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.



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).



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 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.



Data Continues to Support Provenge’s Overall Survival Benefit in Prostate Cancer Patients

This article was adapted from an OncLive story posted on May 21, 2012.

Leonard G. Gomella, M.D, chair of the Department of Urology at Thomas Jefferson University Hospital and director of Clinical Affairs, Jefferson’s Kimmel Cancer Center, was part of the team to present new findings from the IMPACT trial looking at the immunotherapy sipuleucel-T (Provenge) in men with advanced prostate cancer.

The abstract was presented at the American Urological Association (AUA) Annual Meeting in Atlanta.

Results from the exploratory, multi-institutional analysis provides important insight into how the cross-over design of the IMPACT trial may have affected the overall survival findings, and supports a greater treatment effect of sipuleucel-T than previously reported.

In the study,  researchers administered the vaccine APC8015F to a group of patients from the control arm of three randomized, Phase 3 clinical trials evaluating sipuleucel-T, a similar, FDA-approved cancer vaccine for metastatic castrate resistant prostate cancer.

APC8015F is made from immune system cells taken from a patient with prostate cancer; however, unlike sipuleucel-T, which is never frozen, APC8015F is cryopreserved at a time before the disease progressed.

Of the 249 men in the control arm, 155 received APC8015F. Those receiving APC8015F demonstrated similar benefits to those receiving sipuleucel-T. However, these patients were grouped with the placebo arm, when the benefits were calculated.

Removing the patients that received APC8015F and comparing just the patients that received placebo alone to those receiving sipuleucel-T alone more than doubles the 4.1-month median survival benefit found in the IMPACT trial.

“From my viewpoint, the benefit of sipuleucel-T has been understated because many of the patients who received the frozen product on the control actually enjoyed a longer survival, decreasing the difference between the control arm and the treatment arm,” Dr. Gomella tells OncLive.

“In fact, if you look at our analysis of the patients who received the frozen product on the control arm and those that did not receive it, there was a significant survival advantage to those patients who did receive the frozen product. So it actually made a difference between the control arm and treatment arm much closer. And if you actually take those patients out who did not receive the frozen product on the control arm, that survival difference actually approaches 10 to 11 months.”

Watch the full interview here: http://www.onclive.com/onclive-tv/Dr-Gomella-on-the-IMPACT-Trial-Survival-Benefit

Source: OncLive



Jefferson’s Kimmel Cancer Center to Host Tribute Dinner Honoring Steve Sabol, President of NFL Films

Steve Sabol

Jefferson’s Kimmel Cancer Center will host a tribute dinner to honor legendary filmmaker Steve Sabol, President of NFL Films, with the Spirit of Courage Award at the Union League of Philadelphia on June 5.

The award is presented to an individual who has demonstrated great personal courage, strength and dignity while battling cancer and supporting others in their fight against cancer.

Since being diagnosed with brain cancer in March of 2011, Mr. Sabol, who is currently being treated at the Kimmel Cancer Center, has helped people understand the impact of this disease, all while acting as a role model of perseverance.

“It’s an honor to be recognized by the Kimmel Cancer Center at Jefferson with this award, and, more importantly, to be part of what will be a memorable event recognizing the importance of advancing clinical care and cancer research,” said Mr. Sabol. “Because of Jefferson’s treatment and Dr. Kevin Judy of the Jefferson Hospital for Neuroscience, I’ve been able to move forward through this battle. I thank everyone at the KCC for that and for the support of everyone attending the event.”

Sidney and Caroline Kimmel will be attending the event to honor Mr. Sabol, with Mrs. Kimmel giving some introductory remarks. Richard Pestell, M.D., Ph.D., FACP, Director of Jefferson’s Kimmel Cancer Center, will present the Spirit of Courage award.

Mr. Sabol is best known as President of Mt. Laurel-based NFL Films, which was founded by his father, Ed Sabol, who was recently inducted into the Football Hall of Fame.  Steve Sabol is recognized for having revolutionized not only how we watch football, but also the very nature of sports broadcasting. While NFL Films has won over 100 Emmys, Sabol himself has received 35 of those Emmys for writing, cinematography, editing, directing, and producing.

No one else in all of television has earned as many Emmys in as many different categories.

Mr. Sabol will also be donating one of his trademark pieces of art for the event for live auction.

