Harnessing cuproptosis against chemoresistant ovarian cancer

The National Cancer Institute awarded Beth Israel Deaconess Medical Center $444,569 on September 3, 2026, under the Cancer Treatment Research program (CFDA 93.395) to investigate cuproptosis—a copper-dependent form of regulated cell death—as a therapeutic pathway against chemoresistant high-grade serous ovarian cancer (HGSOC).

The research addresses HGSOC's clinical challenge: most patients relapse after platinum-based chemotherapy, and recurrent disease develops resistance through adaptive, non-genetic mechanisms. The award funds laboratory and animal model work to test whether FDX1-positive HGSOC cells are inherently sensitive to cuproptosis and whether inducing this pathway can suppress tumor progression and prevent platinum resistance. Work includes testing the copper ionophore elesclomol and a new analog, ESCU002, with improved solubility and pharmacokinetics in orthotopic patient-derived xenograft models. These models allow evaluation of drug pharmacokinetics, pharmacodynamic target engagement, and antitumor efficacy in physiologically relevant settings that cannot be fully replicated in vitro.

The award period runs from September 3, 2026, through August 31, 2028. Performance takes place in Boston, Massachusetts at Beth Israel Deconess Medical Center, a Harvard Medical School-affiliated nonprofit academic medical center.

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.