Dr. Myers Invited To Share His Research At Preventive Oncology Meeting

Ronald E. Myers, Ph.D.

Ronald E. Myers, Ph.D.

Ronald Myers, PhD, Professor of Medical Onocology, was invited to share his work on CRC screening as one of 3 “Best of CEBP” presentations at the recent American Society for Preventive Oncology 39th Annual Meeting in Birmingham, Alabama on March 16, 2015.

For more about the ASPO meeting see the agenda

 



SKCC Scientists Show That Cancer Cells Can Use Exosome Transfer To Pass On Agressive Traits

Dr. Lucia Languino

Dr. Lucia Languino

Until recently, researchers thought that cell division was the only way for an aggressive cancer cell to pass its traits along. New evidence is showing that cancers can become more dangerous by exporting aggressive traits to neighboring cells via exosomes. These small packages — bubbles — of membrane released into the extracellular environment hold pieces of host RNA, DNA and proteins. Now, a new study has shown that exosomes also can hold and transfer integrin molecules known to promote metastasis in several cancers. This discovery was made in a collaborative effort of the labs of Dr. Lucia Languino, Professor of Cancer Biology and Dr. Renato Iozzo, Professor of Pathology. Both are members of the Sidney Kimmel Cancer Center at Thomas Jefferson University.

Because of the role of the αvβ6 intergrin in prostate cancer, Languino, first author Carmine Fedele and colleagues investigated whether the αvβ6 integrin might be transferred between cells via exosomes. The researchers examined the exosomes released from prostate cancer cell lines known to express the αvβ6 integrin and found that the exosomes were enriched with this integrin. The research also was supported by the work of Amrita Singh, a graduate student in Languino’s lab.

The results were published in the Journal of Biological Chemistry. “This is an important addition to the research showing that tumors have novel ways of spreading aggressive traits,” says senior author Dr. Lucia Languino.

For more info see the Journal of Biological Chemistry Article or the ASBMB Press Release



New genomic test can direct appropriate use of radiation therapy following prostate surgery

Dr. Robert Den

Dr. Robert Den

The identification of the right patients for post-operative radiation therapy and the timing of administering that therapy are not easily answered by clinical risk factors alone. The study, published in the Journal of Clinical Oncology, showed that patients with low genomic risk may be optimally managed with observation after radical prostatectomy (prostate surgery), while those with high genomic risk may be better managed earlier with adjuvant radiotherapy. The study, conducted by researchers from Thomas Jefferson University and Mayo Clinic using a commercially available genomic classifier by GenomeDx.

“The optimal timing of post-prostatectomy radiation therapy is a subject of debate,” says Robert Den, M.D., of the Sidney Kimmel Medical College of Thomas Jefferson University and lead author of the study. “Common practice is to wait for prostate-specific antigen (PSA) rise after surgery before intervening with radiation treatment. The results of this study suggest that we can use a genomic test to identify a group of men who will benefit from earlier administration of additional local treatment.”

Current clinical practice guidelines from the American Urological Association (AUA) and the American Society for Radiation Oncology (ASTRO) recommend physicians offer adjuvant radiotherapy after surgery for men who have been diagnosed with intermediate and high-risk prostate cancer. These recommendations are based on evidence from multiple randomized clinical trials, which demonstrated the efficacy of earlier, or adjuvant radiotherapy with reductions in recurrence and progression as compared to a “wait-and-see” approach after surgery. However, not all men receive a benefit from early radiation therapy, and there is an obvious need to identify patients who will and won’t benefit, so as to avoid overtreatment and serious side effects such as incontinence, impotence, and rectal bleeding.

According to the AUA, adjuvant radiation therapy is administered because of adverse pathology after radical prostatectomy, while salvage radiation therapy refers to initiation of radiation therapy only after PSA rise, commonly referred to as biochemical recurrence. Until now, clinicians have used pathology and clinical risk factors, which are less accurate measures of metastatic risk, to select men appropriate for treatment with radiation therapy.

“This potentially practice changing study is an example of the collaborative nature of the multidisciplinary genitourinary group at the Sidney Kimmel Cancer Center at Thomas Jefferson University which provides the highest quality of care to our patients,” says Dr. Leonard Gomella, the Bernard W. Godwin Professor of Prostate Cancer and Chairman of Department of Urology.

