the KCC, and his team previously discovered that cancer cells induce an oxidative stress response (autophagy) in nearby cells of the tumor microenvironment to feed themselves and grow.

In this study, senescent cells appear to have many of the characteristics of these autophagic cancer-associated fibroblasts and to be part of the same physiological process.  In other words, normal neighboring cells that are becoming senescent or “old” are directly making food to “feed” the cancer.  Aging literally fuels cancer cell growth.

Since senescence is thought to reflect biological aging, this research on autophagy-induced senescence may explain why cancer incidence dramatically increases exponentially with advanced age, by providing a “fertile soil” to support the anabolic growth of “needy” cancer cells.

The findings were reported in the June 15 issue of Cell Cycle.

“This research merges the two paradigms of aging and cancer, and it also brings in cell metabolism,” said Dr. Lisanti. “We provide genetic support for the importance of ‘two-compartment tumor metabolism’ in driving tumor growth and metastasis via a very simple energy transfer mechanism. Senescence and autophagy metabolically support tumor growth and metastasis.”

Simply put, aging is the metabolic engine that drives cancer growth.

To test this link, the researchers developed a genetically tractable model system to directly study the compartment-specific role of autophagy in tumor growth and metastasis.  First, they took human fibroblasts immortalized with telomerase and transfected them with autophagy genes.

Next, they validated that these fibroblasts show features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, with increases in lactate and ketone production, mimicking the behavior of cancer-associated fibroblasts.  They observed that autophagic-senescent fibroblasts promoted metastasis, when co-injected with human breast cancer cells, by more than 10-fold.

Thus, metastasis may be ultimately determined by aging or senescent cells in the tumor microenvironment, rather than by the cancer cells themselves.  This finding completely changes how we view cancer as a disease.

This observation directly calls into question the longstanding notion that cancer is a cell-autonomous genetic disease. Rather, it appears that cancer is really a disease of host aging, which fuels tumor growth and metastasis, thus, determining clinical outcome.  Normal aging host cells are actually the key to unlocking effective anti-cancer therapy.

In the study, the autophagic fibroblasts also showed features of senescence. What’s more, the senescent cells shifted toward aerobic glycolysis, and were primarily confined to the tumor stromal compartment.

Autophagy action is also clearly compartment specific, since the researchers showed that autophagy induction in human breast cancer cells resulted in diminished tumor growth. Therefore, selective induction of self-cannibalism in cancer cells is a new therapeutic target for the prevention of tumor growth and metastasis. In this strategy, cancer cells actually eat themselves, reversing tumor growth and metastasis.

To stop tumor growth and metastasis, researchers will need to “cut off the fuel supply” which is provided by aging senescent cells, before it gets to cancer cells by targeting autophagy and senescence in the tumor microenvironment.

These findings are paradigm shifting and will usher in a completely new era for anti-cancer drug development, according to the researchers. Such approaches for targeting the “autophagy-senescence transition” could have important implications for preventing tumor growth and metastasis, and effectively overcoming drug resistance in cancer cells.

“Rapidly proliferating cancer cells are energetically dependent on the aging host tumor stroma,” Dr. Lisanti said. “As such, removing or targeting the aging tumor stroma would then stop tumor growth and metastasis. Thus, the aging stroma is a new attractive metabolic or therapeutic target for cancer prevention.”

A clear byproduct of this research would also be the development new anti-aging drugs to effectively combat, stop or reverse aging, thereby preventing a host of human diseases, particularly cancer.

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This work was supported by grants from the Breast Cancer Alliance the American Cancer Society, Young Investigator Award from the Margaret Q. Landenberger Research Foundation, grants from the NIH/NCI (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660), and the Susan G. Komen Breast Cancer Foundation.  Other grants include NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was supported by the NIH/ NCI Cancer Center Core grant P30-CA-56036 (to R.G.P.). This project is funded, in part, under a grant with the Pennsylvania Department of Health. This work was also supported, in part, by a Centre grant in Manchester from Breakthrough Breast Cancer in the UK and an Advanced ERC Grant from the European Research Council.

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Thomas Jefferson University (TJU), the largest freestanding academic medical center in Philadelphia, is nationally renowned for medical and health sciences education and innovative research.   Founded in 1824, TJU includes Jefferson Medical College (JMC), one of the largest private medical schools in the country and ranked among the nation’s best medical schools by U.S. News & World Report, and the Jefferson Schools of Nursing, Pharmacy, Health Professions, Population Health and the College of Graduate Studies.  Jefferson University Physicians is TJU’s multi-specialty physician practice consisting of the full-time faculty of JMC. Thomas Jefferson University partners with its clinical affiliate, Thomas Jefferson University Hospitals.

