Bench to Bedside: How to Fast Track Targeted Cancer Drugs with Radiation into the Clinic

Researchers from the translational research program of the National Cancer Institute and the Radiation Therapy Oncology Therapy Group have developed new guidelines to help fast track the clinical development of targeted cancer drugs in combination with radiation therapy.

The suggested strategic guidelines, published in the Journal of the National Cancer Institute in a recent commentary with lead author Yaacov Richard Lawrence, MRCP, an adjunct Assistant Professor in the Department of Radiation Oncology at Thomas Jefferson University and Director of the Center for Translational Research in Radiation Oncology at Sheba Medical Center in Israel, offers specific steps in the preclinical and early phase clinical trial process to get well-studied and novel targeted agents into the clinic more quickly.

Over the last decade, molecular agents that target cellular survival and growth, like Erlotinib and Sunitinib, have been developed but alone have had modest effect on improved survival. Combining such targeted agents with radiation therapy, however, has the potential to improve cure rates and long-term overall survival.

“There’s a missed opportunity in today’s cancer care treatment,” says Dr. Lawrence. “There is very promising laboratory data out there, but the clinical development of these new drugs with radiation has been limited. Here, we have put together a road map to help overcome obstacles and speed the development of new pipeline drugs with radiation.”

Adding radiation therapy to existing chemotherapy agents to radiation therapy has improved survival, and the authors of the commentary, which includes Adam P. Dicker, Chair of the Department of Radiation Oncology at Jefferson, believe new targeted therapies can follow in the same path.

“We know we want to repeat that success with new biological drugs,” says Dr. Lawrence. “In order to do that, we need direction, which is sorely lacking. These guidelines explicitly explain how much evidence is needed to go forward from the lab into the clinic, and furthermore how to design the clinical trials in humans.”

The guidelines discuss key questions when investigating specific targeted agents and tumor types, designing new clinical trials, such as the ‘time-to-event continual reassessment method design’ for phase I trials, and randomized phase II “screening” trials, and the use of surrogate endpoints, such as pathological response.

It also discusses the role and purpose of preclinical studies in radiation oncology drug development and how to identify new, radiation response agents.

There are challenges to drug development with radiation, the authors explain. A major problem is the limited interest from the pharmaceutical industry in developing drugs with radiation, which is of special importance since the pharmaceutical industry fund a large amount of clinical cancer research. Furthermore, significant individual skills and institutional commitments are also required to ensure a successful program. The situation has been extenuated by the decrease in radiation biologists in recent years.

It is hoped that by providing a clear pathway, the guidelines will help the field overcome these barriers and create a focus and interest in drug development.
Some new approaches, the researchers say, include combining radiosensitizers with hypofractionated (high daily dose) radiation schedules and integrating immunomodulators with radiation therapy.

“We feel passionate that a a good way to push clinical care forward for cancer patients is by combining these two types of treatment: advanced radiation treatment together with the new generation of anticancer drugs,” says Dr. Lawrence. “We know where the future lies, and guidelines provide the path to bring us there.”

The full guidelines in the JNCI can be found here: http://jnci.oxfordjournals.org/content/early/2012/12/07/jnci.djs472.full



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.



A New Battlefront: Symposium at Jefferson’s Kimmel Cancer Center to Tackle Geriatric Oncology

Approaches to treating elderly cancer patients are evolving as more of the population ages and the need for specialized care becomes more evident.

To address these issues and others, national thought leaders in geriatric oncology will gather at a unique symposium at the Kimmel Cancer Center at Jefferson (KCC) in Philadelphia on Friday, March 9, 2012, where they will present an overview of the latest advances in the understanding and treatment of cancer in older adults in an effort to impact patient care.

Outside of the annual American Society of Clinical Oncology (ASCO) meeting, this is the first regional symposium of its kind that would be addressing the needs of senior adults.