His collage art is a natural outgrowth of his cinematic vision.  Mr. Sabol has spent his entire career thinking about football and the positive values the game represents.  In the process, football became a prism for looking at American society.  Using symbolic imagery from both the sports world and popular culture, Mr. Sabol has created a unique visual language that hearkens to times past and reminds us of the best in ourselves.

The auctioned artwork and event will benefit cancer research at Jefferson’s Kimmel Cancer Center.

“This is a very special award to the Kimmel Cancer Center because it honors those rare individuals whose courage and dignity have stood out,” said Dr. Pestell. “It’s with great pleasure to give the Spirit of Courage award to Mr. Sabol, who has no doubt inspired and empowered others—throughout his career and his fight against cancer.”

Chairpersons include Roberta Tanenbaum and Joseph Weiss, along with Honorary Co-Chairpersons Anne and Matt Hamilton.

Co-chairpersons include: Dorothy and David Binswanger, Linda Golden and Richard Davidson, Linda and Benjamin Frankel, Janis and Stephen Goodman, Caroline and Sidney Kimmel, Christina and Jeffery Lurie, Nataliia and Richard Pestell, Judy and Marvin Rounick, and Kathy and John Spagnola.

For more information, please contact Mika Harding, Associate Director for Development, Kimmel Cancer Center, 215-503-1195, Mika.Harding@KimmelCancerCenter.Org, or visit http://www.kimmelcancercenter.org/about/tribute-dinner.html



Jefferson Receives $2.6 Million NIH Grant to Study Imaging Method to Stage Prostate Cancer Without Biopsy

Mathew Thakur, PhD, professor of Radiology at Jefferson Medical College of Thomas Jefferson University and the Director of the Laboratories of Radiopharmaceutical Research and Molecular Imaging

Jefferson’s Kimmel Cancer Center and the Department of Radiology at Thomas Jefferson University received a five-year, $2.6 million grant from the National Institutes of Health (NIH) to investigate a potentially revolutionary method that can stage prostate cancers and detect recurrent disease so accurately, it would significantly reduce the number of confirmation biopsies. Such biopsies can be invasive, costly, and often lead to false-positive readings.

The new technique involves the use of a positron emission tomography (PET) scan and a novel imaging agent.

The study is being led by Mathew Thakur, PhD, professor of Radiology at Jefferson Medical College of Thomas Jefferson University and the Director of the Laboratories of Radiopharmaceutical Research and Molecular Imaging.

Prostate specific antigen (PSA) measurements, ultrasonography and magnetic resonance imaging (MRI) remain standard tools for diagnosis and management of prostate cancer; however, each requires an invasive biopsy for histologic confirmation.

Biopsies are associated with morbidity and high costs, and more than 65 percent of the 1.5 million biopsies performed each year in the U.S. show benign pathology, indicating a high false-positive rate for these standard diagnostic tools.

These limitations, the researchers say, demonstrate a dire need for noninvasive methods that can accurately stage prostate cancer, detect recurrent disease and image metastatic lesions with improved reliability.

Dr. Thakur and colleagues are studying Cu-64 peptide biomolecules to evaluate prostate cancer tumors via PET imaging. These agents detect prostate cancer by finding a biomarker called VPAC1, which is overexpressed as the tumor develops.

“The challenge has been to develop an imaging agent that will target a specific, fingerprint biomarker that visualizes prostate cancer early and reliably,” said Dr. Thakur, who is also a member of Jefferson’s Kimmel Cancer Center.

Previous studies with Cu-64 peptides from Dr. Thakur yielded promising results in stratifying breast cancer.  A preclinical study published in the Journal of Nuclear Medicine in late 2009 found that 64Cu-TP3805 detected tumors overexpressing the VPAC1 oncogene more accurately in mice than 18F-FDG, a commonly used agent for imaging tumors.

With this NIH grant, the researchers will test the hypothesis in both mice and humans.  They will evaluate two Cu-64 peptides specific for VPAC1 in mice and perform a feasibility study in 25 pre-operative prostate cancer patients, using the best suited Cu-64 peptide determined from the mouse studies.

“This noninvasive method could significantly contribute to the management of prostate cancer,” said Dr. Thakur. “It would result in a reduction of unnecessary biopsy procedures and under treatment or over treatment that yield minimal benefits, incontinence, or impotence.”

Other researchers include Ethan Halpern, MD, Charles Intenzo, MD, and Sung Kim, MD of the Department of Radiology, Edouard Trabulsi, MD of the Department of Urology and Eric Wickstrom, PhD, of the Department of Biochemistry and Molecular Biology. The team will partner with NuView, a molecular imaging technology firm, on the study.

