Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY High grade serous ovarian cancer (HGSOC) is the deadliest form of ovarian cancer accounting for 70% of all ovarian cases and the fifth leading cause of death in women. Only in the last six years have frontline therapy changed for ovarian cancer patients with breast cancer gene (BRCA) mutation by the addition of PARP inhibitors. Natural products account for 50% of FDA approved drugs used in the clinic today. With the prevalence of drug resistance leading to relapse and death of ovarian cancer patients, new drug treatment and therapeutic strategies are needed. The focus of this proposal is to study the efficacy and mechanism of the novel natural products didesmethylrocaglamide and phyllanthusmin34 isolated and purified by our collaborative team. Didesmethylrocaglamide (DDR) is a naturally occurring derivative of rocaglamide with potent anti-tumor activity isolated from the Aglaia plant species, whereas phyllanthusmin34 (PHY34) is a synthetic derivative of phyllanthusmin D, a natural compound isolated from Phyllanthus species. Recently, we confirmed that these compounds are cytotoxic and apoptotic in HGSOC from different mechanisms of action. DDR inhibits mRNA translation by stabilizing RNA binding of eukaryotic initiation factor (eIF) 4A whereas PHY34 inhibits autophagy by blocking the ATPase subunit (ATPV0A2) and inhibiting lysosomal acidification. DDR like other rocaglates inhibits mRNA translation which leads to cell death; however, a survival mechanism to generate proteins could occur through autophagy. Protein recycling can be halted by blocking autophagy with an inhibitor like PHY34. We hypothesize that DDR combinatorial treatment with the autophagy inhibitor, PHY34, are a rationale combination for HGSOC and will test their efficacy in models that no longer respond to frontline therapy of platinum and taxanes. We therefore aim to study combinatorial effects on tumor burden in a xenograft and syngeneic model. In addition, we will explore interferon response from natural killer (NK) cells in a syngeneic model because phyllanthusmin compounds have been shown to activate NK cells in addition to blocking autophagy. Secondly, we will also determine the mechanism of action for the combinatorial treatment effects of DDR and PHY34 in sensitive and resistant HGSOC cell lines through proteomic analysis prioritized by pathway analysis, fold change, and validated by western blot and qPCR. Overall, we will gain valuable insight into the role of natural products as new strategies to combat HGSOC. Implementing this research program will foster the development of the candidate as an independent researcher and the career goals to establish a research laboratory and tenured faculty position to further enhance diversity in the biomedical field.
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