Global Positioning at the Cancer Frontline

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

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

Dr. Pestell’s recent TEDx presentation “Is Good Health a Choice?” was featured in an “Australia Unlimited” article by David Varga.

The article describes Dr. Pestell’s background and upbringing as well as highlighting his  innovative research involving the “GPS of Cancer” (the biological navigation system that allows malignant cancer cells to spread to the most vulnerable regions of the body).

 



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



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.



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.



Richard Pestell Named AAAS Fellow

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

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

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

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

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

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

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

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

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

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

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



Jefferson Researchers Unlock Key to Personalized Cancer Medicine Using Tumor Metabolism

Identifying gene mutations in cancer patients to predict clinical outcome has been the cornerstone of cancer research for nearly three decades, but now researchers at the Kimmel Cancer Center at Jefferson have invented a new approach that instead links cancer cell metabolism with poor clinical outcome. This approach can now be applied to virtually any type of human cancer cell.

Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center at Jefferson

The researchers demonstrate that recurrence, metastasis, and poor clinical outcome in breast cancer patients can be identified by simply gene profiling cancer cells that are using ketones and lactate as a food supply.

These findings are reported in the April 15th online issue of Cell Cycle. The investigators are calling this new approach to personalized cancer medicine “Metabolo-Genomics.”

High-energy metabolites have long been suspected to “fuel” aggressive tumor cell behavior. The researchers used this premise to generate a gene expression signature from genetically identical cancer cells, but one cell group was fed a diet of high-energy metabolites. These lactate- and ketone-induced “gene signatures” then predicted recurrence, metastasis, and poor survival.

So, it appears that what cancer cells are eating determines clinical outcome, not necessarily new gene mutations.

Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center at Jefferson, together with other researchers,  found that treatment of human breast cancer cells with high-energy metabolites increases the expression of genes associated with normal stem cells,  including genes upregulated in embryonic and neural stem cells.

What’s more, lactate and ketones were found to promote the growth of normal stem cells, which has critical applications for stem cell transplantation and for a host of different human diseases.  It appears that these metabolites increase “stemness” in cancer cells, which drives poorer outcomes.

“Tumors that are using the body’s own nutrients (lactate and ketones) as “fuel” have a poorer outcome for patient survival, a behavior that now can be used to predict if a patient is at a high-risk for recurrence or metastasis,” Dr. Lisanti said. “This is getting to the heart of personalized cancer medicine. Now, we have identified a panel of biomarkers that directly links cancer metabolism with targeted cancer therapy.”

These findings suggest, according to the authors, that high-risk cancer patients (those whose cancer cells use high-energy metabolites) can be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the antioxidant metformin, a drug that is also used to treat diabetes.

“Knowing the gene signatures of patients whose cancer cells are “eating” these metabolites for fuel is a pivotal piece of new information that we can use to diagnose and treat cancer patients,” said Martinez-Outschoorn, M.D., of the department of Medical Oncology at Thomas Jefferson University, and the lead author of the paper. “It’s not just that we know those patients will have poor survival; we know that those patients are using mitochondrial metabolism, which is the type of energy metabolism that we should be targeting with new anti-cancer drugs.”

The researchers propose that this new approach to diagnosis and subsequent treatment be called “Metabolo-Genomics” since it incorporates both cell metabolism and gene transcriptional profiling. This strategy could now be used to direct which patients receive a particular “tailored” anti-metabolic therapy.

Genetic markers, like expression of the mutationally activated HER2 gene, provide biomarkers that can be used to identify breast cancer patients at high-risk for recurrence or metastasis, and to modify their subsequent treatment with targeted therapies (i.e., herceptin, a drug used in aggressive breast cancers).  But with “Metabolo-Genomics,” it is now about using “global” cancer cell metabolism for these predictions.

“Just by feeding cancer cells a particular energy-rich diet, it changes their character, without introducing mutations or altering their genetic profile,” Dr. Lisanti said.  “We’ve only fed them high energy nutrients that help them to use their mitochondria, and this changes their transcriptional profile.  It’s a new biomarker for “lethal” cancers that we can now treat with the right drugs, such as the antioxidant metformin.