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This study was funded by NIH’s National Cancer Institute (Grant No. 1R01CA157372-01A)



A Closer Look at PARP-1 Reveals Potential New Drug Targets

John M. Pascal, Ph.D., an assistant professor in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University

A new study published in Science May 11 is shedding light on the molecular details of PARP-1, a DNA damage-detecting enzyme that when inhibited has been shown to be effective in fighting cancer and other diseases.

The investigation led by John M. Pascal, Ph.D., an assistant professor in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University and Jefferson’s Kimmel Cancer Center, revealed new target sites—including specialized “zinc finger” domains—for drugs aiming to stop PARP-1 activity.

The idea for this area of research is to identify more specific PARP-1 inhibitors that achieve a targeted inhibition, with less potential for side effects.  Drugs inhibiting PARP-1 have also been proven effective in treating inflammation and cardiac disease.

“PARP-1 has been identified as a valuable target, but what’s special about it? What really are its weak points in the way it gets activated?” said Dr. Pascal. “We wanted to define a structural and mechanistic framework to better understand how to specifically inhibit PARP-1.”

The weak points were found to be multi-domain interfaces that are uniquely found in PARP-1.  What researchers now know is that multiple domains of PARP-1 come together and bind to DNA damage, and this “communication” between domains is essential for DNA damage-dependent PARP-1 activity.

PARP-1 is a protein that detects and responds to breaks in the structure of DNA, a potentially lethal form of damage to our genetic information. If PARP-1 activity is impaired, DNA strand breaks are not repaired and instead are converted into more dangerous types of DNA damage.  In normal tissue, a repair mechanism called homologous recombination picks up the slack and fixes the damaged DNA. However, in cancers that carry the BRCA mutation, like certain breast and ovarian cancers, homologous recombination is inactivated.  Therefore, the cancerous cells have become dependent on the role PARP-1 plays in DNA repair.

In a more general scenario, inhibiting PARP-1 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.

Today, many PARP-1 inhibitors being tested in preclinical and clinical studies target the catalytic active site.  But this approach is limiting because the catalytic site is similar to those found in other PARP-like proteins that carry out other essential cellular functions, thus increasing the potential for off target side effects.

“What was exciting in our structure of PARP-1 is that there are specialized sites on the protein that can be inhibited; you can effectively kill catalytic activity without having to touch the catalytic active site,” said Dr. Pascal.

Using X-ray crystallography, researchers studied the interaction amongst the component domains of PARP-1 and their combined role in binding to DNA damage.  The PARP-1/DNA structure revealed a network of interdomain contacts formed upon DNA binding. These domains have to come together and assemble, the researchers found, to have catalytic activity.

“Our work indicates that we should be looking for inhibitors that prevent these domains from coming together,” Dr. Pascal said. “Rather than screen for inhibitors with catalytic activity as a readout, we can screen for inhibitors that disrupt the communication between the PARP-1 domains, which would in turn shut down catalytic activity.”

Closer attention to these specialized domains could inspire the design of a new class of PARP inhibitors.

“Dr. Pascal’s structural and biochemical characterization reveals how recognition of DNA damage and communication between domains control the activity of PARP‑1,” said Barbara Gerratana, Ph.D., who oversees enzyme catalysis grants at the National Institutes of Health’s National Institute of General Medical Sciences, which partially supported the study. “This work is a major breakthrough in understanding an enzyme essential for regulation of cell proliferation and a promising target for cancer therapeutics.”

Other researchers include Marie-France Langelier, Ph.D., Jamie L. Planck, and Swati Roy of the Department of Biochemistry and Molecular Biology at Jefferson.

This work was supported by funds from the National Institutes of Health (5R01GM087282-02), the American Cancer Society, and the Kimmel Cancer Center X-ray Crystallography and Molecular Characterization Facility at Thomas Jefferson University.



Scott Waldman Awarded CURE Grant to Move Colon Cancer Test Closer to Commercialization

Scott Waldman, M.D., Ph.D.

Scott Waldman, M.D., Ph.D., Chair of the Department of Pharmacology and Experimental Therapeutics at Thomas Jefferson University, has been awarded a Commonwealth Universal Research Enhancement (CURE) grant for almost $750,000 to help advance a molecular diagnostic test for colon cancer into commercialization.