“Determining the right patient and the right time for radiation therapy is not straightforward. Patients have to balance the potential complications from radiation treatment with the risk of prostate cancer recurring. This test may enhance our ability in deciding who should or should not be considered for adjuvant radiation versus close monitoring,” says R. Jeffrey Karnes, M.D., associate professor and vice chair in Urology at Mayo Clinic and an investigator on the study.

The study, entitled, “A Genomic Classifier Identifies Men with Adverse Pathology after Radical Prostatectomy Who Benefit from Adjuvant Radiation Therapy,” included 188 prostate cancer patients who received radiation therapy after prostate surgery at Thomas Jefferson University and Mayo Clinic between 1990 and 2009. The genomic classifier stratified patients with low, average, and high genomic risk with 0%, 9%, and 29% five-year cumulative incidence of metastasis (p=0.002). Patients with average-to-high genomic risk who were treated with the more aggressive adjuvant radiation therapy had a five-year metastasis incidence of only 6% compared to 23% (p=0.008) for those who waited for PSA recurrence to trigger initiation of salvage therapy. In addition, the study found no disadvantage for salvage therapy in men with low genomic risk, suggesting that these men may improve quality of life by waiting for possible PSA rise rather than taking a course of immediate radiation therapy after radical surgery.

The researchers included Drs. Adam Dicker, Leonard Gomella, Edouard Trabulsi, and Costas Lallas.

The abstract is available at PubMed and the full publication is available at the Journal of Clinical Oncology.

Discussions of the publication can be found at the UrologyTimes.com and OncologyPractice.com and the GenomeDX Press Release and at the ASCO Post and The “New” Prostate Cancer InfoLink.

Media Only Contact:
Edyta Zielinska
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 2/17/2015



Dr. William Kevin Kelly appointed leader of the Biology of Prostate Cancer Program

Dr. William Kevin Kelly

Dr. William Kevin Kelly

The Sidney Kimmel Cancer Center would like to congratulate Wm. Kevin Kelly, D.O., Professor of Medical Oncology and Director of the Division of Solid Tumor Oncology, on his new appointment as the Leader of the Biology of Prostate Cancer Program.  Dr. Kelly has been a considerable asset to the cancer center and Jefferson as a whole since his recruitment in 2010, and he brings substantial translational and clinical expertise to this role.

In addition to his 25 years of experience as a clinician, Dr. Kelly is a nationally recognized translational researcher, known for his work on urological malignancies and his expertise in drug design and development.  Kelly’s research linking elevated prostate-specific antigen levels to prostate cancer treatment outcomes remains a foundation for drug development in patients with advanced prostate cancer today.

Prior to joining the Jefferson faculty, Dr. Kelly directed the Clinical Research Management Office at the Yale Comprehensive Cancer Center and co-directed prostate and urological oncology program at Yale University. He spent the previous 15 years on the faculty at Memorial-Sloan Kettering Cancer Center in the Genitourinary Oncology Division.



Dr. Andrew Aplin to Lead Basic Science of the Sidney KImmel Cancer Center

Dr. Andrew Aplin

Dr. Andrew Aplin

Congratulations to Andrew Aplin, PhD, for his appointment to lead Basic Science for the SKCC! Dr. Aplin has already distinguished himself as the leader of the Cancer Cell Biology and Signaling Program, and he will bring his energy and scientific expertise to all aspects of basic research here at the Sidney Kimmel Cancer Center. Please join us in congratulating him on this new expanded role.

Dr. Aplin’s research laboratory focuses on melanoma, the deadliest form of skin cancer. Since 2002, he has identified downstream targets of mutant BRAF-MEK-ERK signaling in melanoma, demonstrated the contribution of these targets to the malignant traits, and analyzed the influence of the tumor microenvironment. More recently, his lab has analyzed the determinants of response and mechanisms of resistance to BRAF inhibitors. Through his collaborations with Takami Sato and Carol Shields on the Jefferson campus, Dr Aplin and his team are extending their studies into ocular melanoma. His laboratory also collaborates with clinicians in the Melanoma Center of Excellence at Jefferson and with melanoma researchers at the University of Pennsylvania and the Wistar Institute. Through this research, they aim to promote the bi-directional flow of new discoveries between the laboratory and the bedside.

