MitoTam-01 Trial: Mitochondrial Targeting as Plausible Approach to Cancer Therapy. Comment on Yap et al. Complex I Inhibitor of Oxidative Phosphorylation in Advanced Solid Tumors and Acute Myeloid Leukemia: Phase I Trials. Nat. Med. 2023, 29, 115–126

Abstract

A recent paper published in Nature Medicine reported on the Phase I clinical trial of a mitochondria-targeting anti-cancer agent IACS-01059 in patients with acute myeloid leukemia (AML) and solid tumors [1]. Overall, 23 patients with solid tumors and 17 patients with AML were enrolled into the study.

IACS-010759 is a small molecule (Figure 1) that was originally reported in 2018 as an agent that suppresses oxidative phosphorylation (OXPHOS) in chronic lymphocytic leukemia (CLL) cells by targeting mitochondrial respiratory complex I (CI), thereby promoting glycolysis [2]. Interestingly, the effect of IACS-010759 results in decreased ribonucleotide pool in CLL cells [2].

A follow-up paper reported that IACS-010759 binds to a specific site within CI with the ensuing blockage of reverse and forward electron flow [3]. Of note, the toxicity of IACS-010759 was reinforced by its combination with the glycolysis inhibitor 2-deoxyglucose, [2] the BH3 mimetic venetoclax, [4] or immune checkpoint inhibitors [5].

Recently, IACS-010759 was reported to reverse NOTCH1 signaling, which drives lymphoma [6], as well as being present in cancers with isocitrate dehydrogenase-1 mutations [7]. These findings, together with efficacy in a pre-clinical model of brain cancer and AML [8], resulted in the launch of the clinical trial of IACS-010759, as mentioned above [1].