Such a test would better detect recurrence in a group of colon cancer patients whose metastases are hidden, and help reduce racial disparities, particularly in the African-American community, who are at higher risk of dying from metastatic disease.

The nonformula grant was awarded competitively from the Pennsylvania Department of Health. One of this year’s priorities for the Department’s Health Research Advisory Committee is Cancer Diagnostics or Therapeutics with Commercialization Potential.

About 25 percent of colon cancer patients who are deemed node-negative, or pN0, (meaning the cancer has not spread to the lymph nodes) after treatment end up recurring with metastatic disease.  Known as occult tumors, these hidden metastases often escape detection, be it imaging modalities or histopathology.

Today, no such test exists to distinguish these colon cancer patients, and as a result, they are often treated the same.

To better stratify this group, Dr. Waldman and colleagues have developed a diagnostic test that uses the hormone receptor guanylyl cyclase C (GCC) as a biomarker.

Previous research shows that a quantitative, molecular analysis of lymph nodes in patients deemed colorectal cancer-free was found to be an effective predictor of recurrence. Expression of GCC in the nodes, they found, is associated with an increased risk.

“This approach can improve prognostic risk stratification and chemotherapeutic allocation for these colon cancer patients,” said Dr. Waldman, a member of Jefferson’s Kimmel Cancer Center. “With this CURE grant, we can now move a much-needed technology closer to commercialization, meaning closer to patients.”

The test will ultimately determine who can benefit from adjuvant chemotherapy, which is designed to eradicate whatever occult disease is left after surgery and other treatments.

This test would benefit the African-American community, in particular. Beyond the general population risk, there is an established stage-specific difference in outcomes in pN0 African Americans, who are 40 percent more likely to die from the metastatic colon cancer than whites.

Stratifying these patients could ultimately reduce related racial disparities in mortality and survival.

The primary purpose of this nonformula grant is to support research activities that commercialize and bring to market new cancer diagnostics and therapeutics for which proof of concept has previously been demonstrated and has the capability to solve or diminish a specific problem related to the diagnosis or treatment of one or more malignant diseases.



You Can Help Save PA Research Funding

For more than a decade, Pennsylvania’s Commonwealth Universal Research Enhancement Program (CURE) has supported a broad range of biomedical research at 39 institutions across Pennsylvania. These funds have led to research advances in cancer, cardiovascular disease, diabetes, infectious diseases, and other health areas and improvements in public health.

In his budget for fiscal year 2013, Governor Corbett proposes defunding the CURE program created by Act 77 in 2001, diverting almost $60 million in research funds from the tobacco settlement into the general budget for other purposes.

If the defunding takes place, Jefferson stands to lose $2 to $4 million per year in research funding.

Left intact with sustained funding, the CURE program will advance promising medical discoveries, support the hiring and retention of skilled workers, leverage federal and private research funding, and catalyze the formation of biotechnology companies.

Please voice your support of the CURE program by taking a moment to send a note (see suggested letter HERE) to your PA State representative. You can find your representative on this website.

Jefferson’s Kimmel Cancer Center is a member of the Pennsylvania Cancer Alliance.



Dawn Scardino named 2012 LLS Woman of the Year

Dawn Scardino named LLS Woman of the Year

Dawn Scardino, Coordinator of Academic Services in the Department of Medical Oncology, was named the 2012 Leukemia & Lymphoma Society’s Woman of the Year for the eastern Pennsylvania Chapter.

Dawn took the top recognition for raising almost $27,000 in a 10-week fundraising “race” that began on Jan. 30 and ended on April 12.  Four women and nine men took part in the race.

Participants had 10 weeks (Dawn did it in eight!) to organize and run their campaigns, with the goal of raising the most money in their chapters. The man and woman who raises the most are named the winners.

The winners–the top male prize went to Anthony Falco, who raised over $200,000–were announced at the Grand Finale Celebration at the Union League of Philadelphia on April 12.

In total, the whole group raised almost $443,000.

All proceeds from the effort go to the LLS, whose mission is to cure leukemia, lymphoma, Hodgkin’s disease and myeloma, and to improve the quality of life for patients with these diseases.

The funds Dawn raised are in honor of LLS’s Boy of the Year, Andrew Clark, a 13-year-old leukemia survivor who began his battle with acute lymphoblastic leukemia, or ALL, at the age of 3.

