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.



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.



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



Biomarker Links Clinical Outcome with New Model of Lethal Tumor Metabolism

Researchers at the Kimmel Cancer Center at Jefferson have demonstrated for the first time that the metabolic biomarker MCT4 directly links clinical outcomes with a new model of tumor metabolism that has patients “feeding” their cancer cells.  Their findings were published online March 15 in Cell Cycle.

To validate the prognostic value of the biomarker, a research team led by Agnieszka K. Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson, analyzed samples of patients with triple negative breast cancer, one of the most deadly of breast cancers, with fast-growing tumors that often affect younger women.

A retrospective analysis of over 180 women revealed that high levels of the biomarker MCT4, or monocarboxylate transporter 4, were strictly correlated with a loss of caveolin-1 (Cav-1), a known marker of early tumor recurrence and metastasis in several cancers, including prostate and breast.

“The whole idea is that MCT4 is a metabolic marker for a new model of tumor metabolism and that patients with this type of metabolism are feeding their cancer cells. It is lethal and resistant to current therapy,” Dr. Lisanti said. “The importance of this discovery is that MCT4, for the first time, directly links clinical outcome with tumor metabolism, allowing us to develop new more effective anti-cancer drugs.”

Analyzing the human breast cancer samples, the team found that women with high levels of stromal MCT4 and a loss of stromal Cav-1 had poorer overall survival, consistent with a higher risk for recurrence and metastasis, and treatment failure.

Applying to a Triple Threat

Today, no such markers are applied in care of triple negative breast cancer, and as a result, patients are all treated the same. Identifying patients who are at high risk of failing standard chemotherapy and poorer outcomes could help direct them sooner to clinical trials exploring new treatments, which could ultimately improve survival.

“The idea is to combine these two biomarkers, and stratify this patient population to provide better personalized cancer care,” said Dr. Witkiewicz

The findings suggest that when used in conjunction with the stromal Cav-1 biomarker, which the authors point out has been independently validated by six other groups worldwide, MCT4 can further stratify the intermediate-risk group into high and low risk.

Since MCT4 is a new druggable target, researchers also suggest that MCT4 inhibitors should be developed for treatment of aggressive breast cancers, and possibly other types.  Targeting patients with an MCT4 inhibitor, or even simple antioxidants, may help treat high-risk patients, who otherwise may not respond positively to conventional treatment, the researchers suggest.

Paradigm Shift

But the work stems beyond triple negative breast cancer, challenging an 85-year-old theory about cancer growth and progression.

This paper is the missing clinical proof for the paradigm shift from the “old cancer theory” to the “new cancer theory,” known as the “Reverse Warburg Effect,” said Dr. Lisanti. The new theory being that aerobic glycolysis actually takes place in tumor associated fibroblasts, and not in cancer cells, as the old theory posits.

“The results by Witkiewicz et al. have prominent conceptual and therapeutic implications,” wrote Lorenzo Galluzzi, Ph.D., Oliver Kepp, Ph.D., and Guido Kroemer, M.D., Ph.D. of the French National Institute of Health and Medical Research and Institut Gustave Roussy, in an accompanying editorial. “First, they strengthen the notion that cancer is not a cell-autonomous disease, as they unravel that alterations of the tumor stroma may constitute clinically useful biomarkers”.

“Second, they provide deep insights into a metabolic crosstalk between tumor cells and their stroma that may be targeted by a new class of anticancer agents.”

Dr. Kroemer entitled his commentary “Reverse Warburg: Straight to Cancer” to emphasize that the connective tissue cells (fibroblasts) are directly “feeding” cancer cells, giving them a clear growth  and survival advantage.  New personalized therapies would cut off the “fuel supply” to cancer cells, halting tumor growth and metastasis.



Rawls Palmer Progress in Medicine Award Presented to Dr. Scott A. Waldman

Scott A. Waldman, M.D., Ph.D., will receive the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Rawls–Palmer Progress in Medicine Award at the 2012 Annual Meeting on March 16.

