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Pharmacological Potential of Combined Translation and Autophagy Inhibition in High Grade Serous Ovarian Cancer

Award Number: K99GM155616
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Pharmacological Potential of Combined Translation and Autophagy Inhibition in High Grade Serous Ovarian Cancer - 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 natural products cancer discovery.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $120,972 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	001	2	7/29/2025	NON-COMPETING CONTINUATION	$120,972
2025	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	1	1/20/2025	NEW	$0
														Subtotal = $120,972

Issue Date FY: 2024 ( Subtotal = $120,972 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	1	7/11/2024	NEW	$120,972
														Subtotal = $120,972

Grand Total All Awards = $241,944

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Pharmacological Potential of Combined Translation and Autophagy Inhibition in High Grade Serous Ovarian Cancer

Award Number: K99GM155616

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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