Since 1949, the LLS has funded over $680 million in medical research aimed at curing different cancers. LLS supports therapies that not only help blood cancer patients but are now used to treat patients with rare forms of stomach and skin cancers and are being tested in clinical trials for patients with a range of cancers including lung, brain, breast, pancreatic and prostate.

Dawn started at Jefferson in 1991.  Since her arrival in Medical Oncology in 2008 she has helped with the recruitment of 27 new faculty members to the department. This was Dawn’s first year participating in the LLS campaign race.



Leading the Way to a Cure

It is estimated that more than 70,000 new cases of bladder cancer were diagnosed in 2011, making it the fifth most commonly diagnosed cancer in the U.S.

Please join Team Jefferson and Dr. Jean Hoffman-Censits of the Department of Medical Oncology, Solid Tumor Division and the Kimmel Cancer Center at Jefferson in raising awareness of the disease.

This year’s walk will begin at the Kimmel Cancer Center’s Bluemle Life Sciences Building. Walk with us to Independence Hall, where we will have a tent and table with refreshments and information about bladder cancer and treatment options at Jefferson.

Can’t make it to the walk? Please consider donating to the team. All proceeds will benefit the Bladder Cancer Advocacy Network, host of the annual Bladder Think Tank – the only national scientific meeting focusing solely on bladder cancer. For more information, visit www.bcan.org.

Date and Time: May 5, 2012 at 10 a.m

Location:

Bluemle Life Sciences Building
233 South 10th Street
Philadelphia, PA 19107

Registration Info:

Registration is free and fundraising is optional. Preregister for the event online or contact Teresa Bryant at 215-503-5455 or teresa.bryant@jefferson.edu.



Edith Mitchell, M.D., FACP, Named 2012 Recipient of ASCO Humanitarian Award

Edith Mitchell, M.D., to receive 2012 Humanitarian Award at ASCO annual meeting

Edith  Mitchell, M.D., FACP, a medical oncologist at Thomas Jefferson University Hospital and Jefferson’s Kimmel Cancer Center (KCC) and Clinical Professor of Medicine and Medical Oncology in the Department of Medical Oncology at Jefferson Medical College of Thomas Jefferson University, has been named the 2012 recipient of the American Society of Clinical Oncology (ASCO) Humanitarian Award for her personification of the society’s mission and values, and for going above and beyond the call of duty in providing outstanding patient care.

For her efforts, Dr. Mitchell will be presented with the award during the opening session of the ASCO Annual Meeting on Saturday, June 2.

The ASCO Humanitarian Award recognizes an oncologist who provides outstanding patient care through innovative means or exceptional service or leadership in the United States or abroad. It is presented to an ASCO member who distinguishes himself/herself through voluntary and non-compensated humanitarian endeavors.

“Receiving this award is a great honor, and I thank the Society for the acknowledgement,” said Dr. Mitchell. “A big part of my work over the course of my career has focused on helping those in need of medical care—to reach those who have no access to it, who have no opportunities for health, and no means to seek out conventional medical advice. It is important to help these individuals realize that simple changes in lifestyle can have a dramatic impact on cancer care and one’s health. I look forward to continuing on this path.”

Dr. Mitchell has spent her medical career helping individuals in medically underserved areas and demonstrating the importance of community service and outreach. She has participated in flood relief, supportive patient advocacy, and organized vaccination clinics.

Dr. Mitchell also serves as a program leader of Gastrointestinal Oncology at JMC, Associate Director for Diversity Programs for the KCC, and Director of the KCC’s newly established Center to Eliminate Cancer Disparities.

In addition to her professional roles, she has spent many years in service with the U.S. Air Force and the Air National Guard. Dr. Mitchell entered active duty after completion of her internship and residency in Internal Medicine at Meharry Medical College and a fellowship in Medical Oncology at Georgetown University. She is now a retired brigadier General from the United States Air Force.

Dr. Mitchell received a Bachelor of Science in Biochemistry “With Distinction” from Tennessee State University and her medical degree from the Medical College of Virginia in Richmond.

Dr. Mitchell’s research in pancreatic cancer and other gastrointestinal malignancies involves new drug evaluation and chemotherapy, development of new therapeutic regimens, chemoradiation strategies for combined modality therapy, patient selection criteria and supportive care for patients with gastrointestinal cancer.

As a distinguished researcher, she has received numerous Cancer Research and Principal Investigator Awards, and serves on the National Cancer Institute Review Panel and the Cancer Investigations Review Committee.  She has also authored and co-authored more than 100 articles, book chapters, and abstracts on cancer treatment, prevention, and cancer control. And in 2011, she was named “Practitioner of the Year” Award by the Philadelphia County Medical Society.