Established in 1978 by Dr. W. B. Rawls, the award recognizes scientists who have implemented progressive research techniques and tools to improve patient care.

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

ASCPT will present the award to Dr. Waldman prior to his lecture at the 113th Annual Meeting.

Dr. Waldman is the Samuel MV Hamilton Endowed Professor of Medicine, Vice President of Clinical and Translational Research, and Chair of the Department of Pharmacology and Experimental Therapeutics at Thomas Jefferson University. He is also Director of the Gastrointestinal Malignancies Program at the university’s Kimmel Cancer Center and Associate Dean of Clinical and Translational Sciences at Jefferson Medical College.

As a longtime volunteer leader of ASCPT, Dr. Waldman has participated on various committees and task forces, serving on the Board of Directors, as Society president, and as Editor in Chief of Clinical Pharmacology and Therapeutics since 2006.

Dr. Waldman has chaired numerous scientific review panels for the NIH and is on the editorial boards of Personalized Medicine, Expert Reviews in Clinical Pharmacology, and Regenerative Medicine, among others. He is the inaugural Deputy Editor of Clinical and Translational Science and the inaugural Senior Editor of Biomarkers in Medicine.

Dr. Waldman is a recognized clinician–investigator whose research ranges from molecular biology to cancer diagnostics and therapeutics. He received the 2010 ASCPT Henry Elliott Award and the 2011 Pharmaceutical Research and Manufacturers of America Foundation Award in Excellence for Clinical Pharmacology and Therapeutics.

About ASCPT

ASCPT is the leading forum for the discussion, development, and integration of clinical pharmacology in the drug development continuum—from discovery to safe and effective use. Headquartered in Alexandria, Virginia, ASCPT was established in 1900. Today, more than 2,100 ASCPT members are committed to advancing the science of human pharmacology and therapeutics worldwide.

*This release was reprinted with permission from ASCPT.



PCF Young Investigator Award Goes to Jefferson Researcher

Heather Montie, Ph.D., a post-doctoral research fellow in the Department of Biochemistry and Molecular Biology, has received a Prostate Cancer Foundation Young Investigator Award for her work with androgen receptor (AR) acetylation and its role in castration-resistant prostate cancer.

Young Investigator awards are designed to promote long-term careers in the field of prostate cancer by providing three year grants for transformational research focused on prostate cancer treatments to improve patient outcomes. Since 2007, PCF has invested more than $20 million in Young Investigator grants.

“PCF-supported young investigators have changed the scope of prostate cancer research, advancing treatment sciences and improving the lives of patients worldwide,” said Howard Soule, PhD, chief science officer and executive vice president of PCF. “It is with great pride and appreciation that PCF can now announce our young investigator program spans across six countries and 42 research institutes.”

Prostate cancer is driven by the male hormones, androgens which mediate their activity through the androgen receptor. Unfortunately most prostate cancerous tumors progressively become resistant to the preferred treatment modality, androgen deprivation therapy. One of the mechanisms proposed to enhance the activity of androgen receptors in castration-resistant prostate cancer, even in the absence of androgens, is the addition of a small chemical group/moiety to the AR protein. This modification of AR is termed ‘acetylation’ and is proposed to convert the protein to a ‘super AR.’

However, there is currently no experimental data to show that AR acetylation directly enhances AR-dependent prostate cancer cell viability.

Dr. Montie proposes to evaluate the role of AR acetylation in the enhanced AR functional activity central to CRPC. She will study the precise mechanisms by which this modification of AR enhances its cancer-promoting activity. Dr. Montie will also validate the potential of AR acetylation as a therapeutic target for castrate-resistant prostate cancer.

A total of 15 competitive research grants have been awarded to-date in 2012, bringing the total of young investigators awarded to 89.

Each Young Investigator recipient is awarded $225,000 over a three-year period.

Dr. Montie received the 2012 John A. Moran PCF Young Investigator Award. 

Visit here for more on the Young Investigator awards.



