Oncogenic signaling in uveal melanoma

Uveal melanoma is a rare cancer, and despite adequate local control, more than 50% of patients will develop metastatic disease. Life-expectancy for metastatic uveal melanoma patients is poor and overall survival of patients has not improved with current standard therapies. Tebentafusp, a T-cell directed therapy is the only treatment that has resulted in improved overall survival for patients with metastatic uveal melanoma in a clinical trial setting. The focus of this work was to examine the response patterns of uveal melanoma to current and novel therapies both in vitro and in vivo.

The introductory chapter reviews the immunobiology, genetics, and signaling pathways involved in uveal melanoma survival and proliferation. Current and novel treatments of metastatic uveal melanoma are discussed, including the role of molecular therapies, immunotherapies and liverdirected therapy. Biomarkers of response are also examined with a particular focus on circulating tumour DNA.

The results are presented in four chapters. Chapter 2 describes the signaling and survival effects of protein kinase C inhibitors on a panel of uveal melanoma cell lines. This work is extended in Chapter 3, which includes an analysis of the MAPK, PI3K/mTOR and YAP signaling pathways in uveal melanoma, and the efficacy of selective pathway inhibitors. In Chapter 4, the utility of circulating tumour DNA in uveal melanoma patients treated with protein kinase C inhibitor is explored. Chapter 5 presents transcriptomic signaling analyses in uveal melanoma biopsy samples derived from patients treated with protein kinase C inhibitor-based therapies.

In the concluding chapter we discuss the future directions in uveal melanoma research and treatment.