Therapeutic targeting of the tumor microenvironment in triple negative breast cancer patients at high risk of relapse and preclinical models of lung metastases

Our long-term goal is to significantly improve outcome for patients (pts) with triple negative breast cancer (TNBC). Tumor generated microenvironments in distal target organs provide hospitable sites (“pre-metastatic niches”) that support metastatic colonization and outgrowth. Bone marrow-derived progenitor cells including VEGFR2+ EPCs and VEGFR1+ HPCs, copper (Cu) dependent lysyl oxidase (LOX) and collagen re-modelling constitute underlying metastasis-supporting features of the pre-metastatic niche. Our central hypothesis is that Cu depletion using tetrathiomolybdate (TM) prevents relapse by disrupting three key aspects of metastasis: (1) cancer cell intrinsic mitochondrial bioenergetics that mediates invasion/metastasis/chemoresistance, 2) the “pre-metastatic niche” that supports colonization, and outgrowth of disseminated metastatic tumor cells, and (3) stromal remodeling that promotes immune evasion and immunotherapy resistance. Strikingly, results from our phase II trial of TM in 75 breast cancer (BC) patients at high risk for relapse showed TM decreased VEGFR2+EPCs, reduced circulating LOX levels by > 50% and normalized the collagen microenvironment. Importantly, TM was well tolerated, and relapses were rare past four years on study. The objective of this proposal is to test this hypothesis by conducting a small phase Ib trial of adding 3 years of adjuvant TM to standard 6 months treatment of adjuvant capecitabine and pembrolizumab in high risk for relapse TNBC (RCB 2, 3, risk for relapse >60% at 5 years) after completion of neoadjuvant therapy and surgery to establish the safety of the combination followed by a randomized phase II clinical trial of adjuvant TM and capecitabine vs capecitabine alone. If pembrolizumab was administered in the neoadjuvant setting, it may be continued in the adjuvant setting per investigator discretion. The primary endpoint is the effect of the addition of TM on distant relapse-free survival (DRFS). Secondary endpoints include: (a) Overall Survival (OS) and invasive disease-free survival (iDFS) between the two arms, (b) safety and tolerability of TM, (c) OS and iDFS in patients that complete at least 6 months of TM (d) VEGFR2+ EPCs, LOXL2, ctDNA, (e) Patient-reported quality of life (PROs) and (f) Pharmacokinetics in a sub-study cohort of patients (AIM 1). AIM 2 exploratory translational endpoints include the effect of TM on single nucleotide polymorphisms of ceruloplasmin, and CTR1 on the ability to Cu-deplete pts, the influence of ATOX1 and collagen biomarkers (C1M, ProC3 and C6M) on DRFS and OS and the effect of copper depletion on immune biomarkers and the metabolic profile of a selected cohort of patients enrolled in the trial.