Isoquercetin as a PDI inhibitor: dose-optimization and patient phenotyping

Sloan-Kettering Inst Can Research, New York NY

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Dietary flavonoid ingestion has been linked with a reduction in cardiovascular events. We previously made the serendipitous finding that a specific class of flavonoid quercetins inhibits protein disulfide isomerase (PDI). PDI is an oxidoreductase that is important for protein folding in the endoplasmic reticulum. However, when released into the extracellular environment, PDI promotes thrombus formation. Over the past decade, we studied the use of flavonoid quercetins to target PDI in the context of thrombosis. Our experiments have spanned atomic resolution studies evaluating structural elements of the flavonoid-PDI interactions to cell-based assays to preclinical models to human studies. Recognizing the unmet need to develop an antithrombotic agent that is well tolerated and does not increase the risk of hemorrhage, we focused the clinical development of isoquercetin in patients with cancer at high risk for developing venous thromboembolism. We previously conducted a phase 2 trial in patients with advanced cancer and observed a significant reduction in circulating plasma D-dimer consistent with antithrombotic activity. However, before proceeding with a definitive phase 3 trial, we acknowledge critical gaps in the data package. Importantly, based on recent pharmacodynamic modeling, we remain uncertain of the optimal dosing schedule, as we currently believe that isoquercetin 1000 mg twice daily is preferred rather than the previous phase 2 dosing schedule of 1000 mg once daily. We also identified different prothrombotic mechanisms specifically in cancer, which we believe can identify patients with cancer who are likely to benefit most from primary thromboprophylaxis with isoquercetin. Our aims in this study are 1) to determine the optimal isoquercetin dosing based on target PDI inhibition utilizing a PDI-sensitive thrombin generation assay in patients with ovarian cancer, a group particularly at risk for thrombosis; and 2) to identify which hypercoagulable phenotypes of cancer are most amenable to PDI inhibition, and thus aiming to tailor treatment more effectively and advance a personalized approach to thromboprophylaxis in cancer care. In summary, this study seeks not only to refine isoquercetin therapeutic dosing schedule but also explore function- activity relationships of isoquercetin in specific hypercoagulable contexts, thereby enabling a phase 3 trial to develop a more targeted, safe, and effective approach toward prevention of cancer-associated thrombosis.