She also travels nationally and internationally teaching and lecturing on the treatment of gastrointestinal malignancies.

Dr. Mitchell is one of 12 honorees to receive an ASCO Special Award.

“All of the oncology professionals and leaders who will be receiving this year’s Special Awards have made a great impact on cancer prevention, care and treatment around the globe,” said George Sledge, M.D., ASCO Immediate Past President and Chair of the Special Awards Selection Committee. “We are honored to commend their contributions and accomplishments in the field of oncology with ASCO’s most prestigious awards.”

For more on Dr. Mitchell’s award, please see:

http://www.asco.org/ASCOv2/Press+Center/Latest+News+Releases/Meetings+News/Oncology+Professionals+and+Leaders+Honored+for+Contributions+in+the+Progress+Against+Cancer

http://www.cancer.net/patient/Publications+and+Resources/Find+an+Oncologist/ASCO+Humanitarian+Award



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

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

HuR and Ovarian Cancer

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

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

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

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

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

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

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

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

Radiotherapy and Glioblastoma

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

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

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

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

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

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

This work was supported by a grant from Novartis Pharmaceuticals.

Non-Small Lung Cancer and DACH1

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

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

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

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

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

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

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

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

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

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



AACR: New Biomarker to Identify Hepatitis B-Infected Patients at Risk for Liver Cancer

CHICAGO— Hepatitis B-infected patients with significantly longer telomeres—the caps on the end of chromosomes that protect our genetic data— were found to have an increased risk of getting liver cancer compared to those with shorter ones, according to findings presented by researchers at Jefferson’s Kimmel Cancer Center at the American Association for Cancer Research (AACR) Annual Meeting 2012.

The relative telomere length in hepatitis B-infected cases with liver cancer was about 50 percent longer than the telomere length of the cancer-free hepatitis B-infected controls.

A strong correlation between telomere length and non-cirrhotic hepatocellular carcinoma (HCC), a liver cancer commonly caused from hepatitis B and C viral infections, could help physicians better stratify the hepatitis B population in an effort to better prevent and treat the disease.

Previous reports have suggested telomere length plays a role in cancer prediction; however, there have been conflicting results and the majority of the studies measured telomere length in liver cells (hepatocytes) and white blood cells.

Here, Hushan Yang, Ph.D., of the Division of Population Science at the Department of Medical Oncology at Thomas Jefferson University and Jefferson’s Kimmel Cancer Center, and colleagues used circulating cell-free serum DNA from an existing and ongoing clinical cohort at the Liver Disease Prevention Center at Thomas Jefferson University Hospital.

Tapping into a cohort of almost 2,600 Korean Americans, a population disproportionately infected with hepatitis B, the team analyzed blood samples from over 400 hepatitis B-infected patients to compare relative telomere length using quantitative real-time polymerase chain reaction (qRT-PCR).

This nested case-control study included 140 hepatitis B-HCC cases and 280 cancer-free hepatitis B controls. Demographic and clinical data were obtained for each patient through medical chart review and consulting with treating physicians.

All participants were restricted to Korean hepatitis B patients to control the confounding effects of ethnicity and HCC etiology. The large majority of the patients were infected at birth or childhood, making this population an ideal resource to study the long-term outcome of hepatitis B infection at the population level.

The hepatitis B-HCC cases were found to have a relative telomere length about 50 percent longer than the cancer-free controls (0.31 versus 0.20, P=0.003), a statistically significant difference.

The difference, however, was also only evident in males and in non-cirrhotic patients, and not cirrhotic patients, possibly because that the effect conferred by telomere length was overshadowed by the strong association between cirrhosis and HCC. There were also no statistical differences between cohorts with respect to age and smoking status.

“This is the first study to demonstrate that relative telomere length in circulating cell-free serum DNA could potentially be used as a simple, inexpensive and non- invasive biomarker for HCC risk,” said Dr. Yang. “This sets the stage for further retrospective and prospective investigations, in-depth molecular characterizations, and other assessments to determine the clinical value of serum DNA telomere length in risk prediction and early detection of HCC.”