Dr. Lisanti and his colleagues believe that tumor metabolism is the new big picture for understanding how cancers undergo recurrence and metastasis.



Radiation Oncology Announcements and Appointments

New faculty:

Thomas Jefferson University welcomes two new, seasoned clinicians and researchers to its Department of Radiation Oncology: Nicole Simone, M.D., from the National Institutes of Health’s National Cancer Institute (NCI) and Bo Lu, M.D., Ph.D, from Vanderbilt University.

Nicole Simone, M.D.

Dr. Simone is a board-certified Radiation Oncologist who has treated mostly patients with breast and head and neck cancers, while her research involves radiation’s effect on microRNAs in breast cancer and caloric restriction and radiation therapy—and the ability of both to delay breast cancer tumor growth.

“Dr. Simone is rapidly being recognized as one of the rising stars in the field,” said Adam Dicker, M.D, Ph.D, Professor and Chairman of the Department of Radiation Oncology. “Her research cuts across a number of cutting edge fields, including breast and prostate cancer biology, metabolism, microRNAs and computational biology.  The connection between diet and cancer treatment is very relevant for patients.”

Bo Lu, M.D., Ph.D

Dr. Bo Lu is also a board-certified Radiation Oncologist who comes to Jefferson from Vanderbilt University in Nashville, Tenn., where he was an Ingram associate professor with tenure in the Department of Radiation Oncology and Cancer Biology of the University’s School of Medicine.  He was also an attending radiation oncologist at the Vanderbilt University Medical Center, member of the Ingram Cancer Center, and director of the Translational Research Program and Lung Cancer Research Program.

“I am delighted that Dr. Lu has joined our faculty,” said Dr. Dicker. “He is internationally renowned for his work in clinical and translational radiation oncology, and I have received numerous congratulatory calls and emails from Chairs of Departments of Radiation Oncology around the world recognizing his numerous achievements.”

Dr. Lu’s focus is on radiation-induced cell death in lung patients, among other basic science areas. His clinical interests include the integration of novel targeted agents in the treatment of lung cancer, radiosurgery for lung cancer, and reductionof toxicities from thoracic radiation. More recently, Dr. Lu has looked at cancer stem cells for enhancing radiotherapy in a setting of lung cancer.

Appointments:

Congratulations to Maria Werner-Wasik, M.D., professor in the department of radiation oncology, and radiation oncology residency program director, who was elected as the Radiation Therapy Oncology Group Vice-Chair for Publications. (www.rtog.org)

Maria Werner-Wasik, M.D.

Dr. Werner-Wasik is a member of the RTOG Lung Cancer Steering Committee.  She succeeds William Sause, M.D., of Intermountain Medical Center in Salt Lake City, Utah, who has served as the RTOG publications vice-chair since 1999.

Dr. Werner-Wasik will chair the RTOG Publications Committee which is responsible for the oversight ofpublication quality and timeliness of the results of the group’s trials.

Drs. Timothy Showalter and Robert Den have been selected as recipients of the American Brachytherapy Society sponsored High Dose Rate fellowship program (1 week) for 2011.




“Longevity” Protein SIRT1 May Ward Off Precursor to Prostate Cancer

Dr. Richard G. Pestell

Dr. Richard G. Pestell

Researchers from the Kimmel Cancer Center at Jefferson and two other institutions have discovered new evidence that suggests the “longevity” protein SIRT1, known for its life-spanning effects in different species, can inhibit the development of a known precursor to prostate cancer, prostatic intraepithelial neoplasia (PIN).

“Prostate cancer is one of the malignancies that has a very direct relationship to aging,” says Richard G. Pestell, M.D., Ph.D., Director, Kimmel Cancer Center and Chairman of Cancer Biology at Thomas Jefferson University. “And these results provide a direct link for the first time between the onset of prostate cancer and the Sirt1 gene that regulate aging.”

