Evaluation of novel therapies to prevent CIPN

Abstract

Many patients with cancer are now effectively and commonly treated with chemotherapeutic agents. However, chemotherapies may cause chemotherapy-induced peripheral neuropathy (CIPN), which is problematic, treatment-induced toxicity that can impact the quality of life for cancer patients. Currently, limiting the doses of potentially curative therapy is the only approach to reduce this toxicity, as there are no effective therapies to prevent or treat CIPN. Previous studies provide information on mechanisms that contribute to CIPN; these include activation of Sarm-1, a TIR domain-containing molecule, and reduction in an anti-apoptotic protein Bcl-w. Sarm1 activation produces cADPR to increase intra-axonal Ca2+; while Paclitaxel causes a decrease in axonal Bclw and thereby triggers IP3R1-dependent Ca2+ release. The resultant increase in axonal Ca2+ activates calpain, leading to axon degeneration and ultimately CIPN. To develop new therapeutics for CIPN, we tested whether the neuropathy of CIPN can be uncoupled from the therapeutic benefit of paclitaxel in vivo. We evaluated whether two approaches: SARM1 inhibitor DSRM3716 and Bcl-w mimetic SAHB-12 (Stapled Alpha Helical BH domains) can prevent axon degeneration without affecting the beneficial effects of chemotherapy on tumor progression. As patients with breast cancer are particularly impacted by this side effect, we used an immune-competent mouse model with paclitaxel-susceptible breast cancer to test new potential therapies. As the behavioral effects of CIPN are difficult to assess in tumor-bearing mice due to tumor-associated pain, in parallel experiments we treated normal C57B6J mice with the proposed anti-CIPN therapies or with vehicle control after every two paclitaxel or vehicle injections and monitor behavior, by testing responses to Von Frey filaments and to heat. Our results demonstrated that SARM1 inhibitor is an effective therapy and may not interfere with the immediate anti-tumor effect of paclitaxel. We also revealed the fact that SARM1 may regulate macrophage infiltration in CIPN in vivo.