Randomized Phase 0/I Trial of the Mitochondrial Inhibitor ME-344 or Placebo Added to Bevacizumab in Early HER2-Negative Breast Cancer
| Autor: | Miguel Quintela-Fandino, Juan Antonio Guerra, Juan V. Apala, María Gion, Francisca Mulero, Antonio Lopez-Alonso, Alfonso Cortés-Salgado, Diego Malón, Manuel Muñoz, Javier Cortes, Ariadna Gasol Cudós, Serafin Morales, Joel Salla Fortuny, Eduardo Caleiras, Luis Manso, Silvana Mouron |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
0301 basic medicine Cancer Research medicine.medical_specialty Bevacizumab Receptor ErbB-2 Urology Breast Neoplasms Placebo law.invention 03 medical and health sciences 0302 clinical medicine Breast cancer Randomized controlled trial Fluorodeoxyglucose F18 law Antineoplastic Combined Chemotherapy Protocols medicine Humans Aged Neoplasm Staging Aged 80 and over business.industry Middle Aged Hypoxia (medical) medicine.disease Isoflavones Mitochondria Succinate Dehydrogenase Clinical trial Ki-67 Antigen Treatment Outcome 030104 developmental biology Oncology Positron-Emission Tomography 030220 oncology & carcinogenesis Pharmacodynamics Female Patient Safety Radiopharmaceuticals medicine.symptom Energy source business medicine.drug |
| Zdroj: | Clinical Cancer Research. 26:35-45 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: 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. Patients and Methods: 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. Results: 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. Conclusions: ME-344 has significant biological antitumor activity in HER2-negative breast cancer, particularly after induction of vascular normalization and tissue reoxygenation with bevacizumab. |
| Databáze: | OpenAIRE |
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