The findings were reported in the February 2011 edition of Cancer Research ( pubmed)  ( JeffNews )




Researchers Say Stress Fuels Cancer Growth, Provide Genetic Evidence That Antioxidants Can Help Treat It

Researchers from Jefferson’s Kimmel Cancer Center have genetic evidence suggesting the antioxidant drugs currently used to treat lung disease, malaria and even the common cold can also help prevent and treat cancers because they fight against mitochondrial oxidative stress—a culprit in driving tumor growth.

For the first time, the researchers show that loss of the tumor suppressor protein Caveolin-1 (Cav-1) induces mitochondrial oxidative stress in the stromal micro-environment, a process that fuels cancer cells in most common types of breast cancer.

“Now we have genetic proof that mitochondrial oxidative stress is important for driving tumor growth,” said lead researcher Michael P. Lisanti, M.D., Ph.D., professor of cancer biology at Jefferson Medical College of Thomas Jefferson University and member of the Kimmel Cancer Center at Jefferson. “This means we need to make anti-cancer drugs that specially target this type of oxidative stress. And there are already antioxidant drugs out there on the market as dietary supplements, like N-acetyl cysteine.”

These findings were published in the online February 15 issue of Cancer Biology & Therapy.

Lisanti’s lab previously discovered Cav-1 as a biomarker that functions as a tumor suppressor and is the single strongest predictor of breast cancer patient outcome. For example, if a woman has triple negative breast cancer and is Cav-1 positive in the stroma,

her survival is greater than 75 percent at 12 years, versus less than 10 percent at 5 years if she doesn’t have the Cav-1 protein, according to Dr. Lisanti.

The researchers also established Cav-1’s role in oxidative stress and tumor growth; however, where that stress originates and its mechanism(s) were unclear.

To determine this, Jefferson researchers applied a genetically tractable model for human cancer associated fibroblasts in this study using a targeted sh-RNA knock-down approach. Without the Cav-1 protein, researchers found that oxidative stress in cancer associated fibroblasts leads to mitochondrial dysfunction in stromal fibroblasts.  In this context, oxidative stress and the resulting autophagy (producton of recycled nutrients) in the tumor-microenvironment function as metabolic energy or “food” to “fuel” tumor growth.

The researchers report that the loss of Cav-1 increases mitochondrial oxidative stress in the tumor stroma, increasing both tumor mass and tumor volume by four-fold, without any increase in tumor angiogenesis.

Michael Lisanti, M.D., Ph.D. of the Kimmel Cancer Center at Jefferson

“Antioxidants have been associated with cancer reducing effects—beta carotene, for example—but the mechanisms, the genetic evidence, has been lacking,” Dr. Lisanti said. “This study provides the necessary genetic evidence that reducing oxidative stress in the body will decrease tumor growth.”

Currently, anti-cancer drugs targeting oxidative stress are not used because is it commonly thought they will reduce the effectiveness of certain chemotherapies, which increase oxidative stress.

“We are not taking advantage of the available drugs that reduce oxidative stress and autophagy, including metformin, chloroquine and N-acetyl cysteine,” Dr. Lisanti said. “Now that we have genetic proof that oxidative stress and resulting autophagy are important for driving tumor growth, we should re-consider using antioxidants and autophagy inhibitors as anti-cancer agents.”

The diabetic drug metformin and chloroquine, which is used for the prevention and treatment of malaria, prevent a loss of Cav-1 in cancer associated fibroblasts (which is due to oxidative stress), functionally cutting off the fuel supply to cancer cells.

This research also has important implications for understanding the pathogenesis of triple negative and tamoxifen-resistance in ER-positive breast caner patients, as well as other epithelial cancers, such as prostate cancers.

“Undoubtedly, this new genetically tractable system for cancer associated fibroblasts will help identify other key genetic ‘factors’ that can block tumor growth,” Dr. Lisanti said.



Dr. Leonard G. Gomella Studies the Effect of Dutasteride on the Risk of Prostate Cancer

GomellaLeonardG

Dr. Leonard G. Gomella

Dr. Leonard G. Gomella and colleagues conducted a landmark international
randomized, double-blind, placebo-controlled, parallel-group multi-center
clinical trial to determine whether dutasteride reduces the risk of incident
prostate cancer, as detected on biopsy, among men who are at increased risk for
the disease. Over the course of the 4-year study period, dutasteride reduced
the risk of incident prostate cancer detected on biopsy and improved the
outcomes related to benign prostatic hyperplasia. These results were published
in the New England Journal of Medicine on April 1, 2010 ( Pubmed Abstract ).



