Date of Award

January 2015

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Marcus W. Bosenberg

Subject Area(s)

Oncology, Biology, Medicine

Abstract

Melanoma therapy has changed rapidly due to the emergence of new therapies: MAPK-pathway targeted drugs and immunomodulatory agents. Given the relative success of these new individual drugs, this work set out to evaluate and develop effective melanoma treatments using combination therapies in a preclinical mouse melanoma models. Therapies tested include BRAF kinase inhibition in combination with: immune checkpoint inhibitors anti-CTLA4, anti-PDL1, and with the topical TLR7/8 agonist imiquimod. Drugs efficacies were tested in established melanomas in a conditional inducible mouse melanoma model based on activation of Braf and beta catenin and loss of Pten. 
BRAF inhibition in combination with anti-CTLA-4/anti-PD-L1 was not more effective than BRAF inhibition alone in retarding tumor growth or prolonging survival in these studies. Treatment with imiquimod significantly retarded tumor growth and increased survival. Imiquimod-treated tumors show increased macrophage infiltration, but not increased intratumoral T lymphocytes. Further work remains to identify effective, synergistic drug combinations in preclinical models.

Comments

This is an Open Access Thesis.

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