Arylsulfonamides for the Treatment of Primary and Metastatic Uveal Melanoma

Project Summary/Abstract:Uveal melanoma (UM) is the most common primary malignant eye tumor in adults. Approximately 50% of patients with UM develop metastases, with death occurring in the majority within 1 yr of detecting metastases. High metastatic risk of UM can be identified with validated tools that categorize patients as Class 1 (low metastatic risk) or Class 2 (high metastatic risk: 72% 5 yr metastatic risk). Our goal is to reduce this risk.We have shown that UM patients at high risk for developing metastases display high expression of Hypoxia Inducible Factor (HIF)-regulated gene products CXCR4 and MET. We have developed and optimized proprietary small molecule inhibitors of HIF that block HIF-driven gene expression and can be combined with agents that work in non-hypoxic regions. The HIF inhibitors have an arylsulfonamide structure, and the lead clinical candidate, called 64B, is being advanced in this proposal. Properties that support its selection include 1) its efficacy at blocking primary growth of UM within the eye, inhibiting metastases, and prolonging survival in several mouse models of UM; 2) its ability to be safely given in combination with other cancer therapeutics; 3) its ability to inhibit both HIF-1 and HIF-2-mediated gene expression with similar IC50s and at clinically achievable doses; 4) its low toxicity at clinically effective doses, both alone and in combination with other anticancer drugs; and 5) its unique mechanism of action. This phase 1 SBIR will provide information that is critical for the design of IND-enabling studies and clinical trials targeting high risk UM: 1) the route by which 64B will be delivered in clinical trials for UM (oral or intravenous) and 2) the determination of whether it would be clinically beneficial to combine 64B with Sunitinib, a tyrosine kinase inhibitor (TKI) that is currently being tested for reducing risk of relapse in high-risk UM patients. We anticipate that 64B as a single agent will be comparable to Sunitinib at reducing UM growth and metastases, and we anticipate the combination will dramatically enhance tumor control without exacerbating toxicity. Salt selection and polymorph selection will be used to enhance oral bioavailability, followed by PK/PD studies designed to determine if serum and tissue levels resulting from oral delivery of 64B are sufficient to inhibit HIF function in target tissues. If not, 64B will be delivered parenterally. 64B will be administered by selected delivery route to treat UM in a rabbit model that closely mimics the human disease. Primary tumor growth will be monitored using fundoscopy and high-frequency ultrasound (HF-US). The impact of 64B on metastases and HIF-driven processes and will be assessed at necroscopy. The relationship between circulating tumor DNA and tumor response will also be determined. 64B will be compared to, and combined with, Sunitinib, an agent that works by a distinct mechanism of action. Successful completion of this SBIR will be followed by execution of IND-enabling studies and clinical studies using 64B, possibly in combination with Sunitinib, for high risk UM.Project narrativeUveal melanoma (UM) is the most common malignant eye tumor in adults. In approximately half of the patients, the cancer cells metastasize to the liver despite using either surgery or radiation to control tumors in the eye, and this tumor spread leads to patient demise. This SBIR focuses on advancing a nontoxic drug called 64B that inhibits the function of hypoxia inducible factors (HIFs) and improves tumor control in preclinical models of UM, with the goal of advancing 64B in combination with another drug to reduce metastases and risk of death in patients with UM.