Prolactin Blocks Oncogene Associated with Poor Prognosis in Breast Cancer

Researchers from the Kimmel Cancer Center at Jefferson have found a mechanism by which a hormone responsible for milk production blocks an oncogene that makes breast cancer more aggressive.

Publishing in the journal Cancer Research, the researchers discovered that prolactin, a pituitary hormone that normally stimulates breast development and milk production, in fact reduces levels of an oncogene called BCL6. The BCL6 protein has previously been shown to play a role in poorly differentiated breast cancer, which carries a poorer prognosis.

Read more…



Stromal Biomarker Predicts Advanced Prostate Cancer

The same biomarker was previously identified as a prognostic factor for breast cancer

The absence of a stromal protein called caveolin-1 appears to be a marker for advanced prostate cancer and metastasis, researchers from the Kimmel Cancer Center at Jefferson and Harvard Medical School reported in Cell Cycle.

There was an abundance of stromal caveolin-1 in prostate tissue taken from patients with benign prostate hypertrophy. However, the level of stromal caveolin-1 was significantly decreased in the prostate tissue taken from patients with localized prostate cancer. Furthermore, all tumor tissue taken from patients with metastatic prostate cancer was completely negative for stromal caveolin-1.

Read more…



New Universal Breast Cancer Marker Predicts Recurrence

The marker appears to be widely applicable to all breast cancer patients, regardless of other established prognostic indicators

Dr. Michael Lisanti

Dr. Michael Lisanti

Reporting online in the American Journal of Pathology, researchers from the Kimmel Cancer Center at Jefferson have implicated the loss of a stromal protein called caveolin-1 as a major new prognostic factor in patients with breast cancer, predicting early disease recurrence, metastasis and breast cancer patient survival.

The absence of caveolin-1 in the stroma also appeared to be a marker for drug resistance in patients receiving tamoxifen, according to Michael Lisanti, M.D., Ph.D., professor in the departments of Cancer Biology, Medical Oncology and Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University.

According to Dr. Lisanti, who is also director of the Jefferson Stem Cell Biology and Regenerative Medicine Center at the Kimmel Cancer Center, caveolin-1 is expressed by cells in the stroma called fibroblasts, which are present in the connective tissue surrounding cancer cells. When cancer cells arise, the fibroblasts stop making caveolin-1.

Read more…



Jefferson Scientists Discover a Key Protein Regulator of Inflammation and Cell Death

Reporting in the journal Nature, researchers led by Emad Alnemri, Ph.D., professor of Biochemistry and Molecular Biology in the Kimmel Cancer Center at Jefferson, discovered a key protein component involved in inflammation.

The protein, AIM2 (absent in melanoma 2), is involved in the detection and reaction to dangerous cytoplasmic DNA that is produced by infection with viral or microbial pathogens, or by tissue damage. AIM2 also appears to be a tumor suppressor, and its inactivation may play a role in the development of cancer, according to Dr. Alnemri.

Read more…



Jefferson Scientists Uncover Role of Cancer Stem Cell Marker: Controlling Gene Expression Patterns

Dr. Steven McMahon

Dr. Steven McMahon

Scientists at Jefferson’s Kimmel Cancer Center in Philadelphia have made an extraordinary advance in the understanding of the function of a gene previously shown to be part of an 11-gene “signature” that can predict which tumors will be aggressive and likely to spread. The gene, USP22, encodes an enzyme that appears to be crucial for controlling large scale changes in gene expression, one of the hallmarks of cancer cells.

As a result, USP22 immediately becomes a potential target for new anti-cancer drugs, says Steven McMahon, Ph.D., associate professor of Cancer Biology at Jefferson Medical College of Thomas Jefferson University, who led the work. And it solves a bit of a biological mystery.

Read more…