Dr. Renato V. Iozzo receives an honorary degree from Semmelweis University in Budapest, Hungary

Congratulations to Renato V. Iozzo, M.D., a Professor of Pathology and Cell Biology, and Professor of Biochemistry & Molecular Biology, Thomas Jefferson University, for receiving an honorary degree (Doctor Honoris Causa) from Semmelweis University in Budapest, Hungary.

Dr. Iozzo received this award in November 2011 in recognition for his contributions to the field of Matrix Biology, Cancer and Angiogenesis.

His research focuses on the biology of proteoglycans and their roles in cancer and angiogenesis, and has published over 275 peer-reviewed articles, numerous reviews and edited two books on proteoglycans.

After receiving an M.D. degree summa cum laude from the University of Florence, Italy, Dr. Iozzo moved to the Department of Pathology at the University of Washington, where he completed a five-year Residency/Fellowship. Following a six-year faculty appointment at the University of Pennsylvania, he was promoted to Associate Professor and then moved the same year to Thomas Jefferson University as Full Professor with tenure.

Founded in 1769 by Maria Theresa the Empress of Austria-Hungary, Semmelweis University is one of the oldest universities and medical schools in Europe.



Stronger Intestinal Barrier May Prevent Cancer in the Rest of the Body, New Study Suggests

Scott Waldman, M.D., Ph.D., chair of the Department of Pharmacology and Experimental Therapeutics at Jefferson and director of the Gastrointestinal Cancer Program at Jefferson’s Kimmel Cancer Center

A leaky gut may be the root of some cancers forming in the rest of the body, a new study published online Feb. 21 in PLoS ONE by Thomas Jefferson University researchers suggests.

It appears that the hormone receptor guanylyl cyclase C (GC-C)—a previously identified tumor suppressor that exists in the intestinal tract—plays a key role in strengthening the body’s intestinal barrier, which helps separate the gut world from the rest of the body, and possibly keeps cancer at bay. Without the receptor, that barrier weakens.

A team led by Scott Waldman, M.D., Ph.D., chair of the Department of Pharmacology and Experimental Therapeutics at Jefferson and director of the Gastrointestinal Cancer Program at Jefferson’s Kimmel Cancer Center, discovered in a pre-clinical study that silencing GC-C in mice compromised the integrity of the intestinal barrier.  It allowed inflammation to occur and cancer-causing agents to seep out into the body, damaging DNA and forming cancer outside the intestine, including in the liver, lung and lymph nodes.

Conversely, stimulating GC-C in intestines in mice strengthened the intestinal barrier opposing these pathological changes.

A weakened intestinal barrier has been linked to many diseases, like inflammatory bowel disease, asthma and food allergies, but this study provides fresh evidence that GC-C plays a role in the integrity of the intestine.  Strengthening it, the team says, could potentially protect people against inflammation and cancer in the rest of the body.

“If the intestinal barrier breaks down, it becomes a portal for stuff in the outside world to leak into the inside world,” said Dr. Waldman. “When these worlds collide, it can cause many diseases, like inflammation and cancer.”

The role of GC-C outside the gut has remained largely elusive. Dr. Waldman and his team have previously shown its role as a tumor suppressor and biomarker that reveals occult metastases in lymph nodes. They’ve used to it better predict cancer risk, and have even shown a possible correlation with obesity.

Reporting in the Journal of Clinical Investigation, Dr. Waldman colleagues found that silencing GC-C affected appetite in mice, disrupting satiation and inducing obesity. Conversely, mice who expressed the hormone receptor knew when to call it quits at mealtime.

However, its role in intestinal barrier integrity, inflammation, and cancer outside the intestine is new territory in the field.

A new drug containing GC-C is now on the verge of hitting the market, but its intended prescribed purpose is to treat constipation.

This study helps lays the groundwork, Dr. Waldman said, for future pre-clinical and clinical studies investigating GC-C’s abilities beyond those treatments in humans, including prevention and treatment of inflammatory bowel disease and cancer.

