Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Marcus Bosenberg

Second Advisor

Robert Tigelaar

Abstract

Recently, the FDA approved two new therapeutic agents that showed improved survival in patients with metastatic melanoma in phase III clinical trials: ipilimumab is a monoclonal antibody that blocks CTLA-4 to potentiate antitumor immune responses and vemurafenib is a selective inhibitor of the BRAF kinase. However, even with the recent advances in therapy, each individual drug has limitations. Combining different therapies can theoretically lead to improved outcomes. For instance, the chemotherapeutic agent temozolomide increases DNA methylation and cell apoptosis. This may increase tumor antigen release, which could further potentiate the antitumor response of ipilimumab. Performing trials of combination therapies in a mouse model can help us detect effective combination therapies and understand their mechanisms. This study uses a conditional melanoma mouse model based on the Cre-Lox recombination system to lead to the melanocyte-specific expression of activated BRAF, loss of PTEN, and stabilization of β-catenin. The model allows us to grow melanoma driven by mutations relevant to human melanoma in an immune competent setting. Mice were treated with different combinations and schedules of chemotherapeutic agents (decitabine or temozolomide) and immunomodulatory agents (anti-CTLA4 antibody). Preliminary data suggests that the combination of chemotherapeutic agents and immunomodulatory agents may result in improved anti-melanoma responses. Finding an optimal combination and schedule in animal models can eventually be translated into clinical trials for humans.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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