The all-day symposium, “The New Battlefront: Geriatric Oncology,” part of an annual series at the KCC, will be held at the Bluemle Life Sciences Building on Jefferson’s campus. Co-hosted by the KCC Cancer Network and Rothman Institute at Jefferson, it will provide comprehensive updates on basic science research and the latest updates on chemotherapy, surgery, and radiation in the care of senior adult patients.

Personalized Treatment

Geriatric patients make up 60 percent of new cancer diagnoses and 70 percent of all cancer deaths. And those numbers are expected to increase as the geriatric population doubles in size by 2030.

These patients also often must battle cancer in the context of multiple chronic conditions, decreased organ reserve, and all too often cognitive impairments.  What’s more, there’s currently a shortage of geriatric oncology physicians to treat them.

“Recognizing and addressing the particular co-morbidities, functional, and cognitive concerns, and identifying collaborations with other disciplines will help us better serve the population,” said Andrew E. Chapman, DO, FACP, who directs the KCC’s Senior Adult Oncology Center along with Christine A. Arenson, M.D, of the Department of Family and Community Medicine at Thomas Jefferson University Hospital.

A joint effort between the Departments of Medical Oncology and Family and Community Medicine, Division of Geriatrics, KCC’s Senior Adult Oncology Center provides a comprehensive assessment, usually during a single visit, to identify problems related to aging and cancer.   The program has medical oncologists, a geriatrician, a nurse navigator, a pharmacist specially trained in oncology and geriatrics, a registered dietician, and a social worker.

Facing this New Battlefront Together

During the symposium, the full spectrum of geriatric oncology care and research will be discussed by clinicians and researchers from top institutions, including Jan van Duersen, Ph.D., of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic in Rochester, Minn., and Arati V. Rao, M.D. of Duke University’s Division of Geriatrics.

The conference will provide an overview of the biology of cancer in aging, describe the state-of-the-art model of Shared Care for older cancer patients, and review critical issues of chemotherapy toxicity and optimal chemotherapy management.

Specific concerns for radiation therapy and surgery in the geriatric oncology patient will be also addressed. Finally, the latest advances in the management of hematologic and solid malignancies in the elderly will be shared.

Several of the talks also directly address patient and medication safety and improving communication among physicians, patients and other health care personnel.

Discussions will also focus on safe and effective use of chemotherapy and pharmacology safety issues, with talks by Arti Hurria M.D., director of the Cancer and Aging Research Program at the City of Hope National Medical Center and Stuart M. Lichtman, M.D., Professor of Medicine, 65+ Geriatric Clinical Program at Memorial Sloan-Kettering Cancer Center.

John A. Abraham, M.D., Chairman of the Division of Orthopedic Oncology at the Rothman Institute at Jefferson, will also speak about managing orthopedic issues in geriatric oncology patients.

“This symposium is an opportunity for players in the geriatric medicine and oncology, surgery and radiation fields to come together and highlight the innovative discoveries and best practices we believe will be important for the next generation of treatment and therapeutics in patients,” said Richard Pestell, M.D., Ph.D., director of the KCC and Professor and Chair of the Department of Cancer Biology at Jefferson Medical College of Thomas Jefferson University.

Other speakers include Rani P. Anné, M.D., Associate Professor of Radiation Oncology, Clinical Program Director at Jefferson Medical College at Thomas Jefferson University; William Dale, M.D., Ph.D., Chief of Section of Geriatrics and Palliative Medicine at University of Chicago Medical Center; Elizabeth M. Gore, M.D., Associate Director, Radiation Oncology at Medical College of Wisconsin; Supriya Gupta Mohile, M.D., M.S., Associate Professor of Medicine, Hematology/Oncology, University of Rochester Medical Center; Richard C. Wender; Alumni Professor and Chair, Family and Community Medicine, Jefferson Medical College; and Michael Zenilman, M.D., Professor of Surgery, Vice Chair and Director, National Capital Region, Johns Hopkins Medicine.

