To ensure that patients have access to the widest variety of treatment options, Jefferson physicians are actively involved in cancer research on many fronts; at any given time, about 100 oncology clinical trials are being conducted here. The Clinical Research Organization (CRO) is the arm of the Sidney Kimmel Cancer Center (SKCC) that manages and supports this important work. It ensures that trials comply with all federal, state and institutional regulations.
Department Specific Clinical Research Summary
Medical Oncology faculty members are significantly involved in clinical and basic research activities. While faculty have initiated Phase II and to a lesser extent Phase I trials in their respective areas of oncologic expertise, Dr. Russell Schilder leads the Early Drug Development Office (EDDO) at Jefferson. In addition, the Department participates in trials sponsored by the National Clinical Trials Network (NCTN) such as ECOG-ACRIN Cancer Research Group and NRG Oncology, as well as in trials performed in collaboration with pharmaceutical companies. The Department seeks to maintain a balance between trials testing our own internally developed concepts and trials originating from these external sources. External reviews, such as the Sidney Kimmel Cancer Center site visits, require demonstration both of internal creativity and initiative as well as good citizenship in the larger research community. The former is represented by investigator-initiated trials and the latter by participation in cooperative group studies. Since the success rates for treatment of many cancers can still be improved considerably, it should be our goal to ensure that the majority of our patients are treated on well-designed trials that will help to advance the state-of-the-art.
Eastern Cooperative Oncology Group (ECOG): With efforts from a group of individuals, led by Dr. Edith Mitchell, special assistance from Charmaine Green and Josha Schoppe, Jefferson became a full member of ECOG. Joint efforts between Jefferson, ECOG, and the National Medical Association has resulted in nationally acclaimed programs receiving tremendous publicity on Cancer Disparities. Additionally Jefferson has contributed to other cooperative group efforts through the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Radiation Therapy Oncology Group (RTOG).
Much of the research activity in the Hematologic Malignancies program focuses on efforts to extend allogeneic transplantation to patients who lack well-matched family donors and to reduce the overall morbidity and mortality of this treatment. An area of our particular interest is the development of selective immunosuppressive approaches to prevent GVHD without compromising other immune responses. The development of a two-step transplant approach has dramatically reduced transplant mortality resulting in transplantation options for many patients for whom an acceptable matched related donor could not be previously found. Dr. Margaret Kasner has also launched several investigator initiated trials attempting to reverse chemotherapy resistance in aggressive hematologic malignancies and received a Career Development Award from the American Society for Clinical Oncology for this work.
The Melanoma Program, led by Dr. Michael Mastrangelo, is a consortium of clinicians, clinical scientists and basic researchers engaged in translational research. Their focus is on improving the prognosis of melanoma patients through a better understanding of the biology of the disease and the development of innovative new therapies. Their major effort is devoted to the immunobiology and immunotherapy of melanoma. Dr. Takami Sato is pursuing new regional and systemic treatments for metastatic uveal melanoma including immunoembolization of hepatic metastases with GM-CSF, Yttrium-90 radiosphere, and drug-eluting bead treatments for hepatic metastases. These novel contributions have been recognized through awards of a number of grants and patents. Furthermore, Dr. Sato developed a method to selectively expand natural killer cells from peripheral blood. Translation of these novel approaches to cancer patients is underway in collaboration with Dr. Selvan who has been newly recruited to help build a cellular immunotherapeutics program.
In addition, members of the Department support the institutional and SKCC research infrastructure by serving on the Protocol Review Committee (PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee (DSMC). Dr. William Kevin Kelly serves as Associate Director of Clinical Research in both the Department and Cancer Center. Dr. Flomenberg serves as Chair of one of NIH’s DSMC for its transplant trials network while Dr. Carabasi is a member of their other DSMB.
The Division of Population Science also had a very productive year with regard to their research efforts and their extramural research support. Dr. Ronald E. Myers’ current efforts include a variety of initiatives to improve colorectal cancer screening in general patient populations and among African Americans served by primary care practices in particular. He is also engaged in efforts to promote informed decision making by patients about genetic and environmental risk assessment related to colorectal cancer, in patients offered adjuvant therapy following surgery for pancreatic cancer, and concerning clinical trials participation in general.
Dr. Hushan Yang, one of the department’s more recent recruits, has been studying the effects of a comprehensive panel of genetic variations in the inflammation and immune-response pathway genes on the risk of developing Hepatocellular Carcinoma in patients with chronic Hepatitis B virus infection. He has received a prestigious V Scholar Award, from the V Foundation for Cancer Research, to identify genetic biomarkers in microRNA-related genes that may predispose to HBV-related Hepatocellular Carcinoma. Dr. Yang has also received funding for The American Cancer Society for a pilot study to examine genetic variations in inflammation pathways as predictive markers for risk of hepatocellular carcinoma as well as funding from NCI.
Dr. Amy Leader, another new member of the Population Science Division has a particular interest in eliminating health disparities. Within that context, her current research focuses on assisting patients in making an informed decision about cancer prevention behaviors. In addition, Dr. Leader is principal investigator of a study funded by the Pennsylvania State Department of Health aimed at increasing hepatitis C (HCV) testing in a primary care. She is also the principal investigator on two studies related to human papilloma virus (HPV) prevention. One, funded by the American Cancer Society, seeks to uncover the factors that might influence a young African American male to be vaccinated against HPV. The other aims to reduce cervical cancer disparities among African Americans by assisting women in making an informed decision about HPV prevention behaviors.
Dr. Martinez- Outschoorn has continued his ground breaking studies of a metabolic basis for how the stem cell niche and tumor microenvironment promotes the growth of normal and cancerous stem cells. In FY2011, these initial paradigm-shifting observations were extended, suggesting that cancer cells metabolically behave as a “parasitic organism” extracting nutrients from the tumor microenvironment, in a form of metabolic-coupling they have termed “Parasitic Cancer Metabolism”. This may also be the basis of drug resistance, and will provide a new mechanism for achieving personalized cancer medicine based on “Metabolo-Genomics”. The Reverse Warburg Effect in human breast cancers was first proposed by Jefferson investigators in December 2009 based on studies indicating that aerobic glycolysis (a.k.a, the Warburg Effect) actually takes place in tumor associated fibroblasts, and NOT in cancer cells. This has important consequences for tumor growth and progression. Aerobic glycolysis in cancer associated fibroblasts results in the production of high-energy metabolites (such as lactate and pyruvate), which can then be transferred to adjacent cancer cells, which are undergoing oxidative mitochondrial metabolism. This would then result in increased ATP production in cancer cells, driving tumor growth and metastasis. Essentially, in this new paradigm, stromal fibroblasts are literally “feeding” cancer cells via the transfer of high-energy metabolites, via a monocarboxylate transporter (MCT). This concept has been termed “The Reverse Warburg Effect”, to distinguish it from the conventional Warburg Effect, which was originally thought to take place in epithelial cancer cells.
The Reverse Warburg Effect is a characteristic of a high risk tumor micro-environment. Importantly, researchers have shown, using a co-culture system, that a loss of stromal Cav-1 can be effectively prevented by treatment with anti-oxidants (such as N-acetyl cysteine (NAC); quercetin; and metformin), or with autophagy inhibitors (chloroquine). This is very promising as these drugs/supplements are now currently available off the shelf from health food stores, or are already FDA-approved drugs. All of these drugs have previously shown anti-tumor activity in pre-clinical models, however their mechanism of action was not attributed to “The Reverse Warburg Effect”.