Co-authors of the study were Shaogui Wan, Xiaoying Fu, Ronald Myers, Ph.D., Division of Population Science, Department of Medical Oncology, Thomas Jefferson University; Hie-Won Hann, M.D., Richard Hann, Jennifer Au, M.D., Division of Hepatology and Gastroenterology, Department of Medicine, Thomas Jefferson University; and Jinliang Xing, Department of Cell Biology, Fourth Military Medical University in China.

This study was supported by two grants from the National Cancer Institute, a Tobacco Grant from the Pennsylvania Department of Health, an American Cancer Society grant, and a Research Scholar Award from the V Foundation for Cancer Research.



AACR: Eliminating the ‘Good Cholesterol’ Receptor May Fight Breast Cancer

CHICAGO— Removing a lipoprotein receptor known as SR-BI may help protect against breast cancer, as suggested by new findings presented at the American Association for Cancer Research Annual Meeting 2012 by Jefferson’s Kimmel Cancer Center researchers.

In vitro and mouse studies revealed that depletion of the SR-BI resulted in a decrease in breast cancer cell growth.

SR-BI is a receptor for high-density lipoproteins (HDL) that are commonly referred to as “good cholesterol” because they help transport cholesterol out of the arteries and back to the liver for excretion.

The team, including Christiane Danilo, of the Department Stem Cell Biology and Regenerative Medicine at Thomas Jefferson University, and Philippe G. Frank, Ph.D., an assistant professor in the Department of Stem Cell Biology and Regenerative Medicine at Jefferson, had good reason to believe that SR-BI played a role in breast cancer growth: Previous lab research had revealed that mice fed a high cholesterol diet develop more advanced tumors and their tumors produce more SR-BI.

To further investigate SR-BI’s role in breast cancer tumors, the team manipulated levels of the receptor in human breast cancer cell lines and examined its effect on tumor formation in a mouse model.

In vitro, they found that ablation of the receptor protein in breast cancer cells led to a decrease in cancer cell proliferation, migration and invasion. Mouse models also showed that depletion of the receptor could confer protection against tumor growth.

Environmental factors, such as diet and obesity, have long been considered risk factors for the high breast cancer incidence in the Western world, and epidemiologic evidence indicates that cancer patients display abnormal levels of cholesterol carrying lipoproteins. However, the role of cholesterol in breast cancer had not yet been specifically examined.

“The results of this novel study show that depletion of SR-BI reduces cancer cell and tumor growth, suggesting that it could play an important role in breast cancer,” said Dr. Frank. “More studies are warranted to further characterize the role of SR-BI in tumor progression.”

Other researchers include Michael P. Lisanti, M.D., Ph.D., Chairman of the Department of Stem Cell Biology and Regenerative Medicine at Jefferson, and Maria Antonietta Mainieri of the University of Calabria, Rende, in Italy.

The study was funded by the Susan G. Komen Foundation.



Dr. Leonard Gomella, Program Director for IPCC in New York

Dr. Leonard Gomella, Program Director of 2012's IPCC

Leonard G. Gomella, M.D., FACS, Chair of Urology at Thomas Jefferson University Hospital and Director of Clinical Affairs at the Kimmel Cancer Center at Jefferson, will serve as the Program Director for the Fifth Annual Interdisciplinary Prostate Cancer Congress (IPCC) at the New York Marriott East Side in New York City on March 31.

This full-day continuing medical education (CME) activity entitled Novel Perspectives – Evolving Therapies and Advances In Standard of Care will address the differences that currently exist between urologists’, medical oncologists’, and radiation oncologists’ approaches to treating prostate cancer.

World-renowned thought leaders have been brought together to foster consensus about the best management of prostate cancer from the vantage point of interdisciplinary care teams. Topics of vital interest that will be include: hormonal therapies; imaging and staging; surgical advances; radiation therapies; and emerging multimodal therapies.

The IPCC will include interactive cases designed to highlight multidisciplinary approaches for the management of prostate cancer with the overall goal of improving patient outcomes.

Topics include  prostate-specific antigen testing in diagnosing patients with prostate cancer, and emerging bone-related therapies for treating prostate cancer.

Dr. Gomella told OncLive that the value of the conference for attendees is its focus on practical applications of these new developments. “When they go back to the patient setting, they can actually use [this information] in their daily patient care,” he said.

For more information, please visit, http://cancerlearning.onclive.com/index.cfm/fuseaction/conference.showOverview/id/5/conference_id/702/index.php

http://www.onclive.com/publications/Oncology-live/2012/january-2012/IPCC-Conference-to-Focus-on-Issues-Facing-Clinicians