The Wistar/Penn Spore in Skin Cancer
PI, M. Herlyn
Co-PI, L. Schuchter, D.E. Elder
P50CA CA93372 2001-present
The intent of the Wistar/Penn SPORE in Skin Cancer is to decrease the morbidity and mortality of skin cancers through improved understanding of the pathogenesis of these diseases using novel, validated molecular biomarkers of prognosis and the development of targeted therapies. This SPORE investigates three major skin cancers, melanoma, cutaneous T cell lymphoma (CTCL) and squamous cell carcinoma (SCC) with the projects focusing on the leading cause of skin cancer deaths, melanoma. The overall goals of this SPORE are to address two fundamental areas of translational research: 1) Prognosis. We have developed novel classification models in primary melanoma for prognosis and prediction of metastasis. We will develop biomarkers in Project 2 that distinguish between patients at low or high risk for metastasis and test the hypothesis that the selected biomarkers, singly or in panels, have significant association with time to super-regional metastasis even when controlling for current prognostic factors. In Project 3 we will define sub-populations of melanoma cells that are most critical for self-renewal (tumor maintenance and progression) and will investigate how their presence or absence correlates with determinants for risk for recurrence. Specific sub-populations are then followed for prediction of therapy outcome hypothesizing that melanoma cells require the long-term elimination of defined sub-populations. 2) Therapy. We will investigate novel therapies for advanced melanoma in Projects 1 and 4. Project 1 on targeted therapies builds on a record of investigations with novel inhibitors to explore how BRAF-targeted therapeutics given to patients with BRAF-mutant melanomas produce differential response based on PI3K/AKT and mTOR/S6K signaling . We will then develop drug combinations for the selective inhibition of co-activated pathways expecting that a sub-group of patients will respond to combinations of BRAF and PI3K pathway inhibitors. Project 4 will test the hypothesis that agonistic antibodies to CD40 can specifically activate antigen-presenting cells. We will assess the anti-tumor immune response in clinical trials in which anti-CD40 antibodies are delivered alone or in combination with chemotherapy or CTLA4-blocking monoclonal antibodies. We will then explore whether RNA-loaded, CD40-activated B-cells can induce a melanoma-specific immune response as a first step towards developing a novel form of adoptive immunotherapy.
In addition to an administrative core, the Wistar/Penn SPORE projects are supported by a Biospecimen and Information Core and a Biometrics Core. The Career Development Program and the Developmental Research Program will continue to ensure the future growth of the SPORE. The Developmental Research Projects extend to CTCL and SCC in a synergistic integration of research efforts towards goals shared by the melanoma-focused projects. The SPORE receives significant support through the commitments of both institutions.
Projects and Cores of the Wistar/Penn Skin SPORE (2009-2014)*
Four Translational Projects
Project 1: Individualized therapy with signal transduction inhibitors in melanoma
Lead Investigators: Katherine Nathanson, M.D. and Lynn Schuchter, M.D.
Dr. Schuchter represents the clinician and Dr. Nathanson the translational research investigator.
Project 2: Prognostic/predictive models in primary melanoma
Lead Investigators: Phyllis Gimotty, Ph.D. and Xiaowei Xu, M.D., Ph.D.
Dr. Gimotty is the translational investigator and Dr. Xu the clinical and experimental pathologist.
Project 3: Melanoma subpopulations with stem cell-like properties and their significance for melanoma diagnosis, progression and therapy outcome
Lead Investigators: Meenhard Herlyn, D.V.M., D.Sc and David Elder, M.B., Ch.B., F.R.P.A.
Dr. Herlyn represents the basic research investigator and Dr. Elder the clinical pathologist.
Project 4: T cell immunity in Melanoma
Co-Lead Investigators: Robert Vonderheide, M.D., Ph.D., Daniel Powell, Ph.D., Carl June, M.D. Dr. Vonderheide represents the clinical and translational investigator, and Drs. Powell and June serve as the basic translational investigators.
Three Cores
Administrative Core A
Core Co-Leaders: Meenhard Herlyn, D.V.M., D.Sc., Lynn Schuchter, M.D., and David Elder, M.B, Ch.B, F.R.P.A
Biospecimen and Information Core B
Core Co-Leaders: David Elder, M.B., Ch.B., F.R.P.A. and Peter Kanetsky, Ph.D., M.P.H.
Biometrics Core C
Core Co-Leaders: Phyllis Gimotty, Ph.D. and Wei-Ting Hwang, Ph.D.
