Melanoma is the deadliest form of skin cancer. Landmark genomic and immunologic studies have translated into multiple approved targeted and immune therapies for patients with metastatic disease. While targeted therapies achieve high response rates, most of those responses are transient. Immunotherapies can achieve long-term responses but only in a subset of patients, and often with serious toxicities. Several key challenges remain to maximize the clinical benefit of immunotherapy: 1) poorly understood markers and mechanisms of resistance to immunotherapy, and a lack of effective strategies to overcome them; 2) limited experience or efficacy in patients with central nervous system involvement, a common metastatic site and a leading cause of death from melanoma and multiple other cancers; and 3) lack of benefit in patients with non-cutaneous melanomas, particularly the uveal melanoma subtype. The central hypothesis of this SPORE proposal is that an integrated analysis of immune and molecular features in patients with advanced melanoma will improve our understanding of response and resistance to immunotherapy, and lead to more effective treatments. To test this hypothesis, we will focus on the most critical unmet needs of melanoma patients, building on current immunotherapeutic strategies and developing our own novel concepts to identify more effective treatment options by:
- Addressing resistance to the PD-1 immune checkpoint inhibitor through inhibition of the PI3K pathway in PTEN-null metastatic melanoma patients (Project 1).
- Determining the clinical utility of PD-1 blockade using nivolumab administered intrathecally in metastatic melanoma patients with leptomeningeal disease (LMD) (Project 2).
- Evaluating a new therapeutic strategy for uveal melanoma that uses adoptive cell therapy to target an immunogenic epitope of the melanosomal transport protein SLC45A2 (Project 3).
Three cores (Administrative Core, Clinical Database, Tissue Resource, and Translational Pathology Core [Core 2] and Biostatistics and Bioinformatics Core [Core 3]) provide specialized services to support our SPORE investigators and their proposed research studies. Together, these three projects and cores, and our Career Enhancement Program (CEP) and our Developmental Research Program (DRP), will provide a comprehensive attack on critical unmet needs for patients battling these deadly manifestations of melanoma, and pave the way for other cancers with limited therapeutic options.
Each publication, press release or other document that results from the research funded by this SPORE award must include an acknowledgment and disclaimer of federal funding such as:
" Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant award number P50CA221703. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health."