The Wistar/Penn Spore in Skin Cancer
PI, M. Herlyn
Co-PI, L. Schuchter
The Wistar/Penn Spore (M.Herlyn PI) focuses on melanoma with each of the four projects being highly collaborative. Each project is directed by two co-leaders, coming from basic research or clinical science. Our SPORE was initiated in 2001 with a major emphasis on therapy and disease outcome prediction. It is multi-disciplinary with expertise coming from tumor biology, oncology, pathology, genetics, epidemiology, immunology, surgery, and dermatology. The investigators have been highly collaborative for decades. In September 2008 we applied for funding in the next cycle (2009-2013). Since the last submission five years ago, we have rejuvenated the leadership by bringing in young investigators. Seven out of the 12 co-leaders came in recent years as junior investigators to the group.
Project 1 is co-directed by the clinical oncologist Keith Flaherty and cancer geneticist Katherine Nathanson. The project builds on the first-in-human trials using BRAF targeted therapy; use of these inhibitors may rapidly change the way we treat this malignancy. Phase I trials for PLX4032, a mutant BRAF inhibitor, and RAF 265, a pan-RAF inhibitor, are nearing completion at Penn. From each patient, prior to therapy, tumor tissue is extracted to establish a molecular signature for optimal therapy selection and treatment monitoring. We hypothesize that not all melanoma patients will respond equivalently to these drugs. Patients on these trials will be pre-selected for BRAF gene, and centers on identifying determinants of non-response focusing on the PI3K pathway. We also will study melanoma cell lines, with genetic and proteomic aberrations reflective of what is observed in the patients, to identify combination therapies to move into the clinic. The project is an example of personalized medicine for melanoma patients and will expand to target other signaling molecules critical for melanoma cells.
Project 2 has co-leaders Lynn Schuchter, a clinical oncologist, George Xu, a pathologist, and Phyllis Gimotty, a biostatistician. It deals with risk assessment of patients with primary melanomas. Previously, we had shown that proliferation of tumor cells is important for predicting metastatic progression. We now hypothesize that not all low-risk primary melanomas are the same, but few are high risk and patients should be treated more aggressively. Similarly, not all high-risk lesions, as assessed by standard criteria, are indeed high-risk and these patients should be treated less aggressively than others in this group. We are developing a new series of markers that will help us to better select patients’ therapies and avoid over- or under-treatments. The project is supported by a large database of 8000 patients and their lesions that dates back to 1975, the year our group was founded by the late Wallace Clark.
Project 3 has as co-leaders Meenhard Herlyn, a tumor biologist, and David Elder, a pathologist, who have worked together since 1977. The working hypothesis is that not all tumor cells are the same but that there are sub-populations (we avoid using the term cancer stem cells) that have specific functions for tumor progression towards metastasis and for drug resistance. The focus is on a sub-population that usually does not proliferate but can burst into high proliferation cycles and invasion mode by yet unknown signals. For example, after chemotherapy, these cells suddenly ‘explode’. We expect to develop new criteria for cancer diagnosis and prognosis and will assess whether we need to develop two therapies, one for the major population representing the bulk of the tumor and one for the minor tumor-initiating populations.
Project 4 is our immunotherapy project and has co-leaders Robert Vonderheide, an oncologist, Daniel Powell, a newly recruited immunologist from the Rosenberg group, and Carl June, a senior immunologist at the forefront of immunotherapy trials in cancer. The project rests on the principle of stimulating a sub-population of lymphocytes (APC), using antibodies to CD40, to enhance the cytotoxic response while blocking inhibitory lymphocytes. The project will build on ongoing clinical trials to develop novel vaccines that are expected to be highly effective.
These projects are supported by three Cores: Administration, Biospecimen and Information, and Biometrics. In addition, the SPORE supports awards for Career Development and Developmental Research Programs, although most of the funding for these programs comes from both Institutions as institutional commitment.