Department of Medical Oncology
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 Management Office (CRMO) is the arm of the Kimmel Cancer Center (KCC) that manages and supports this important work. The CRMO 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. Nancy Lewis has been recruited to head a Phase I, Cancer Drug Development program here at Jefferson. In addition, the Department participates in trials sponsored by national cooperative groups such as the Eastern Cooperative Oncology Group (ECOG), the Gynecologic Oncologic Group (GOG), Radiation Therapy Oncology Group (RTOG), National Surgical Adjuvant Breast and Bowel Project (NSABBP) 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 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.
Within GI Oncology, the Department has developed major programs for the identification of individuals with hereditary predisposition toward developing colon cancer and for their counseling and treatment. In collaboration with Dr. Scott Waldman, important efforts have been made to use molecular approaches to detect early spread of colon cancer to draining lymph nodes, below the resolution of conventional pathologic techniques. Furthermore, Dr. Waldman and Dr. Sato started developing a novel cancer vaccine approach for colon cancer patients using mucosal antigen, guanylyl cyclase 2C (GCC) and have received Pennsylvania State Tobacco funding for this research. Prevention studies using aspirin and novel treatment approaches are also ongoing. Dr. Mitchell together with Dr. Rui, have secured a large award from the Komen Foundation for treatment of triple negative breast cancer, a more aggressive form of the disease, the frequency of which varies in different racial and ethnic populations.
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 recent 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. This has received federal support in the form a stimulus package grant to launch a transplant effort for sickle cell anemia. Dr. Margaret Kasner has also launched two-investigator initiated trials attempting to reverse chemotherapy resistance in several aggressive hematologic malignancies and has 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. A vaccine approach, developed originally by Drs. Mastrangelo and Berd, continues to be investigated through industry-based efforts. Dr. 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. Collaboration with basic researchers at Kimmel Cancer Center has been focused on the development of humanized mice as a model for human cancer immunotherapy. Reversal of cancer-induced immune suppression by IL-10 antagonist has also been a focus of international and intramural collaborative research work.
In addition, members of the Department support the institutional and KCC research infrastructure by serving on the CCRRC, IRB, DSMB, and as study medical monitors. Dr. Carabasi serves as Director of Clinical Research in both the Department and Cancer Center. Dr. Flomenberg serves as Chair of one of NIH’s DSMB 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. 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. This year, he 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. The other aims to reduce cervical cancer disparities among African Americans by assisting women in making an informed decision about HPV prevention behaviors.
Drs. Martinez- Outschoorn and Lisanti have continued their 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 Dr. Lisanti and colleagues 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).
Dr. Lisanti and colleagues termed this new idea “The Reverse Warburg Effect”, to distinguish it from the conventional Warburg Effect, which was originally thought to take place in epithelial cancer cells. These new findings reverse over 85 years of dogma surrounding cancer cell metabolism, and explain the lethality of a caveolin-1 (Cav-1) deficient tumor microenvironment. More specifically, a loss of Cav-1 in stromal fibroblasts drives onset of “The Reverse Warburg Effect”, due to the autophagic destruction of mitochondria (mitophagy) in these stromal cells. Cancer cells induce “The Reverse Warburg Effect” in adjacent stromal fibroblasts by using oxidative stress, to promote aerobic glycolysis, under conditions of normoxia.
Importantly, a loss of stromal Cav-1 is a powerful biomarker for “The Reverse Warburg Effect”, and predicts early tumor recurrence, lymph node metastasis, and drug-resistance in virtually all of the major subtypes of human breast cancer. For example, in triple negative (TN) breast cancer, patients with high stromal Cav-1 have a survival rate of >75% at 12 years post-diagnosis. In striking contrast, TN breast cancer patients with absent stromal Cav-1 have a survival rate of <10% at 5 years post-diagnosis. Similar results have also been obtained with DCIS and prostate cancer patients, suggesting that stromal Cav-1 could serve as a diagnostic marker for identifying the high-risk population in many different types of human cancer.
Thus, “The Reverse Warburg Effect” is a characteristic of a “lethal” 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”.
Similarly, a loss of stromal Cav-1 was prevented by treatments with HIF1 and NFkB inhibitors. HIF1 and NFkB are the upstream transcription factors that control the onset of autophagy/mitophagy in cancer associated fibroblasts. Genetic studies have now shown that activation of HIF1 or NFkB is sufficient to promote the cancer associated fibroblast phenotype, driving increased tumor growth and metastasis, without any increase in tumor angiogenesis.
Finally, Dr. Lisanti and colleagues propose that the conventional Warburg effect may still occur, but would be associated with a good clinical outcome, as the tumor cells would produce less energy due to defective mitochondrial metabolism.