Pilot Study To Investigate Targetable Metabolic Pathways Sustaining Triple Negative Breast Cancer

Overview

The primary objective is to describe and discover new insights into the glucose, amino acid, and lipid metabolic dependencies of TNBC via nuclear magnetic resonance (NMR) spectroscopy analysis of in vivo \[1,2-13C\] glucose-labeled breast cancer biopsies. The secondary objectives are to correlate the dominant metabolic dependencies of TNBCs with pathologic response to preoperative chemotherapy, and with the cancers' molecular signaling pathways assessed via NGS and RPPA.

One of the recognized hallmarks of cancer cells is deregulated cellular metabolism, characterized by enhanced metabolic autonomy compare with non-transformed cells. Tumor cells typically display an overall increase in glucose metabolism, associated with enhanced aerobic glycolysis and decreased oxidative phosphorylation, accompanied by a requirement for a high rate of protein, nucleotide, and fatty acid synthesis to provide the raw materials for cell division. 13C-glucose is a non-radioactive stable isotope tracer that has been widely used in vitro, in vivo, and in patients in a variety of disease settings to study glucose, amino acid, and lipid metabolism, at steady state and following intervention. \[1,2-13C\] glucose can provide additional information on the activity of the oxidative pentose phosphate pathway versus glycolysis. Administration of intravenous 13C-glucose is a convenient and affordable approach to analyzing the metabolomics of human cancers in their native microenvironments. The metabolic dependencies of the various breast cancer subtypes are poorly understood. Importantly, in depth analyses of the in situ metabolic processes utilized by triple-negative breast cancers (TNBCs) using state-of-the-art in vivo \[1,2-13C\]-glucose infusions in patients with TNBC has never been done. In TNBC, oncogenic activation of key signaling pathways leads to altered metabolic programming resulting in an increased dependence on exogenous nutrients such as glucose and glutamine. These data further suggest a hypothesis that TNBCs may employ a cellular mechanism called macropinocytosis to ingest and degrade interstitial albumin to accumulate glutamine. This process may then be exploited for therapeutic gain through enhanced uptake by cells that utilize macropinocytosis to meet their metabolic requirements. In this study, administration of \[1,2-13C\]-glucose to patients with TNBC will be done prior to patients undergoing a biopsy of their breast cancer as well as blood sample collection which will allow for in depth evaluation of glycolysis as well as lipid and amino acid metabolism by Joshua Rabinowitz, PhD, at Princeton University who is an international expert in cancer metabolomics. RAS and PI3K pathway and other genomic alterations as well as pathway activation status will be determined by next generation sequencing (NGS) and by reverse phase protein array (RPPA), and will be correlated with the metabolic findings, and both will be assessed in the context of the patients' response to standard preoperative chemotherapy.

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Locations (1)

Outcomes