Novel first-in-class small molecule targeting APE1/Ref-1 to prevent and treat chemotherapy-induced peripheral neuropathy (CIPN).

Abstract

229 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is an acute and chronic debilitating side effect of a number of chemotherapeutic agents lacking FDA-approved interventions or strategies resulting in dose-limiting neurotoxicity. CIPN can persist following discontinuation of the drug with up to 40% of patients having continued CIPN five years after treatment ends. Thus, CIPN directly affects cancer survivorship, quality of life, and may limit future treatment options if cancer recurs. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage caused by anticancer therapies could contribute to the neuropathy. Methods: Using an experimental model of isolated sensory neurons in culture, we established a causal relationship between cancer-therapy-induced neurotoxicity and DNA damage and repair. Results: Genetically reducing the activity of APE1 increased the neurotoxicity produced by platin treatment, whereas augmenting the activity of APE1 lessened neurotoxicity. Furthermore, using a targeted small-molecule, APX3330, which increases DNA repair of APE1 in neurons, it lessened neurotoxicity using a variety of endpoints ex vivo; e.g. DNA damage, CGRP release. We will present data using animal models of CIPN demonstrating a protective effect of APX3330 using either cis- or oxaliplatin without diminishing the anti-tumor effect of the platins. A Phase 1 clinical trial for safety/RF2D for APX3330 has completed (NCT03375086). Conclusions: Effective prevention and management of CIPN hinges on understanding its pathophysiology. While multiple causal mechanisms may be at work, we believe that the induction of oxidative DNA damage in sensory neurons is a major cause of CIPN. Thus, enhancement of oxidative DNA damage repair by APX3330 results in reduction of CIPN.