Digoxin as an inhibitor of global hypoxia inducible factor-1α (HIF1α) expression and downstream targets in breast cancer: Dig-HIF1 pharmacodynamic trial.

TPS1144 Background: Unlike normal cells, tumor cells thrive in a hypoxic microenvironment, and intratumoral hypoxia correlates with increased tumor invasiveness, metastasis, and poor prognosis in cancer. The hypoxic microenvironment is primarily mediated through HIF1α, a transcription factor for over 200 genes involved in cellular metabolism, proliferation, and angiogenesis. In pre-clinical models, cardiac glycosides, including digoxin, act as potent inhibitors of HIF1α protein synthesis and expression of HIF1α target genes (Zhang et al, PNAS 09). Methods: Trial design: The proposed study is a randomized, controlled, two arm, pre-surgical study. Eligible patients include women with stage I-III carcinoma of the breast scheduled to undergo definitive surgery, tumor size ≥ 1cm, grade 2/3 or Ki-67 ≥ 10%, normal organ function, and no known cardiac arrhythmias. Participants will receive oral digoxin daily, or no therapy, for 14 days (±4 days) prior to scheduled surgery. Trial Objectives: 1) To evaluate whether daily oral digoxin therapy, as compared to no study drug, reduces HIF1α expression by IHC and mRNA or its target genes (VEGF, CA-9, and GLUT1) in breast cancer tissue. 2) To evaluate whether daily oral digoxin therapy, as compared to no study drug, reduces levels of serum VEGF & PAI-1, reduces tissue Ki-67 expression, and modulates proteomic profiles of breast cancer tissue. 3) To assess safety and tolerability of digoxin therapy in the pre-surgical setting. Statistical methods: The primary hypothesis is that 2 weeks of digoxin therapy will reduce the level of HIF1α expression in breast cancer tissue assessed by pathologists blinded to the treatment assignment. Our preliminary study shows the mean HIF1α expression level is 2.43. A 33% reduction would be considered clinically relevant. Allowing for up to 20% attrition, a total sample size of 64 will provide more than 85% power to detect 33% reduction with a two-sided significance level of 0.05. Target accrual: 64 (32 each arm). Funding and Acknowledgement: Dept. of Defense, Commonwealth Foundation, ASCO YIA. Contact Person: Dr. Vered Stearns, Email: vstearn1@jhmi.edu .ClinicalTrials.gov Identifier: NCT01763931. Clinical trial information: NCT01763931.