DF/HCC Skin SPORE renewed
The DF/HCC Skin SPORE, led by Thomas Kupper, MD (BWH), has been highly successful in creating cohesion in the Cutaneous Oncology and Melanoma program, sparking new collaborative grants, fostering innovative ideas in cancer research, and advancing the careers of junior investigators. The National Cancer Institute has renewed funding for the SPORE. The DF/HCC Skin SPORE will continue the translation of biological and technological advances into clinically meaningful advances for patients with and at risk for skin cancers. The SPORE consists of five projects:
ABCB5 and Melanoma Stem Cells: Implications for Prognosis and Therapeutic Targeting
PI: George Murphy, MD (BWH)
Co-Investigator: Markus Frank, MD (BWH)
ABCB5 is a multidrug resistance transporter recently shown to be preferentially expressed by cells of melanocytic lineage and to be responsible for conferring resistance to chemotherapy in vitro. Project one will explore the clinical relevance of ABCB5 as a biomarker of melanoma progression, prognosis, and outcome, as well as to demonstrate the therapeutic efficacy of ABCB5 targeting in relevant animal models of human malignant melanoma. The technologies that will be employed to accomplish these goals range from tissue microarrays to detailed analysis of primary human melanomas supported by prognostic and outcome data to murine bioassays in which melanomas develop in xenografted human skin in a manner that recapitulates naturally-occurring disease and in which ABCB5+ tumor cells may be therapeutically targeted. These approaches will determine the clinical relevance and therapeutic importance of this biomarker, and pave the way to eventual clinical therapeutic trials focused on targeting of ABCB5+ melanoma stem cells.
Molecular Signatures of Melanoma: Predicting Response to Therapy and Targeting the MITF Pathway
PI: Todd Golub, MD (DFCI)
Co-Investigator: Lyn Duncan, MD (MGH)
Working with data from the last funding period establishing the transcription factor MITF as a new melanoma oncogene, project two will employ a novel chemical genomic approach toward the development of anti-MITF therapeutics. The approach is based on the modulation of gene expression signatures using the Gene Expression-Based High Throughput Screening (GE-HTS) method developed in the Golub laboratory. The expectation is that as a result of this effort, compounds with high potential for clinical translation will be identified. Specific aims include: defining a gene expression signature of MITF activation through a combination of gain-of-function experiments, loss-of-function experiments (shRNA-mediated), and computational analysis of MITF-associated gene expression patterns in melanoma patient samples; using the MITF signature in a high throughput screen to identify small molecule compounds capable of modulating the MITF signature, and by inference, capable of modulating MITF activity; and validating the hits that emerge from the screen, identifying those compounds with the greatest potency, most biological activity in melanoma transformation assays, and prioritize these compounds for possible future clinical development.
Generation of a Therapeutic Antibody Directed Against CCR4 for Patients with Advanced Cutaneous T Cell Lymphoma
PI: Thomas Kupper, MD (BWH)
Co-Investigators: James Campbell, PhD (BWH), Wayne Marasco, MD, PhD (DFCI)
The long-term goal of project three is to produce a therapeutic human monoclonal antibody (Mab) capable of immunodepleting malignant CTCL cells while minimizing collateral damage to an already compromised immune system. Based upon prior work by the SPORE, the target is the chemokine receptor CCR4 which is uniformly expressed at high levels on CD4+/CLA+ CTCL cells at all stages of disease. The project will focus efforts on completing humanization of Mab1567 with a target binding affinity for CCR4 of ≤1 nM. Additional studies will examine the ability of Mab1567 to immunodeplete primary blood cell populations expressing CCR4 from health donors and CTCL patients. The project will also evaluate the ability of Mab1567 to modulate CTCL viability and function in vitro and to delineate its mechanism(s) of action. In vivo studies in SCID mouse models of CTCL and in non-human primates will provide validation of this Mab’s ability to cause immunodepletion of CD4+CCR4+ cells.
Targeting Raf in Melanoma: Mechanisms for Effect and Resistance and Opportunities for Rational Combination Therapy
PI: James Mier, MD (BIDMC)
Co-Investigators: Michael Atkins, MD (BIDMC) Levi Garraway, MD, PhD (DFCI)
The B-RAF gene is mutated in approximately 60 percent of cutaneous melanomas. Project four focuses on the clinical development of RAF inhibitors in the treatment of melanoma. Specific aims include: identifying genetic and other factors associated with the antiproliferative and apoptotic effects of these drugs; determining if the enhancing effects of GSK-3β, JNK, or STAT3 inhibition on sorafenib-induced apoptosis in vitro can be reproduced in a xenograft model using the more potent raf inhibitor RAF-265; and conducting an Inter-SPORE phase I/II trial of RAF-265 to determine its safety, pharmacokinetics, and pharmacodynamics and in the extension phase of the trial, to determine its clinical efficacy.
Correlating Environmental and Genetic Risk Factors with Molecular Signatures in Melanoma
PI: David Hunter, MPH, ScD (HSPH)
Co-Investigator: Hensin Tsao, MD, PhD (MGH), Lyn Duncan, MD (MGH)
Molecular analysis, including transcriptional profiling (TP), has revealed unexpected heterogeneity in some cancers, informing management and outcome. In past SPORE funding periods, Harvard Skin SPORE investigators have performed TP on > 200 melanomas. Strikingly, bio-informatic analysis has revealed two distinct classes of melanoma defined by TP signatures: one characterized by higher expression of MITF and related genes, and the other by higher expression of immune, inflammatory, and growth factor genes (IIG). In project five, investigators will correlate the MITF/IIG TP signatures of primary melanomas with: genetic variables, including somatic (NRAS*/BRAF*) and germline (MCIR); risk and environmental exposure variables (NHS1,2 and HPFS); and prognosis and outcome measures (MLSN 1&2 with the goal of informing prevention, diagnosis, management, and outcome strategies for this cancer.