“We’ve shown that when you pull away GC-C in animals, you disrupt the intestinal barrier, putting them at risk for getting inflammatory bowel disease and cancer.  And when you treat them with hormones that activate GC-C it helps strengthen the integrity of the intestinal barrier,” Dr. Waldman said.  “Now, if you want to prevent inflammation or cancer in humans, then we need to start thinking about feeding people hormones that activate GC-C to tighten up the barrier.”



Taxpayers Give Back for Cancer: Jefferson Researcher Awarded ‘Refunds for Research’ Grant

Takemi Tanaka, Ph.D., of Thomas Jefferson University’s School of Pharmacy and the Kimmel Cancer Center

Takemi Tanaka, Ph.D., of Thomas Jefferson University’s School of Pharmacy and the Kimmel Cancer Center, received a $50,000 grant toward her breast cancer research, as part of the Pennsylvania Breast Cancer Coalition’s (PBCC) “Refunds for Breast and Cervical Cancer Research” initiative.

The PBCC’s grants are made possible through contributions from state taxpayers who choose to contribute all or part of their state income tax refund to the program.

Dr. Tanaka’s research focuses on breast cancer metastasis. When cancer metastasizes, cancer cells enter the distal organs through the blood vessels. Dr. Tanaka envisions those vessels as a gateway for the cells and wants to close it as tight as possible to prevent the cancer from spreading further.

Her team developed a new drug called ESTA to block the entry of breast cancer cells into the tissue.  Early data show that mice treated with the drug had 60 percent less metastases without toxicity.

From the left: Ashiwel Undieh, Chair of Pharmaceutical Sciences, Pat Halpin-Murphy, founder of PBCC, Dr. Tanaka, and Rebecca Finley, Dean of the Jefferson School of Pharmacy

“I would like to express my sincere gratitude to the tax payers for their generous support for my breast cancer research to help eradicate this deadly disease,” Dr. Tanaka said. “We believe that success with our strategy may transform current breast cancer therapy and move us one step closer to a cure.”

Dr. Tanaka is one of three researchers who received funding through PBCC’s Breast and Cervical Cancer Research initiative. The other recipients are from the University of Pennsylvania and Penn State Hershey Cancer Institute.

“We’re extremely proud of Dr. Tanaka’s recognition by the Pa. Breast Cancer Coalition and thankful for the people in Pennsylvania who donated to help support these grants, as well as the PBCC for their efforts to raise awareness about breast cancer,” said Rebecca Finley, PharmD, M.S., Dean of Jefferson’s School of Pharmacy. “Dr. Tanaka’s work with this promising new drug will only help us better understand and potentially better treat this important health issue in women.”

The PBCC kicked off its annual Refunds for Breast and Cervical Cancer Research campaign to fund the cancer researchers on Monday, Feb. 13 at City Hall with Councilmen Dennis O’Brien.

Since 1997, more than $2.8 million has been donated to the Refunds for Research campaign and 71 grants have been awarded to Pennsylvania researchers looking for the cause of and cure for these common cancers in women.



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

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

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

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

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

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

Investigating the Powerhouse

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

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

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

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

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

Personalized Treatment

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

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

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



Blocking Receptor in Key Hormone Fires Up Enzyme to Kill Pancreatic Cancer Cells

Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University

Pancreatic cancer researchers at Thomas Jefferson University have shown, for the first time, that blocking a receptor of a key hormone in the renin-angiotensin system (RAS) reduces cancer cell growth by activating the enzyme AMPK to inhibit fatty acid synthase, the ingredients to support cell division.

With that, a new chemopreventive agent that inhibits the angiotensin II type 2 receptor—never before thought to play a role in tumor growth—could be developed to help treat one of the fastest-moving cancers that has a 5-year survival rate of only 5 percent.

Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University and the co-director of the Jefferson Pancreatic, Biliary and Related Cancers Center, and her fellow researchers, including the chair of the Department of Surgery at Jefferson, Charles J. Yeo, M.D., FACS, present their findings in the August issue of Surgery.

