Novel Target for Melanoma Therapeutic Development

Linda Malkas, PhD

Mentor Long Gu, PhD
Award Type Established Investigator Award
Institution Beckman Research Institute of the City of Hope
Description:

Melanoma is one of the fastest growing malignancies and accounts for 5.5% of all new cancer cases in the United States. Treatment options and prognosis of melanoma patients depend on the risk stratification. Survival is excellent in low risk groups and localized diseases often require simple surgery only. In fact, a very thin melanoma may be removed entirely during the biopsy and require no further treatment. In contrast, metastatic melanoma is very difficult to treat. The current standard of care uses aggressive multi-regimen treatment, which could cause severe side effects. The 5-year survival rate for patients with metastatic melanoma is less than 25%. There is a significant unmet medical need for new therapies to improve the treatment outcomes of this aggressive cancer phenotype. Proliferating cell nuclear antigen (PCNA) is a protein that helps regulate DNA synthesis and repair. It is an attractive molecular target to develop a drug to treat melanoma, because melanoma cancer cells depend on PCNA for growth and survival. While studying this protein, we discovered a cancer-associated isoform of PCNA (caPCNA) that is present in a broad range of cancer cells and tumor tissues (including melanoma), but not present in otherwise healthy cells. We tested a series of drugs designed by computer modeling and medicinal chemistry to target caPCNA and identified AOH1996, a potent inhibitor that selectively melanoma cells but causes no significant toxicity to a broad range of normal cells. The pharmacologic and therapeutic properties of AOH1996 are extremely favorable in animal studies. When orally given to mice, AOH1996 suppresses the growth of a broad range tumor types without causing any observable side effects, including weight loss.

Based on our communication with the US Food and Drug Administration (FDA), we are confident that we will readily meet the FDA’s regulatory requirement for a new investigational drug (IND) filing. The information derived from this proposal will inform the design and implementation of the expected clinical trials. Specifically, our proposal will determine the effective dose range for clinical trials. It will also validate biomarker(s) in tumor cells that will enable us to select melanoma patients who are likely to respond to AOH1996 treatment. Based on its favorable therapeutic properties seen so far in our animal studies, AOH1996 is likely to lead to a novel class of drug and significantly improve treatment options and outcomes of patients with metastatic melanoma.