To register for the event, please visit http://www.kimmelcancercenter.org/symposium/



Jefferson’s Kimmel Cancer Center Establishes Center to Eliminate Cancer Disparities

Dr. Edith Mitchell, director of newly-established Center to Eliminate Cancer Disparities, and Robin Evans, a patient.

PHILADELPHIA—In an effort to reduce and eventually eliminate cancer disparities among adults in the Philadelphia region, the Kimmel Cancer Center at Jefferson has established the Center to Eliminate Cancer Disparities.

Edith P. Mitchell, M.D., FACP, a medical oncologist at Thomas Jefferson University Hospital and Clinical Professor of Medicine and Medical Oncology in the Department of Medical Oncology at Jefferson Medical College of Thomas Jefferson University, will serve as its Director.

Despite the decline in cancer incidence and mortality rates in the United States, disparities in cancer burdens continue to exist among certain population groups and the gap continues to widen.  The Philadelphia region in particular has a disproportionately high number of residents suffering from cancers, many of which are preventable and treatable.

Such disparities include differences in incidence, prevalence, mortality and burden of cancer and related adverse health conditions. Disparate population groups may be characterized by gender, age, race and ethnicity, income, social class, disability, geographic location or sexual orientation.

“I have dedicated my career to the treatment of cancer patients and have had the opportunity to experience, as a physician and as a researcher, the significance cancer disparities can have on the outcome of a patient’s treatment,” said Dr. Mitchell. “The first step in the elimination of these disparities is to raise awareness through public and professional education about what resources are available to groups in their fight against cancer.”

The Center aims to accomplish its mission through the facilitation of disparities-focused research, researcher and clinician education, training and teaching, and increased patient access to quality supportive services, such as palliative care, cancer screening and prevention, and survivorship programs.

Dr. Mitchell and her fellow clinicians and researchers at Jefferson are dedicated to the ongoing study of cancer and other health disparities among patients of diverse ethnic and socioeconomic backgrounds. They have created strategic priorities for eliminating such disparities through innovative research, education and training, advocacy, community outreach, and quality medical care.

The need for research into cancer, and other health care disparities, has become increasingly evident in recent years as doctors and scientists learn more about how slight variations in genetic makeup can have drastic effects on the way cancer invades an individual’s body.  Knowing that these disparities exist can improve how screening processes are established and help doctors understand which treatments will and will not be effective.

Dr. Mitchell has spent her medical career helping individuals in medically underserved areas to realize that simple changes in lifestyle can have a dramatic impact on cancer care. Through her work, Dr. Mitchell has demonstrated the importance of community service and outreach especially to those individuals who may not have the means to seek out more conventional medical advice.

She holds board certifications in both Internal Medicine and Medical Oncology and is a Fellow in the American College of Physicians. She has also served as the Program Leader in gastrointestinal oncology for more than 15 years and has a focused research effort in aggressive breast cancers.

“We want all researchers and clinicians to be aware of the disparities that exist in cancer diagnoses among diverse ethnic groups so that they can incorporate these important factors into their research efforts and clinical practice,” said Dr. Mitchell.

“The Center will also provide patients with contact information for cancer advocacy and support groups both locally and nationally that serve the needs of their demographic background. We are proud to host and sponsor several annual events where patients can come together to share their stories and plan for a future free of cancer disparities,” she said.



Kimmel Cancer Center Hosts Interurban Clinical Club

On Friday, October 28, the Kimmel Cancer Center at Jefferson hosted the 204th meeting of the Interurban Clinical Club at Jefferson Medical College of Thomas Jefferson University.

Drs. Michael Lisanti, Richard Pestell, Carrie Sims and Michael Root at the 204th meeting of the Interurban Clinical Club at the Union League of Philadelphia.

The Interurban Clinical Club is a prestigious club founded by Sir William Osler in 1905 for the purpose of exchanging ideas and fellowship among medical teachers in some of the leading Eastern medical schools.