Angiotensin II (AngII) is the principal hormone in the RAS that regulates our blood pressure and water balance; it has two receptors: type 1 and type 2. AngII is also generated actively in the pancreas and has been shown to be involved in tumor angiogenesis.

Previous studies have pointed to the hormone’s type 1 receptor as the culprit in cancer cell proliferation and tumor inflammation; however, the idea that type 2 had any effect was never entertained.

By looking at pancreatic ductal adenocarcinoma (PDA) cells in vitro, Jefferson researchers discovered that the type 2 receptor, not just type 1, mediates the production of fatty acid synthase (FAS), which has been shown to supply the cell wall ingredients necessary for cancer cells to multiply.

FAS was previously identified as a possible oncogene in the 1980s. It is up-regulated in breast cancers and is indicator of poor prognosis, and thus believed to be a worthwhile chemopreventive target.

“AngII is not just involved in cell inflammation and angiogenesis; it’s involved in tumor metabolism as well,” said Dr. Arafat, a member of the Kimmel Cancer Center at Jefferson. “It promotes FAS with both receptors, which makes the tumor grow.”

“Blocking the type 2 receptor reduces PDA cell growth with the activation of AMPK, revealing a new mechanism by which chemoprevention can exploit,” she added. “In fact, maybe combined blocking of the two receptors would be more efficient than just blocking one receptor.”

AMPK, or adenosine monophosphate-activated protein kinase, is the focus of several agents today, including ones for diabetes and related metabolic diseases. It is a master metabolic regulator for cells that is activated in times of reduced energy availability, like starvation. Activation of AMPK has been shown to improve energy homeostasis, lipid profile and blood pressure. The enzyme also activates a well-known tumor suppressor, p53.

“The main thing is activation of AMPK in tumor cells,” said Dr. Arafat. “AMPK is the perfect candidate as it regulates multiple targets that both halt tumor cell division and activate programmed cell death. Although it is yet to be determined how the type 2 receptor imposes deregulation of AMPK activity, identification of the type 2 receptor as a novel target for therapy is very exciting”

Next, Dr. Arafat and fellow researchers are proposing to take this research into animal studies. They hope to target the receptors early on in the disease to better understand its prevention capabilities and also study its treatment potential. Considering pancreatic cancer is typically detected in later stages, finding better ways to treat cases that have progressed further along would be of great benefit to patients.



Leukemia Drug Reverses Tamoxifen-Resistance in Breast Cancer Cells

Researchers at the Kimmel Cancer Center at Jefferson demonstrate drug combination’s “antioxidant effect” on cancer cells and fibroblasts

Taking a leukemia chemotherapy drug may help breast cancer patients who don’t respond to tamoxifen overcome resistance to the widely-used drug, new research from the Kimmel Cancer Center at Jefferson suggests.

Interestingly, researchers found that tamoxifen combined with dasatinib, a protein-tyrosine kinase inhibitor, reverses the chemo-resistance caused by cancer-associated fibroblasts in the surrounding tissue by normalizing glucose intake and reducing mitochondrial oxidative stress, the process that fuels the cancer cells.

Previous animal studies have confirmed that combining tyrosine kinase inhibitors with anti-estrogen therapies, like tamoxifen, can prevent drug resistance, but none have suggested that the target of the inhibitors is the cancer-associated fibroblasts.

The researchers report their findings in the August 1 issue of Cell Cycle.

About 70 percent of women diagnosed with breast cancer will have estrogen receptor positive (ER(+)) disease, which indicates that the tumor may respond to tamoxifen. However, a large percentage of these tumors—up to 35 percent—have little to no response to the drug or eventually develop resistance to it.

In this study, researchers sought to better understand drug resistance by looking at the metabolic basis in an ER (+) cell line and cancer-associated fibroblasts. The researchers have previously established a relationship between the two, where cancer cells induce aerobic glycolysis by secreting hydrogen peroxide in adjacent fibroblasts via oxidative stress. In turn, these fibroblasts provide nutrients to the cancer cells to proliferate, a process that ultimately makes tumors grow.