Two Programs
Developmental Research Program
Director: Meenhard Herlyn, D.V.M., D.Sc
Co-Director: Lynn Schuchter, M.D.
Career Development Program
Director: Lynn Schuchter, M.D.
Co-Director: Meenhard Herlyn, D.V.M., D.Sc
*All Project and Core Leaders except Dr. Herlyn are at the University of Pennsylvania
The overall organization of our SPORE is described in Figure 1.
Project 3: Melanoma subpopulations with stem cell-like properties and their significance for melanoma diagnosis, progression and therapy outcome
Lead Investigators: Meenhard Herlyn, D.V.M., D.Sc. and David Elder, M.B., Ch.B.,
Like most human malignancies, melanoma is characterized by heterogeneous phenotypes and its metastatic state is notorious for resistance to conventional chemo- and radiation therapies. Despite their easy access in the skin, primary melanomas have been difficult to evaluate for accurate prognosis. Metastases are equally challenging regarding their prediction to therapy outcome. Our overall hypothesis is that melanomas contain distinct sub-populations, which are responsible for driving progression and therapy resistance. In preliminary studies we have defined two sub-populations of melanoma cells with tumor-initiating properties including self-renewal, differentiation and tumorigenicity: CD20+, and label-retaining/JARID1B+ cells. In Aim 1, we will determine the biological properties for each sub-population by isolating cells from patients’ lesions and determining their ability to self-renew, differentiate, induce tumors in immunodeficient NOD/SCID/gc-/- mice, and resist therapies. We will compare the parameters for sub-populations with ‘classical’ diagnostic criteria for tumor stages. We expect individual populations to be associated with specific properties that are important for tumor growth, survival, invasion, and therapy resistance. We will then develop strategies for therapeutic elimination of sub-populations, using an antibody against CD20 as proof-of-principle for both preclinical and clinical studies. In Aim 2, we will determine how the presence or absence of sub-populations or the their relative ratios correlate with determinants for prognosis using our unique archive of pigmented lesions with long-term follow-up. We will then compare the sub-populations with poor treatment outcome using specimens from patients treated by isolated limb perfusion and anti-CD20 therapy. The project represents a novel approach in biomarker analysis because it attempts to validate the presence or absence or quantitative change of antibody-defined biomarkers with presence or absence of sub-populations of tumor cells within tumors. Thus, marker expression by malignant cells is closely associated with biological properties. They are expected to be useful for predicting risk for recurrence. The results in this project will yield new biomarkers to better understand therapy success or failure and will spurn new strategies in melanoma therapy.
External Advisory Board for the SPORE on Cancers of the Skin
The SPORE External Advisory Board (EAB) includes outstanding investigators with particular expertise in population science, translational research, and clinical research.
Vernon Sondak, M.D., Chief, Division of Cutaneous Oncology, Professor of Surgery & Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute. Dr. Sondak is a surgeon, immunologist and a successful organizer of a new melanoma program. He is been chair of the committee since its inception.
Michael Atkins, M.D., Professor, Department of Medicine, Harvard Medical School. Dr. Atkins has a long- standing interest in experimental and clinical therapy of melanoma. He is also the PI of Harvard’s SPORE in renal cell cancer and is a co-PI of its SPORE in skin cancer.
Marianne Berwick, Ph.D., Professor of Epidemiology, University of New Mexico. Dr. Berwick has been associated with this SPORE since its inception. She is an eminent epidemiologist.
Andrew Godwin, Ph.D., Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia. Dr. Goodwin plays a leadership role in the Fox Chase/Penn SPORE in ovarian cancer with a research interest in translational studies.
Ruth Halaban, Ph.D., Senior Research Scientist, Department of Dermatology, Yale University School of Medicine. Dr. Halaban is the PI of the Yale SPORE in skin cancer .
Andre Klein-Szanto, M.D., Department of Pathology & Histopathology, Fox Chase Cancer Center, Philadelphia, PA. Dr. Klein-Szanto is a clinical and experimental pathologist with extensive experience in Tissue Resource Management.
David Rimm, M.D., Ph.D., Professor of Pathology, Yale University School of Medicine. Dr. Rimm is an accomplished pathologist with major expertise in biomarkers and imaging technologies.
Jeremy Taylor, Ph.D., Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI. Dr. Taylor is an expert in biostatistics, epidemiology, clinical trial design and evaluation.