Several prominent physicians and researchers from institutions in the Philadelphia region presented the latest in their cancer research and other disciplines.

Many KCC researchers spoke at the all-day event, including opening remarks by Richard Pestell, M.D., Ph.D., director of the KCC, Steven McMahon, Ph.D., Erik Knudsen, Ph.D., Michael Lisanti, M.D., Ph.D, and Michael Root, M.D., Ph.D.

That night, a black tie cocktail reception and dinner were held at the Union League of Philadelphia, with a special performance by “The Arrhythmia, a capella group made up of a dozen students in such fields as medicine, pharmacy, and doctoral studies at Jefferson Medical College.

This year, the Sir William Osler Young Investigator Award was given to Jordan Orange, M.D., Ph.D., an Associate Professor of Pediatrics at the University of Pennsylvania School of Medicine.

Dr. Mark Zeidel, the ICC President, also presented Dr. Alfred Knudson, of Fox Chase Cancer Center, with a gift as a “thank you” and in recognition of his extensive accomplishments in cancer research.

There are five to nine active members of the ICC  from each city, including Baltimore, Boston, New Haven, New York and Philadelphia. Existing members of the ICC from the Kimmel Cancer Center at Jefferson include Richard Pestell, M.D., Ph.D., Barry J. Goldstein, M.D., Scott Waldman, M.D., Ph.D, and Michael Lisanti, M.D., Ph.D.

See below for photographs from the event:

The Arrhythmias performing at the Union League of Philadelphia before the dinner and lecture

Dr. Wafik El-Deiry (ICC Secretary/Treasurer), Dr. Michael Levine, Dr. Jordan Orange, Dr. Steven Douglas, Dr. Richard Pestell. Dr. Orange is being presented with the 2011 Sir William Osler Young Investigator Award

Dr. Rochelle Hirschhorn and Dr. Kurt Hirschhorn at the Union League of Philadelphia

Dr. Pestell, Dr. Mark Zeidel (ICC President), and special guest speaker Dr. Alfred Knudson. Dr. Zeidel was presenting Dr. Knudson with a gift as a thank you and in recognition of his extensive accomplishments in cancer research




Half-Match Bone Marrow Transplant Procedure Yields Promising Outcomes for Cancer Patients

Dolores Grosso, DNP, Co-Principal Investigator and lead author of the article

Half-matched bone marrow or stem cell transplants for blood cancer patients have typically been associated with disappointing clinical outcomes. However, a clinical trial conducted at the Kimmel Cancer Center at Jefferson testing its unique, two-step half-match procedure has produced some promising results: the probability of overall survival was 45 percent in all patients after three years and 75 percent in patients who were in remission at the time of the transplant.

Reporting in the journal Blood in a published-ahead-of-print article dated August 25, Neal Flomenberg, M.D., Chair of the Department of Medical Oncology at Thomas Jefferson University Hospital, Dolores Grosso, DNP, Co-Principal Investigator and lead author of the article, and colleagues discuss the results of 27 patients treated on this phase I/II trial who had diagnoses that included leukemia, lymphoma and myelodysplasia.

The patients received their transplant in two steps. First, after receiving radiation therapy to further treat their disease, the patients were given a specified dose of T cells (a type of immune cell that fights infection) from their half-matched family donor. The donors were parents, siblings or children of the patient. The patients next received the drug cyclophosphamide to help the newly infused donor T cells to be more tolerant to the patient’s body. The second step of the transplant occurred when the patients received a dose of their donors’ stem cells to help their blood counts return to normal and further strengthen their new immune system.

Dr. Flomenberg and his team found that after a follow-up of 28-56 months, overall survival for the patients after one year was 54 percent and 48 percent at three years. Patients in remission at the time of the transplant fared better with an overall survival of 75 percent. Seventeen of the 27 patients—with a median age of 52 years old—were alive six months after their transplant, which was the official end point of the trial.