Here, they investigated and then demonstrated that this interaction was also the basis of tamoxifen resistance.

In a sense, the drug combination had an “antioxidant effect” in these types of cancer cells, according to 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 Kimmel Cancer Center.

“The fibroblasts are what make ER (+) cancer cells resistant to the tamoxifen,” said Dr. Lisanti. “But the tamoxifen plus dasatinib maintained both fibroblasts and cancer cells in a ‘glycolytic state,’ with minimal oxidative stress and more cell death, most likely because of an absence of metabolic coupling. The supply between the two was cut.”

“This suggests resistance to chemotherapeutic agents is a metabolic and stromal phenomenal,” he added.

Researchers showed that ER (+) cancer cells alone responded to tamoxifen but when co-cultured with human fibroblasts had little to no effect. Similarly, dasatinib, a chemotherapy drug used to treat leukemia patients who can no longer benefit from other medications, had no effect on fibroblasts alone or cancer cells. Together, however, the drugs prevented the cancer cells co-cultured with the fibroblasts from using high-energy nutrients from the fibroblasts.

This combination resulted in nearly 80 percent cell death, the team reported—a two to three fold increase when compared with tamoxifen alone.

“The drugs have no effect when they are used alone—it’s in unison when they effectively kill the cancer cells in the presence of fibroblasts,” said Dr. Lisanti. “This opens up the door for possible new treatment strategies. This ‘synthetic lethality’ may help patients overcome resistance in the clinic.”

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Researchers involved in the study include Ubaldo E. Martinez-Outschoorn, of the Jefferson Stem Cell Biology and Regenerative Medicine Center and Department of Medical Oncology; Zhao Lin, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology;Ying-Hui Ko, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology; Allison F. Goldberg, of the Department of Surgery; Neal Flomenberg, chair of the Department of Medical Oncology; Chenguang Wang, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology; Stephanos Pavlides, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology; Richard G. Pestell, director of the Kimmel Cancer Center at Jefferson and Chair of the Department of Cancer Biology; Anthony Howell, of the Manchester Breast Centre & Breakthrough Breast Cancer Research Unit; and Federica Sotgia, of the Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology.



KCC Research: Cancer Cells Accelerate Aging & Inflammation in Body to Drive Tumor Growth

Researchers at the Kimmel Cancer Center at Jefferson have shed new light on the longstanding conundrum about what makes a tumor grow—and how to make it stop.  Interestingly, cancer cells accelerate the aging of nearby connective tissue cells to cause inflammation, which ultimately provides “fuel” for the tumor to grow and even metastasize.

Michael Lisanti, MD, PhD

This revealing symbiotic process, which is similar to how muscle and brain cells communicate with the body, could prove useful for developing new drugs to prevent and treat cancers.  In this simple model, our bodies provide nourishment for the cancer cells, via chronic inflammation.

“People think that inflammation drives cancer, but they never understood the mechanism,” said 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. “What we found is that cancer cells are accelerating aging and inflammation, which is making high-energy nutrients to feed cancer cells.”

In normal aging, DNA is damaged and the body begins to deteriorate because of oxidative stress. “We are all slowly rusting, like the Tin-man in the Wizard of Oz,” Dr. Lisanti said. “And there is a very similar process going on in the tumor’s local environment.”  Interestingly, cancer cells induce “oxidative stress,” the rusting process, in normal connective tissue, in order to extract vital nutrients.

Dr. Lisanti and his team previously discovered that cancer cells induce this type of stress response (autophagy) in nearby cells, to feed themselves and grow. However, the mechanism by which the cancer cells induce this stress and, more importantly, the relationship between the connective tissue and how this “energy” is transferred was unclear.

“Nobody fully understands the link between aging and cancer,” said Dr. Lisanti, who used pre-clinical models, as well as tumors from breast cancer patients, to study these mechanisms.  “What we see now is that as you age, your whole body becomes more sensitive to this parasitic cancer mechanism, and the cancer cells selectively accelerate the aging process via inflammation in the connective tissue.”

