Mechanisms of Copper Depletion in TNBC Metastasis- From Bedside to the Bench
Project Investigators: Vivek Mittal, Claudia Fischbach
Additional Collaborators: Linda Vahdat (Weill Cornell Medicine) Noah Elias Dephoure (Weill Cornell Medicine)
Triple-negative breast cancer (TNBC) patients exhibit the worst outcome due to high rates of metastasis compared to non-TNBC. There are currently no specific TNBC-directed therapies in the adjuvant, neoadjuvant or metastatic setting. Recently, metals have emerged as promising and viable therapeutic targets for a new generation of anticancer and anti-metastatic agents . Particularly, copper (Cu), an essential trace element serves as an important catalytic cofactor in several biological functions, and increased Cu uptake by malignant cells , makes Cu a prospective target for developing novel anti-cancer therapeutics. In this context, we recently published results of a successful Phase 2 pilot clinical trial of an oral Cu-chelator, Tetrathiomolybdate (TM) [3-5], in >70 patients with high risk for recurrent breast cancer (BC). The efficacy of TM was demonstrated, as with an overall median follow-up time of 6.3 years, the event free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% and 84%, respectively , which is a significant advance as previous studies  have shown 50% EFS for stage 3 and <5% OS for Stage 4 patients. Currently, a major challenge in advancing TM into larger randomized trials is the lack of a mechanistic understanding of drug action. Therefore, to determine the cellular and molecular mechanisms governing therapeutic efficacy of Cu depletion in TNBC metastasis, we propose studies using a combination of TNBC organoids and preclinical models. Our recent preclinical finding showed that TM abrogated Cu binding protein lysyl oxidase (LOX) in pre-metastatic lungs, resulting in diminished collagen crosslinking and impaired metastasis . Consistent with the preclinical findings, circulating LOX was found to be reduced in patients that were copper depleted in the trial. Recently, we have demonstrated that TM also impacts Cu binding protein, MEK1/2 , and impacts the ERK signaling in metastatic BC cells. Together, these findings have led to the hypothesis that TM-mediated Cu-depletion suppresses two key aspects of metastasis: cancer cell intrinsic signaling pathways that support invasion/proliferation; and the “pre-metastatic niche” that supports colonization, and outgrowth of disseminated metastatic tumor cells.