While more recent studies have shown promising increases in overall survival for patients undergoing half-match transplants, historically, clinical outcomes for these types of transplants have been poor, which has limited the use of this type of procedure.

The results of the Jefferson trial represent a very promising improvement in this area.

Bone marrow or stem cell transplants are performed in order to replace a patient’s diseased immune system with that of a healthy donor. Traditionally, the use of a genetically fully matched donor has been associated with the best results in bone marrow transplant, but many patients lack a fully-matched related or unrelated donor. Almost every patient will have a half-matched donor (also known as a haploidentical donor) in their family, however.

The successful use of haploidentical donors would greatly expand the number of donors available to a patient, extending this therapy to almost everyone who would benefit from receiving a transplant.  This would include minority patients, including patients with sickle cell anemia, who do not have as many fully-matched unrelated donors available to them.

“Our half-match bone marrow transplant results open up many doors for different types of patients who can’t find an exact match,” said Dr. Flomenberg. “It also justifies recommending that patients at high risk for relapse should consider having a half-match transplant early in the treatment of their disease.”

“Jefferson’s two-step procedure provides promising results that could serve as the basis for further exploration and optimization of the technique,” he added.

Jefferson medical oncologists’ approach is unique in that the dosage, timing and treatment of donor T cells was carefully controlled and optimized. No other transplant regimen controls the exact amount of donor T cells given.  The investigators believe that dosing the T cells in this way helped avoid many of the life-threatening side effects of this type of transplant.

“We believe the dosage and timing of T cells from the donor into the patient is essential for success. In fact, it’s equally as important as prescribing specific doses of radiation and chemotherapy to initially treat the disease,” said Dr. Grosso. “The goal of this two-step regimen was to develop a better technique for half-matched patients with relapsed blood cancers initially, but we also showed that it can be appropriate for high risk patients earlier in their disease who lacked fully matched donor options.”



Edith Mitchell Talks to WHYY Radio about African American Doctors in Medicine

Edith Mitchell, M.D., associate director of Diversity Services for the Kimmel Cancer Center

Jefferson medical oncologist Edith Mitchell, M.D., FACP, works on diversity efforts as associate director of Diversity Services for the Kimmel Cancer Center at Jefferson.

In a recent WHYY Radio interview, Dr. Mitchell shares some of her experiences with African American patients and gives her perspective on race and medicine today. She believes that listening to patients is crucial and says that patients are more likely to follow doctor’s orders and stick with a care plan when they’re comfortable with their physician.

See the full “In the Gap: African American Doctors” article.



Director of KCC, Dr. Richard Pestell, in July issue of Runner’s World

July 2011 Issue of Runner's World

Dr. Richard Pestell, director of the Kimmel Cancer Center at Jefferson and former national-class distance runner, was featured in the July issue of Runner’s World.

Dr. Pestell spoke with the magazine for the cover story titled “Outrunning Cancer”–which focused on the running community’s ability to raise million of dollars each year to fight cancer.

“When the story of cancer meets a runner’s story, the combination can be quite powerful,” said Dr. Pestell.

Read the full feature story here: “Outrunning Cancer: Team Effort” by John Brant.

Dr. John Wagner, of the medical oncology department and also a runner, was mentioned in the article, as well.



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.



KCC American Cancer Society Research Symposium

The 3rd Annual Kimmel Cancer Center American Cancer Society Research Symposium will be held today at 2 p.m. in 101 BLSB.

KCC Director Richard Pestell, M.D, Ph.D, will present the keynote address and 2010 American Cancer Society-Institutional Research Grant Award recipients.

Amy Leader, DrPH, MPH, and Hushan Yang, Ph.D, will discuss their research. A reception will follow.

This event celebrates the ACS Institutional Research Grant at Thomas Jefferson University, which provides support for junior faculty members performing cancer research.



