Description:

The Hippo pathway in cancer, mediated by YAP1, has been implicated in therapy resistance and aggressive tumor behavior in melanomas treated with targeted therapies. However, the role of this pathway in response and resistance to immunotherapy has not yet been characterized. There is existing data suggesting that activation of this pathway may lead to immune evasion by tumors. Therefore, we hypothesize that concurrent inhibition of the Hippo pathway in combination with immunotherapy may be complementary. We will use a unique resource of longitudinal tumors from patients treated with immunotherapy in whom analysis of molecular data is already underway to assess if there is regulation of the Hippo pathway during treatment with immunotherapy in melanoma and if this correlates with response or resistance to therapy (Aim 1). We will then use cell lines to establish the mechanism of Hippo pathway activity in melanoma (Aim 2), and finally will examine the impact of activating/inactivating the Hippo pathway in combination with immunotherapy in a mouse model of melanoma. This proposal draws from our respective strengths in translational medicine (Dr. Boland), computational biology (Dr. Liu) and mechanisms of gene regulation (Dr. Saladi).