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.
Recommended Citation
Lockhart, Billy, "Evaluating Targeted And Immunomodulatory Therapies For Melanoma In A Genetically Engineered Mouse Melanoma Model" (2015). Yale Medicine Thesis Digital Library. 1994.
https://elischolar.library.yale.edu/ymtdl/1994
This Article is Open Access
Comments
This is an Open Access Thesis.