KCC Team to Walk for Bladder Cancer

It is estimated that more than 70,000 new cases of bladder cancer were diagnosed in 2010, making it the 5th most commonly diagnosed cancer in the U.S.

Please join Dr. Jean Hoffman-Censits, of the Department of Medical Oncology, Solid Tumor Division, and the Kimmel Cancer Center at Jefferson Team in raising awareness of the disease by walking the Radnor Trail, in Wayne, Pa., on Saturday May 7 at 9:00 a.m.

The walk is taking place on the Radnor Trail off Route 30 in Wayne, Pa. Meet at 9 a.m. behind the parking lot of the VIST Financial Bank, 600 West Lancaster Avenue (at the intersection of Sugartown Road and Old Eagle Road) near the sign for the entrance to the trail.

For more information or to join our Jefferson Team, please contact Teresa Bryant at 215-503-5455 or visit  http://www.firstgiving.com/fundraiser/thomasjefferson/walkforbladdercancer to sign up for the walk or make a donation.

For more information regarding the Bladder Cancer network visit, WWW.bcan.ORG

Learn more  by watching BCAN’s Bladder Cancer Awareness Video.



Dr. Edith Mitchell attends National Summit on Health Disparities, Hon. Nancy Pelosi and Sen. Harry Reid honored

Edith Mitchell, M.D., clinical professor of Medicine and Medical Oncology at Jefferson Medical College of Thomas Jefferson University, attended the 8th Annual National Summit on Health Disparities Meeting & Awards Dinner in Washington, D.C., on April 11 and 12.

Dr. Edith Mitchell and Hon. Nancy Pelosi at the National Summit on Health Disparities. Photo Courtesy of Don Baker/NMQF

The summit, organized by The National Minority Quality Forum and the Congressional Black Caucus Foundation, in collaboration with the CBC Health Braintrust, brings together members of congress, senior healthcare executives, clinicians, payers, and allied members of the healthcare industry to discuss solutions to disease disparities.

Four consummate Americans were honored for their deep commitment and contributions in the area of health care, including Senator Harry Reid and Former Speaker Nancy Pelosi, who both received the Lifetime Achievement Award.

Dr. Mitchell moderated the “Cancer Biomarkers, Clinical Trials, & New Treatment Options” session, which included Roy Herbst, M.D., Ph.D., Chief of Medical Oncology, Yale Cancer Center and Joseph Sparano, M.D., Associate Chairman, Department of Oncology, Montefiore Medical Center.

Francis Collins, M.D., PhD, Director of the National Institutes of Health, also gave a special address.

The National Minority Quality Forum is a non-profit healthcare research and educational organization dedicated to the elimination of health disparities.



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.



Dr. Leonard Gomella co-chairs ASCO GU in Orlando

Dr. Leonard G. Gomella, chair of the Department of Urology and director of Clinical Affairs at the Kimmel Cancer Center at Jefferson, co-chaired the American Society of Clinical Oncology (ASCO) 2011 Genitourinary (GU) Cancers Symposium meeting in Orlando on Feb. 17 though Feb. 19.

The “2011 Genitourinary Cancers Symposium: An Evidence-based Multidisciplinary Approach,” was a three-day Symposium that offered educational sessions and oral and poster abstract presentations focused on genitourinary cancers of the prostate, penis, urethra, testis, bladder and kidney.

Over 1,800 physicians, researchers, care givers and survivors attended the meeting sponsored by ASCO, the American Society for Radiation Oncology (ASTRO) and the Society of Urologic Oncology (SUO).

Orlando, FL – 2011 Genitourinary Cancers Symposium – Dr. Leonard G Gomella, co-chair the 2011 Genitourinary Cancers Symposium (GU) meeting at the Marriott World Center on Thursday, February 17, 2011. Photo by © Todd Buchanan

Dr. Gomella’s talk during the opening remarks was titled “Decision Making Based on Predictors of Clinical Progression.”

To learn more about this symposium, visit http://gucasymposium.org/Home.aspx