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Harnessing Cuproptosis Against Chemoresistant Ovarian Cancer

Award Number: R21CA317274
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/03/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Harnessing Cuproptosis Against Chemoresistant Ovarian Cancer - ABSTRACT High-grade serous ovarian cancer (HGSOC) remains the deadliest gynecologic malignancy, with most patients relapsing after initial response to platinum-based chemotherapy. Recurrent disease is almost uniformly drugresistant, reflecting adaptive, non-genetic mechanisms that allow tumor cells to survive and regrow following treatment. Identifying and targeting such adaptive vulnerabilities is a critical unmet need. Recent discoveries from our laboratory have revealed a novel form of regulated cell death we teremed cuproptosis, which is triggered by copper overload in mitochondria. Cuproptosis selectively kills cells in a process regualted by FDX1 and resulting in copper targeting lipoylated and Fe-S cluster proteins, leading to catastrophic proteotoxic stress. Preliminary data from our patient-derived xenograft (PDX) models show that HGSOC cells exhibit enhanced sensitivity to cuproptosis, particularly when cultured in ascites-derived media that mimic the tumor microenvironment. Notably, the copper ionophore elesclomol (ES), previously tested in cancer clinical trials without mechanistic guidance, emerges as a potent cuproptosis inducer in FDX1 + HGSOC models. We have further developed a new analog, ESCU002, with improved solubility, pharmacokinetics, and in vivo efficacy. Animal models are required because drug exposure, copper delivery, tumor growth, ascites-associated microenvironmental effects, and platinum response cannot be fully modeled in vitro. Orthotopic HGSOC PDX models allow us to test pharmacokinetics, pharmacodynamic target engagement, and antitumor efficacy in a clinically relevant and physiological settings. This R21 proposal tests the hypothesis that FDX1 + HGSOC cells are intrinsically sensitive to cuproptosis and that inducing this pathway can suppress tumor progression and prevent the emergence of platinum resistance. We will test this hypothesis in the following two aims: Aim 1 will define the molecular and pharmacodynamic features of cuproptosis in HGSOC PDX models, establishing the intracellular copper threshold required for cell killing, mapping the transcriptional response, and validating biomarkers of target engagement in vivo. Aim 2 will evaluate the efficacy of elesclomol and ESCU002 as single agents and in combination with platinum in orthotopic PDX models, including pharmacokinetic assessment to correlate drug exposure with antitumor effects and biomarker responses. Together, these studies will determine whether inducing cuproptosis is a feasible and effective therapeutic strategy for drug-resistant ovarian cancer. By leveraging improved copper ionophores such as ESCU002, this work will lay the foundation for translating copper-dependent cell death into a novel treatment approach for highgrade serous ovarian cancer.


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: 2026 ( Subtotal = $444,569 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	1	9/3/2026	NEW	$444,569
														Subtotal = $444,569

Grand Total All Awards = $444,569

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Harnessing Cuproptosis Against Chemoresistant Ovarian Cancer

Award Number: R21CA317274

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/03/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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