P2, N=24, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

We find that bedaquiline (ATP synthase inhibitor) outperforms oligomycin A in specificity, VLX600 (electron transport chain inhibitor) shows superior selectivity to rotenone/metformin, and CPI-613 (tricarboxylic acid cycle blocker) surpasses other glutaminase inhibitors. MitoATP-nFCM establishes a quantitative single-organelle platform that profiles elevated mitoATP levels in cancer cells and enables precision screening of OXPHOS-targeting inhibitors.

P1/2, N=75, Terminated, University of Michigan Rogel Cancer Center | Completed --> Terminated; Loss of funding

Based on this insight, we demonstrate that co-targeting this metabolic vulnerability with an inhibitor (devimistat) alongside an anti-TGFβ agent significantly enhances therapeutic efficacy in gastric cancer models. This combination approach presents a promising strategy to overcome the limitations of current therapies.

P1, N=8, Terminated, Medical College of Wisconsin | Active, not recruiting --> Terminated; The pharmaceutical funder pulled funding and no longer plans to develop the drug further.

Functional experiments demonstrated that radioresistant ESCC cells (KYSE410R) exhibited elevated OXPHOS activity, which is reversed by targeting TCA cycle enzymes (CPI-613 (Devimistat), fumarate hydratase-IN-1 (FH-IN-1), etc.) or Oxidative phosphorylation (OXPHOS) inhibitors (IACS-010759, Rotenone, etc.). Clinically, high Amphiregulin/Epiregulin (AREG/EREG) levels correlated with nCRT resistance and poor prognosis. Collectively, the CEBPB/AREG/EREG axis drives radioresistance by reprogramming OXPHOS, suggesting inhibition of this pathway or OXPHOS itself as a promising strategy to enhance ESCC therapeutic responses.

P1, N=64, Active, not recruiting, Geistlich Pharma AG | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Jun 2026 | Trial primary completion date: Sep 2024 --> Jun 2026

P1, N=8, Active, not recruiting, Medical College of Wisconsin | Recruiting --> Active, not recruiting

Here, we explored the rationale behind combining TKIs with an inhibitor of glucose metabolism (dichloroacetate, DCA), focusing on the synergistic effects from dual inhibition of oncogenic and metabolic reprogramming...These changes in tumor behaviour leads to a higher pro-apoptotic status responsible for an increased tumor response and, in parallel, the lower doses reduced alternative evasion pathways contributing to decrease of tumor invasion and resistance mechanism. This study shed light on a new potential combined therapeutic approach to improve clinical outcomes in targeted cancer therapy scenarios.

Treatment with CPI-613 significantly inhibited the excessive proliferation and differentiation of erythroid progenitor cells of the PV patients. These findings demonstrates the critical role of OGDC in normal erythroid development, suggesting that inhibiting its activity could be a novel therapeutic strategy for treating PV.

Notably, FAT1-mutant HNSCC cells exhibit resistance to the TCA cycle inhibitor CPI-613 through activation of CPT1A-mediated FAO, whereas genetic ablation of mutant FAT1 restores sensitivity to CPI-613...Collectively, these findings establish that mutant FAT1 drives CPT1A-dependent FAO, facilitating a metabolic bypass that confers resistance to TCA cycle inhibition in HNSCC. This mechanistic insight highlights promising opportunities for combinatorial therapeutic strategies co-targeting genetic and metabolic vulnerabilities in cancer.

In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell-mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC)...These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.