This helps explain why cancers exist in people of all ages, but susceptibility increases as you age.  If aggressive enough, cancer cells can induce accelerated aging in the tumor, regardless of age, to speed up the process.

The researchers’ findings were published in the June 1 issue of Cell Cycle in three separate papers.

One paper analyzes the gene profiles of the laser-captured connective tissue, associated with lethal tumors, in human breast cancer patients.  In this paper, lethal cancers show the same gene expression pattern associated with normal aging, as well as Alzheimer’s disease.  In fact, these aging and Alzheimer’s disease signatures can identify which breast cancer patients will undergo metastasis. The researchers find that oxidative stress is a common “driver” for both dementia and cancer cell spreading.

In another study, the researchers explain that cancer cells initiate a “lactate shuttle” to move lactate—the “food”—from the connective tissue to the cancer cells. There’s a transporter that is “spilling” lactate from the connective tissue and a transporter that then “gobbles” it up in the cancer cells.”

The implication is that the fibroblasts in the connective tissue are feeding cancer cells directly via pumps, called MCT1 and MCT4, or mono-carboxylate transporters.  The researchers see that lactate is like “candy” for cancer cells.  And cancer cells are addicted to this supply of “candy.”

“We’ve essentially shown for the first time that there is lactate shuttle in human tumors,” said Dr. Lisanti. “It was first discovered nearly 100 years ago in muscles, 15 years ago in the brain, and now we’ve shown this shuttle also exists in human tumors.”

It’s all the same mechanism, where one cell type literally “feeds” the other.  The cancer cells are the “Queen Bees,” and the connective tissue cells are the “Worker Bees.” In this analogy, the “Queen Bees” use aging and inflammation as the signal to tell the “Worker Bees” to make more food.

Researchers also identified MCT4 as a biomarker for oxidative stress in cancer-associated fibroblasts, and inhibiting it could be a powerful new anti-cancer therapy.

“If lethal cancer is a disease of “accelerated aging” in the tumor’s connective tissue, then cancer patients may benefit from therapy with strong antioxidants and anti-inflammatory drugs,” said Dr. Lisanti. “Antioxidant therapy will “cut off the fuel supply” for cancer cells.”  Antioxidants also have a natural anti-inflammatory action.



Highlights from KCC American Cancer Society Research Symposium

From left to right: Marja Nevalainen, MD, PhD – Department of Cancer Biology, co- Director of ACS Institutional Research Grant at KCC, Hushan Yang, PhD - Department of Medical Oncology, Pilot Project Recipient, Richard Pestell, M.B.B.S., M.D., Ph.D., M.D. (Hon. Causa), F.R.A.C.P., F.A.C.P. – Department of Cancer Biology, Director of ACS Institutional Research Grant at KCC, Larry Slagle – ACS, Distinguished Gifts Officer, Amy Leader, DrPh, MPH - Department of Medical Oncology, Pilot Project Recipient

The Kimmel Cancer Center at Jefferson hosted the 3rd Annual American Cancer Society Research Symposium: Celebrating the ACS Institutional Research Grant at KCC on May 6, 2011.

Dr. Nevalainen welcomed members of the KCC and TJU community and the American Cancer Society.

Richard Pestell, MD, PhD gave the Keynote Address, “Cancer Invasion and Metastasis and a New Role for Junk DNA”.

Following this, the IRG Pilot Project recipients for 2010 presented the results of their research: Amy Leader, DrPh, MPH, of the Department of Medical Oncology, discussed “Factors Influencing Decision Making About Human Papillomavirus (HPV) Vaccination Among African American Adolescent Males And Their Caregivers”; while Hushan Yang, PhD, also of the Department of Medical Oncology, presented “Genetic Variations in Inflammation-Related Genes And The Risk Of Hepatocellular Carcinoma in HBV Patients”.

Larry Slagle represented the American Cancer Society.



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.