Author ORCID Identifier

0000-0002-2393-2172

Date of Graduation

8-2017

Document Type

Thesis (MS)

Program Affiliation

Clinical and Translational Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Michael Davies, M..D., Ph.D.

Committee Member

Peiying Yang, Ph.D.

Committee Member

Lorenzo Cohen, Ph.D.

Committee Member

Patrick Hwu, M.D.

Committee Member

Carrie Daniel-MacDougall, Ph.D.

Committee Member

Powel Brown, M.D., Ph.D.

Abstract

While the FDA approval of targeted and immune therapies in metastatic melanoma (MM) have dramatically improved outcomes in this disease, de novo and/or acquired resistance can limit the clinical benefit of these agents. The IGF-1/PI3K/AKT pathway has been implicated in resistance to both targeted and immune therapy. The IGF-1/PI3K/AKT pathway has also been shown to play a key role in the pathogenesis of obesity in other malignancies. To date, the impact of energy balance on clinical outcomes and therapeutic response in MM has not been studied. I hypothesized that energy balance would impact the molecular biology, behavior, and drug sensitivity of melanoma.

The association of body mass index (BMI) with overall survival (OS) and progression-free survival (PFS) was studied in independent cohorts of >1900 MM patients treated with targeted therapy [dabrafenib and trametinib (D+T) and vemurafenib and cobimetinib], immunotherapy [ipilimumab and anti-PD-1/PDL-1], and chemotherapy. The functional significance of obesity was tested using a mouse model of diet-induced obesity (DIO) injected subcutaneously with murine melanoma cells. Tumors were followed for growth and assessed by proteomics and flow cytometry. The effect of DIO on therapeutic sensitivity was tested in tumor-bearing mice treated with a) D+T and b) anti-PD1.

Obesity was associated with significantly improved PFS and OS in MM patients treated with both targeted therapy and immunotherapy but not chemotherapy. Improved outcomes were not attributable to differences in clinical prognostic factors or treatment-related adverse events. The association of BMI with improved outcomes was driven by markedly improved survival in obese compared to normal BMI males, whereas no significant associations were observed in females. In a subcutaneous model of mouse melanoma, DIO led to increased tumor growth, increased PI3K pathway activation, and decreased immune infiltrates. There were no differences in sensitivity to D+T or anti-PD1 between diets in this model.

Obesity is associated with markedly improved outcomes in MM patients treated with targeted and immune therapies. In a subcutaneous model of murine melanoma, DIO increased tumor growth, recapitulating clinical associations in early stage melanoma. The biological basis for the paradoxical association of obesity with improved outcomes in MM should be explored further.

Keywords

melanoma, obesity, BMI, immunotherapy, targeted therapy, cancer

Available for download on Saturday, August 11, 2018

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