Andrew’s expertise and accomplishments in both basic and translational research, combined with his natural leadership skills, gives us the utmost confidence in his ability to take the helm of this important position.



Dr. Nevalainen wins SKCC Innovator of the Year Award

Drs. Pestell and Nevalainen

Drs. Pestell and Nevalainen

On December 16, 2014, Dr. Marja Nevalainen was awarded the 2014 Sidney Kimmel Cancer Center Innovator of the Year award. The award was presented presented by Dr. Richard G. Pestell, Director of the Sidney Kimmel Cancer Center.




2014 SKCC Consortium: Symposium and Poster Session

On October 1st, 2014 the Sidney Kimmel Cancer Center Consortium held a Symposium and Poster Session. Senior Leadership presented overviews of the work being done across the Sidney Kimmel Cancer Center Consortium. Also, progress reports were presented by the recipients of the 2013 SKCC Consortium Pilot Project Awards.  The afternoon portion of the event was composed primarily of a Poster Session from SKCC Consortium graduate students and post-doctoral fellows. Below, is list of the winners from the Poster Session:

Post-Doctoral Fellowship Poster Awards:
1st    Fernando Blanco, PhD
2nd   Edward Hartsough, PhD
3rd   Atul Goyal, PhD

Graduate Student Poster Awards:
1st    Debra Klopfenstein
2nd  Sergey Karakashev
3rd   Valerie Sodi

Below is a selection of photos from the day’s event and here is the days agenda.



Dr. Gomella, Associate Director for Clinical Affairs Appointed to NCI Genitourinary Cancers Steering Committee

Dr. Leonard Gomella

Dr. Leonard Gomella

Dr. Leonard Gomella, Chairman of the Department of Urology and Associate Director for Clinical Affairs for the Sidney Kimmel Cancer at Jefferson has been appointed to serve on the NCI Genitourinary Cancers Steering Committee (GUSC). The GUSC is one of sixteen steering committees formed to leverage current NCI-supported NCTN Groups, Consortia, SPOREs and Cancer Center structures to design and prioritize national cancer related clinical trials. The GUSC charge is to prioritize and review concepts for phase 2 and phase 3 clinical trials and provide a forum for critical review of concepts for new trials by a broad spectrum of experts from across the NCI-supported clinical trials enterprise and from international partners.

Dr. Gomella, one of the founding members of the Sidney Kimmel Cancer Center, also serves as Clinical Director for the Jefferson Sidney Kimmel Cancer Network and as Urology Chair for NRG, formerly the Radiation Therapy Oncology Group. In addition to being recognized as an outstanding clinician in regional and national “Top Doctor” listings, he is involved in translational basic science and clinical research in the development of new diagnostic techniques and treatments for prostate, bladder and kidney cancer.



Dr. Gomella elected to the Clinical Society of Genitourinary Surgeons

Dr. Leonard Gomella

Dr. Leonard Gomella

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



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

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

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


“Spirit of Caring” Awardee:

Wm. Kevin Kelly, D.O.

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

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

“Spirit of Courage” Awardee:
Anthony DiPrimio, PhD

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

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

“Spirit of Commitment” Awardee:
Neal Rodin

President, International Financial Company, LLC

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

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

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



ACS-IRG Pilot Projects Awarded for 2013

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

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



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

Karen Knudsen, Ph.D.

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

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

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

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

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

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

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

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

The authors declare that they have no conflicts of interest.

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



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

Richard Pestell, MD, PhD and Andrew Quong, PhD

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

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

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

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

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



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

Massimo Cristofanilli, M.D.

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

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

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

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

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

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

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

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

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

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

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

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

The authors declare that they have no conflicts of interest.

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



Protein in Blood Exerts Natural Anti-Cancer Protection

Renato V. Iozzo, M.D.

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

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

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

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

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

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

Absence of decorin promotes tumor growth

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

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

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

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

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

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

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

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

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

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



Researchers Discover Molecule That Drives Aggressive Breast Cancer

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

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

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

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

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

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

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

Tracing how EYA1 leads to poor outcomes

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

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

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

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

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

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

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

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



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

Isidore Rigoutsos, Ph.D.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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



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

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

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

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

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

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



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

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



HIV Drug May Slow Down Metastatic Triple-Negative Breast Cancer

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

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

These results were originally reported in Cancer Research.

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