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Ref Type Journal Article
PMID (31597662)
Authors Quintela-Fandino M, Morales S, Cortés-Salgado A, Manso L, Apala JV, Muñoz M, Gasol Cudos A, Salla Fortuny J, Gion M, Lopez-Alonso A, Cortés J, Guerra J, Malón D, Caleiras E, Mulero F, Mouron S
Title Randomized Phase 0/I Trial of the Mitochondrial Inhibitor ME-344 or Placebo Added to Bevacizumab in Early HER2-Negative Breast Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 26
Issue 1
Date 2020 01 01
URL
Abstract Text We previously demonstrated that mitochondrial inhibitors' efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Vascular normalization can be tracked with 2[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. We tested the efficacy of the mitochondrial inhibitor ME-344 or placebo added to bevacizumab in early breast cancer.Treatment-naïve HER2-negative patients with T > 1 cm (any N) underwent a breast-centered 18F-fluorodeoxyglucose (FDG)-PET (day 1) and received a single dose of bevacizumab (15 mg/kg), followed by a second FDG-PET (day 8). Patients were then randomized (1:1) to Arm A (ME-344 10 mg/kg intravenous on days 8, 15, and 21) or Arm B (placebo). Tumors were biopsied on days 0 and 29. Succinate dehydrogenase enzyme histochemistry (SDH-EHC), confocal microscopy of vessel architecture, and HIF1α staining were performed in pre- and posttreatment biopsies to assess the pharmacodynamics, vessel normalization, and tissue re-oxygenation by bevacizumab, respectively.ME-344 displayed significant biological activity versus placebo: compared with a 186% increase in Arm B, Ki67 decreased by 23.4% from days 0 to 28 in Arm A (P < 0.001) (N = 42 patients). FDG-PET predicted vascular normalization in about one-third of the patients in each arm, which was confirmed using confocal microscopy and HIF1α staining. In the subgroup with vascular normalization, ME-344 induced a Ki67 decrease of 33.4% (placebo: 11.8 increase). SDH-EHC suggested on-target effects of ME-344.ME-344 has significant biological antitumor activity in HER2-negative breast cancer, particularly after induction of vascular normalization and tissue reoxygenation with bevacizumab.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
ME-344 ME-344 is an isoflavone derivative which interferes with mitochondrial energy production in tumor cells resulting in caspase-independent cell death (PMID: 25411085, PMID: 31597662).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Her2-receptor negative breast cancer not applicable ME-344 Phase 0 Actionable In a Phase 0/I trial, addition of ME-344 to Avastin (bevacizumab) treatment resulted in a 23.4% decrease of Ki67 in treatment-naive patients with early-stage Erbb2 (Her2)-negative breast cancer, compared to a 186% increase in the placebo arm (PMID: 31597662; NCT02806817). 31597662