Click the red plus signs to see detailed information on research projects within the Melanoma SPORE.
Project 1: Targeting The P13K Pathway To Overcome Resistance To Immunotherapy In Melanomas With Loss Of PTEN
Our previous studies demonstrated that loss of function of the tumor suppressor PTEN in melanomas, activates the oncogenic PI3K-AKT pathway, and thereby suppresses the anti-tumor immune response and promotes resistance to anti-PD-1 immunotherapy. In this Project we will focus on analyzing biospecimens collected from a novel phase I/II clinical trial of combination therapy with the selective PI3Kβ inhibitor GSK2636771 and the anti-PD-1 antibody pembrolizumab in PD-1-refractory metastatic melanoma patients with loss of PTEN to determine if this regimen inhibits the PI3K-AKT pathway, promotes anti-tumor immune function, and overcomes clinical resistance to anti-PD-1. We will also use preclinical models to investigate additional strategies to further improve the efficacy of anti-PD-1 immunotherapy in tumors with PTEN loss.
Project 2: Intrathecal Anti-pd-1 Immunotherapy For Metastatic Melanoma Patients With Leptomeningeal Disease (LMD)
Patients with leptomeningeal disease (LMD) from melanoma have a very poor prognosis and very few treatment options. We will conduct the first-ever clinical trial to determine the safety, maximum tolerated dose, efficacy, and immune and molecular effects of combined intrathecal (IT) and intravenous (IV) treatment with the anti-PD-1 antibody nivolumab in metastatic melanoma patients with LMD. The results from these studies will provide critical information about this novel IT+IV nivolumab combination, increase our understanding of the pathogenesis of LMD, and inform the design of future clinical trials for this patient population.
Advanced uveal melanoma is refractory to conventional therapy, highly prone to development of metastatic disease, and associated with dismal one-year patient survival. We propose a Phase I study evaluating the use of adoptive cell therapy directed against an epitope of SLC45A2, a protein with elevated expression in and capable of driving a potent cytotoxic response against uveal melanoma cells. These analyses will determine persistence of transferred SLC45A2-specific T cells in the patient, their ability to induce antigen spreading, and search for additional immunogenic epitopes with the goal of identifying a safe and effective new therapy option for uveal melanoma patients for further clinical development.
Click the red plus signs to see detailed information on cores within the Melanoma SPORE.
The Administrative Core (Core 1) will be responsible for the successful execution and management of all SPORE activities related to financial oversight and coordination, organization of all necessary meetings, and publicity and record keeping for all projects and the two other cores. This group will also provide regulatory oversight activities for clinical trials; ensure compliance with all institutional, federal, and NCI-specific regulations; and oversee the peer-review and oversight processes of the Career Enhancement Program and Developmental Research Program.
The primary goal of the MD Anderson SPORE in Melanoma is to translate our fundamental understanding of melanoma into improved patient care by improving melanoma prevention, detection, and therapy. Building upon this experience and to further this goal, it is essential to continue to conduct high-impact, well-planned, translational research involving well-annotated curated biospecimens and relevant clinical data to identify the pathophysiologic mechanisms of melanoma and the metastatic cascade, identify biomarkers and targets for antitumor therapy, and evaluating the mechanisms of response and resistance in new treatment strategies. The Melanoma Clinical Database, Tissue Resource, and Translational Pathology Core (MelCore; Core 2) will be a resource for clinicopathologic data, well-annotated biospecimens, and for optimized acquisition, processing, distribution and analyses that facilitate integration of conventional biomarkers, molecular and immunologic data, with clinicopathologic, treatment, recurrence and follow-up. Overall, these approaches will facilitate the discovery of clinically impactful predictive and prognostic biomarkers, as well as enhanced approaches to anti-tumor therapy across several clinically unmet needs for patients with melanoma.
The Biostatistics and Bioinformatics Core 3 provides comprehensive service to guide design of experiments, to optimize quantitative data analysis, and to maintain statistical justification and interpretation of results. Specifically, Core 3 will implement sound experimental design principles that are tailored to address specific scientific questions for each project. Core 3 will also carry out data analyses using suitable statistical methods and bioinformatics algorithms, and will contribute to the interpretation of results through written reports and frequent interactions with project investigators. Whenever appropriate, Core 3 will develop new analysis tools to address new challenges in the analysis of various data, especially high-throughput genomic and proteomic data. Members of Core 3 will participate in monthly SPORE meetings with all project investigators, ensuring that statistical and data analysis/management issues are carefully considered during all phases of each SPORE experiment. Thus, from inception to reporting and publication, basic laboratory and translational experiments will benefit from the SPORE program that will be used to augment existing MD Anderson Cancer Center biostatistics resources.