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Key References:  Capparelli et al.

http://www.landesbioscience.com/journals/cc/article/20717/

http://www.landesbioscience.com/journals/cc/article/20718/

http://www.landesbioscience.com/journals/cc/article/20920/

http://www.landesbioscience.com/journals/cc/article/20964/

Also see:

http://tumor-microenvironment.com/

http://www.cancer.gov/newscenter/pressreleases/2011/ThosJeffersonUStudyofTamoxifenResistance

http://blog.kimmelcancercenter.org/?p=2773
http://physics.cancer.gov/news/2011/march/po_news_a.asp
http://physics.cancer.gov/news/2011/may/po_news_a.asp

http://physics.cancer.gov/news/2011/june/po_news_e.asp

http://physics.cancer.gov/news/2011/june/sept/po_news_d.asp
http://physics.cancer.gov/news/2011/sept/po_news_d.asp
http://physics.cancer.gov/news/2012/jan/po_news_f.asp
http://physics.cancer.gov/news/2012/feb/po_news_e.asp



Kimmel Cancer Center at Jefferson Hosts a Patient Symposium Focusing on Melanoma of the Eye

The Kimmel Cancer Center will host the inaugural Eyes on a Cure: Patient and Caregiver Symposium”  on June 16 and 17.

The symposium will bring uveal melanoma 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.

Uveal melanoma, also known as ocular melanoma (OM), is diagnosed in about 2,000 people a year in this country. Though rare, it is the most common eye cancer in adults.

The Community United for Research and Education of Ocular Melanoma, or CURE OM, was created by the Melanoma Research Foundation (MRF).

Over 100 patients, along with their families, are expected to attend the event.

The Kimmel Cancer Center at Jefferson is a major center for the treatment of OM. Medical oncologist Takami Sato, MD, PhD, one of the leading specialists in the disease,has seen more than 100 new patients with metastatic uveal melanoma every year since 1999.

David Eschelman, MD, and Carin F. Gonsalves, MD of the Division of Cardio-Interventional Radiology at Jefferson, have performed more than 300 embolization procedures for the liver metastases from uveal melanoma last year.

And the Jefferson team works closely with Jerry Shields, M., and Carol Shields, MD, of Wills Eye Institute in Philadelphia, who see more than 500 patients with primary uveal melanoma every year.

All are scheduled to speak over the course of the two days.

“Not many patients know about the disease and many have struggled with finding an appropriate treatment,” says Dr. Sato. “This is an opportunity to educate, as well as provide patients with support from both social workers and doctors—and hopefully foster research collaborations and funding opportunities. We are very honored to be hosting it.”

Director of CURE OM Sara Selig, Timothy Turnham, Ph.D., the Executive Director of the Melanoma Research Foundation, Daniel Brown, MD, of the Department of Interventional Radiology, and Rani Anne, M.D., of the Department of Radiation Oncology will also speak.

To learn more about the CURE OM Conference at the Kimmel Cancer Center click here.

To read the blog post about Sara Selig and her husband’s battle with OM and their efforts to bring more attention to the disease, click here.



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.




Jefferson Kimmel Cancer Center Tribute Dinner Honoring Steve Sabol, President of NFL Films

On Tuesday, June 5, 2012, the Kimmel Cancer Center at Jefferson and 300 guests honored Steve Sabol, President for NFL Films benefiting cancer research and patient care at the Union League of Philadelphia. The evening’s remarks were delivered by Sidney and Caroline Kimmel; and NFL Films special guests, Greg Cosell, and Pat Kelleher. Also in attendance was Head Coach for the Philadelphia Eagles, Andy Reid and his wife, Tammy; along with other key members of the Eagles organization. The silent auction, which featured an original art piece by Steve Sabol entitled, “Hippocratic Oath” as well as a private tour of NFL Films was emceed by Philadelphia’s own, “The Geator with The Heater”, Jerry Blavat.

Dr. Richard Pestell, Director of the Kimmel Cancer Center, presented Steve Sabol with the Spirit of Courage Award, presented to an individual who has demonstrated great personal courage, strength and dignity while battling cancer and supporting others in their fight against cancer. Receiving the Spirit of Commitment Award was Roberta Tanenbaum, Kimmel Cancer Center Advisory Board member, and Joseph Weiss, Kimmel Cancer Center Advisory Board Member and Chairman of Electronic Ink, 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.

