Project Summary: Although recent advances in immune and targeted therapies have dramatically improved outcomes for many patients with advanced cancer, durable responses are achieved in only a minority of patients, and treatment is frequently limited by significant side effects. There is an urgent need to identify new therapeutic targets and efficacious pharmacologic agents that selectively engage them. Orally deliverable, well-tolerated, and easily synthesized small molecule cancer therapeutics that work in combination with existing standard-of-care drugs are especially desired. Recent work by us and others established that many cancer types are inhibited by nonclassical estrogen signaling through a widely expressed surface receptor called G protein-coupled estrogen receptor (GPER). Linnaeus has used Phase I and Phase II Small Business Technology Transfer (STTR) and Small Business Innovation Research (SBIR) awards (R41/R44 CA228695), along with venture capital funding, to advance a GPER agonist called LNS8801 to human trials. Preclinical work has established that (1) LNS8801 has potent antitumor effects across a wide range of malignancies and that this activity depends on GPER expression in the tumor cells; (2) LNS8801 has beneficial combinatorial effects with targeted therapies, chemotherapies, and immunotherapies; and (3) LNS8801 has a large safety window in rats and dogs. Linnaeus also developed an orally bioavailable and manufacturable formulation of LNS8801. Together, this work enabled us to receive clearance of an Investigational New Drug Application as well as Fast Track designation from the FDA in anti-PD1 refractory melanoma; Orphan Designation from the FDA in uveal melanoma; initiate a multisite phase 1 clinical trial (NCT04130516) and complete dose escalation at 7 cancer centers in the United States; and formalize a drug supply collaboration with Merck for pembrolizumab. To date, 28 evaluable patients with treatment-refractory advanced cancer have received LNS8801 either alone or in combination with pembrolizumab, which has proven safe and well tolerated at all dose levels. We have observed depletion of c-Myc protein after LNS8801 treatment, validating the mechanism of action. LNS8801 has demonstrated clinical benefit in several patients, particularly in cutaneous and uveal melanoma. The purpose of this Phase IIB proposal is to further evaluate these initial clinical efficacy signals in cutaneous and uveal melanoma, validate predictive and prognostic biomarkers, and to develop optimized drug product. Completion of these aims will result in the identification of defined patient subgroups most likely to benefit from LNS8801 in future pivotal registration trials.