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theses

Melanoma is the most dangerous type of skin cancer due to the frequency of metastasis and resistance to therapies, including radiation, traditional chemotherapies, and targeted therapies. Drug resistance and immune evasion are two issues currently gaining attention in the areas of melanoma research and treatment. To combat drug resistance, various combination treatment strategies are under investigation. Immune checkpoint blockade, a popular area of immunotherapy, aims to harness a patient’s cytotoxic T cell response to combat tumor growth. Previously, our group identified the ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (mGluR1) in the etiology of melanoma development and pathogenesis. When aberrantly expressed in melanocytes, mGluR1 activates two of the most commonly dysregulated signaling cascades, MAPK and P13K/AKT pathways that promote cellular proliferation while inhibiting apoptosis. To interrupt signaling through mGluR1, we took advantage of the anti-glutamatergic activity of riluzole. Riluzole is an FDA approved drug for the treatment of amyotrophic lateral sclerosis (ALS). In the current study, in addition to using riluzole as an antagonist to mGluR1, we also used a newly developed prodrug for riluzole, FC4157. Tumor biopsies from patients who participated in our Phase 0 and 2 clinical trials with riluzole suggest those who benefit from the drug have suppression of angiogenesis and increased leukocyte numbers at the tumor-stroma interface. Based on these observations, we began to test in a preclinical experimental model system, the efficacy of combining either riluzole or FC4157 with PD-1 checkpoint blockade. We observed a significant reduction in tumor volumes in animals receiving either riluzole or FC4157 in combination with PD-1 blockade, as compared to vehicle or monotherapy treated groups. Western blot analysis on excised tumor lysates showed evidence of alterations to PD-1 ligand and DNA damage markers, suggesting tumors from animals receiving combination therapies may be less likely to evade cytotoxic T cell responses and may respond better to anti-PD-1 treatment. Finally, ELISA array data from tumor tissues, splenic tissues, and serum samples indicate a dynamic, but ultimately favorable tumor microenvironment for an anti-tumor immune response.

ETD_8373

M.S.

Includes bibliographical references

by Ann K. Robinson

doi:10.7282/T3NP27K5

ETD graduate

The author owns the copyright to this work.