The Lead Sponsor was the Sidney Kimmel Foundation. Kimmel Cancer Center at Thomas Jefferson University and Hospitals would also like to thank our generous Sponsors and Committee:

Program (13 MB PDF)

Chairpersons

Roberta Tanenbaum
KCC Board Member

Joseph Weiss
KCC Advisory Board Member
Chairman, Electronic Ink

Honorary Co-chairpersons

Anne and Matt Hamilton

Co-chairpersons

Dorothy and David Binswanger
Linda Golden and Richard Davidson
Linda and Benjamin Frankel
Janis and Stephen Goodman
Caroline and Sidney Kimmel
Christina and Jeffrey Lurie
Nataliia and Richard Pestell
Judy and Marvin Rounick
Kathy and John Spagnola

Committee

Ken Adelberg
Betty Gross Eisenberg
Stephen Foxman
Judy Losben
Linda Massey
Al Pizzica
Rita Rome
Claire Rose
Wendy Voron
Renee Zuritsky



HIV drug may slow down metastatic breast cancer

The HIV drugs known as CCR5 antagonists may also help prevent aggressive breast cancers from metastasizing, researchers from the Kimmel Cancer Center at Jefferson suggest in a preclinical study published in a recent issue of Cancer Research.

Such drugs target the HIV receptor CCR5, which the virus uses to enter and infect host cells, and has historically only been associated with expression in inflammatory cells in the immune system. Researchers have now shown, however, that CCR5 is also expressed in breast cancer cells, and regulates the spread to other tissue.

What’s more, blocking the receptor with the CCR5 antagonists Maraviroc and Vicriviroc, two drugs that slow down the spread of the HIV virus by targeting the CCR5 co-receptor of the chemokine CCL5, also prevents migration and spread of breast cancer cells, the researchers found.

“These results are dramatic,” said Richard Pestell, M.D., Ph.D., FACP, Director of Jefferson’s Kimmel Cancer Center and Chair of the Department of Cancer Biology at Thomas Jefferson University, and study senior author. “Our team showed that the CCR5/CCL5 axis plays a key role in invasiveness, and that a CCR5 antagonist can slow down the invasion of basal breast cancer cells.”

“This suggests it may prove to be a viable adjuvant therapy to reduce the risk of metastasis in the basal breast cancer subtype,” he added.

Basal tumors, which do not express the androgen or estrogen receptors or HER-2, are typically associated with metastasis and often do not respond to hormonal therapies. Current treatments include chemotherapy, radiation, and surgery, but all demonstrate poor outcomes, thus highlighting the urgent need for a specific targeted therapy for the subtype.

For the study, Dr. Pestell and colleagues investigated the CCL5/CCR5 axis expression in human breast cancer cell lines and the effect of CCR5 antagonists in vitro and in vivo.

An interrogation was conducted using a microarray dataset to evaluate CCR5 and CCL5 expression in the context of 2,254 patient breast cancer samples. Samples in the dataset were assigned to five breast cancer subtypes, including luminal A, B, normal-like, basal and HER-2 overexpressing disease.

The analysis revealed an increased expression of CCL5 and CCR5 in patients with basal and HER-2 subtypes, with 58 percent indicating a positive CCR5 and CCL5 signature. The team showed that oncogenes turn on the CCR5 receptor in normal breast cells as they became transformed into cancer cells. Spread of those cells is also regulated by CCR5, they found.

To evaluate the functional relevance of CCR5 in cellular migration and invasion, the team tested the drugs in 3-D invasion assays with two different cell lines. Here, too, they discovered that both antagonists inhibited breast cancer cell invasiveness.

Next, to determine its effects in vivo, the team injected mice with the antagonists and tracked invasiveness of the basal breast cancer cells to other tissue, i.e. lung, with bioluminescence imaging. Mice treated with the drug showed a more than 90 percent reduction in both the number and size of pulmonary metastases compared to untreated mice.

“Our preclinical studies provide the rational basis for studying the use of CCR5 antagonists as new treatments to block the dissemination of basal breast cancers,” said Dr. Pestell.

These findings may also have implications for other cancers where CCR5 promotes metastasis, such as prostate and gastric.



ASCO: Younger Colon Cancer Patients Have Worse Prognosis at Diagnosis, Yet Better Survival

Younger patients with colorectal cancer were more likely to present advanced stage tumors at diagnosis and metastasize much sooner, yet had better than or equal survival to patients 50 and older, according to data being presented at the 2012 American Society of Clinical Oncology Annual Meeting in Chicago. (Abstract #3621, Monday, June 4, 8:00 AM – 12:00 PM CST, S Hall A2).

