ME-344 in Early HER2-negative Breast Cancer With Antiangiogenic-induced Mitochondrial Metabolism

Antiangiogenic agents are the most widely used biologic agents in oncology and are approved by the Food and Drug Administration (FDA) for use against many different malignancies based on the results of several randomized phase III trials. However, acquired resistance to antiangiogenics is a major problem in cancer therapeutics. Some signaling nodes have been implicated in therapeutic resistance in preclinical studies. However, a global tumor-reprogramming interrogation based on changes in the delivery of oxygen and nutrients has not been undertaken. The findings link acquired resistance to a powerful anticancer drug class with aberrant cancer metabolism. Under selective pressure, tumor plasticity allows sustained tumor growth in the long term despite exposure to antiangiogenic TKIs, and it renders mitochondrial metabolism essential for survival When one energy source (glycolysis) is pharmacologically limited, the tumors become vulnerable to the inhibition of the other (mitochondrial metabolism). Pharmacological blockers of the nutritional stress regulators can abrogate mitochondrial respiration and tumor growth in this situation, which the investigators have termed "metabolic synthetic lethality". The investigators hypothesized that in cases in which antiangiogenics lead to hypoxia normalization, chronic high-rate glycolysis is offset and tumors might switch to an alternative metabolic source. If this source is essential for tumor survival, it would open a therapeutic opportunity. The administration of ME-344 in animals where antiangiogenics have induced a mitochondrial phenotype seems promising. The investigators aim to extend these observations in humans. However, several questions remain, prior to launch a large trial: * Which percentage of patients experience a mitochondrial shift when exposed to a given antiangiogenic. * In case this happens, whether it is possible to trace this response accurately. * What is the benefit of adding ME-344 in those cases showing the mitochondrial shift, and what is the benefit, if any, of adding it in the remainder cases. For that purpose, investigators will conduct a pilot randomized phase 0 trial, where a cohort of patients will be treated with a single bevacizumab dose prior to surgery and a second cohort with bevacizumab plus ME-344. The purpose of this clinical trial is to evaluate if the addition of ME-344 to antiangiogenic agents in the cases where the mitochondrial phenotype has been induced will enhance antitumor activity.