The study was led by Edith Mitchell, M.D., a clinical professor in the Department of Medical Oncology at Jefferson Medical College of Thomas Jefferson University. Dr. Mitchell is also Director of the newly-established Center to Eliminate Cancer Disparities at Jefferson’s Kimmel Cancer Center.

“We’re seeing more advanced tumors in this population because the cases aren’t being caught early enough,” said Dr. Mitchell. “Screening isn’t recommended until age 50, and the younger a patient is, the more likely they are to ignore symptoms of more advanced stages of the disease.”

The objective of this study was to assess pathological features and outcomes of colorectal cancer in patients less than age 50 using an institutional sample and comparing to the Surveillance, Epidemiology and End Results (SEER) database.

Dr. Mitchell and colleagues obtained data from the tumor registry of Thomas Jefferson University Hospital (TJUH) on 4,595 patients treated for colorectal cancer from 1988 to 2007. They compared those data with data obtained from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database on 290,338 patients with colorectal cancer treated from 1988 to 2004. The researchers collected data on location, stage and histologic grade of the cancer.

Patients under age 50 with colorectal cancer presented with more advanced stage tumors in both data sets (SEER and TJUH), and had more poorly differentiated tumors than older patients, the researchers found. Patients under 50 also had more mucinous/signet ring cell tumors with 12 percent to 8.1 percent in the TJUH data and 13.2 percent to 10.3 percent in the SEER data, with younger males having the highest prevalence in both data sets.

Younger patients had fewer right-side tumors than patients 50 and over, and a higher proportion of rectal tumors. Patients under age 50 were also more likely to have positive nodes at all stages relative to 50 and over, as well as more likely to develop peritoneal metastases, but less likely to have lung metastases than older patients.

Despite their poor pathologic features, patients under age 50 had better than or equal survival to those 50 and older, which may in part be explained by their overall health. Early evidence suggests that younger patients are able to tolerate more aggressive cancer therapies because of fewer co-morbidities, said co-author Scott Goldstein, M.D., of Jefferson’s Department of Surgery.

“Ongoing studies will help clarify the survival disparity and assess differences in treatment and molecular features between younger and older colorectal cancer patients,” Dr. Mitchell said.

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Other researchers included Allan Topham, Pramila R. Anne, of Jefferson’s Department of Radiation Oncology, Gerald Isenberg, M.D., of Jefferson’s Department of Surgery, Fran Guiles of Jefferson’s Oncology Data Services, and Juan Palazzo, M.D., of Jefferson’s Department of Pathology, Anatomy and Cell Biology.

Also see: Thomas Jefferson University Hospital Oncologists and Surgeons Treating More Colon Cancer Patients Under 50



ASCO: Liver Metastases and its Prognostic Significance in Men With Metastatic Castration-Refractory Prostate Cancer

Liver metastases predicts shorter overall survival in men with metastatic castration-refractory prostate cancer (mCRPC), according to data being presented at the 2012 American Society of Clinical Oncology Annual Meeting in Chicago. (Abstract # 4655, Sunday, June 3, 8:00 AM – 12:00 PM CST, S Hall A2).

In a phase III trial, lead study author William Kevin Kelly, DO, Thomas Jefferson University Hospital and the Kimmel Cancer Center at Jefferson, and colleagues from the Alliance for Clinical Trials in Oncology, found that men without liver metastases lived 8.2 months longer compared to men whose cancer did metastasize, despite both groups having similar progression free survival and response to docetaxel based chemotherapy.

The multi-institutional study included 1,050 patients from the CALGB 90401 trial, a randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with mCRPC.

For the investigation, researchers assessed the prognostic significance of liver metastases in predicting overall survival and progression free survival, adjusting for stratification factors.

Fifty-nine (5.6%) of those patients had documented liver metastases.  Patients with liver metastases had higher baseline alkaline phosphatase (ALK) and lactate dehydrogenase (ADH) levels compared to patients without liver metastases. The median overall survival time in patients with liver metastases was 14.4 compared to 22.6 months for patients without liver metastasis(hazard ratio (HR) 1.4) . The HR for treatment effect (docetaxel and prednisone with either bevacizumab or placebo) for liver metastases was not statistically significant for either group.

The full abstract can be found here. http://abstract.asco.org/AbstView_114_96038.html