Damage-associated molecular patterns in chemotherapy toxicity

Paclitaxel, one of the most widely used antineoplastic drugs, is highly effective in treating a variety of solid tumors, including breast and non-small cell lung cancer (NSCLC). However, the clinical use of paclitaxel is limited by the development of dose-limiting paclitaxel-induced peripheral neuropathy (PIPN) by most cancer patients who receive paclitaxel. Unfortunately, current strategies to prevent or treat PIPN are ineffective, and our understanding of the molecular mechanisms underlying PIPN remains incomplete. In addition to directly damaging neurons within the dorsal root ganglia (DRG), the site of injury for PIPN, paclitaxel also induces neuroinflammation and the recruitment of immune cells to the DRG, which has recently emerged as a key driver of PIPN; however, druggable targets within this cascade have remained elusive. In pursuit of our long-term goal to decrease adverse events associated with paclitaxel, we have identified S100A9, an inflammatory damageassociated molecular pattern (DAMP) with readily available pharmacologic inhibitors, as a candidate target to reduce PIPN and neuroinflammation. In preliminary studies, we found that mice treated with paclitaxel developed a PIPN-like phenotype and had upregulated S100A9 in their DRG. Functional validation studies in S100A9deficient and matched wild-type (WT) mice demonstrated that S100A9 deficiency protected mice from neuropathy in both acute and chronic models of PIPN. Next, to elucidate whether the protection conferred by deficiency of S100A9 is related to neuroinflammation involving immune cells recruited from the bone marrow, we performed allogeneic transplant experiments and found that only mice with S100A9-deficient bone marrow were protected from PIPN. To provide proof-of-principle and demonstrate the translational relevance of this target, we found that multiple pharmacological inhibitors of S100A9 also protected against PIPN without affecting paclitaxel’s plasma levels or its cytotoxic potential against multiple breast cancer cell lines. Based on these preliminary findings, we now outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted inhibition of S100A9 can reduce paclitaxel’s toxicity and downstream neuroinflammatory cascade without negatively influencing its plasma pharmacokinetic profile or antitumor properties: (i) characterize the mechanism underlying S100A9-induced PIPN, with an emphasis on neuroimmune interactions; (ii) determine an optimal regimen to pharmacologically inhibit S100A9 and prevent PIPN utilizing PK-PD modeling; (iii) safety, toxicokinetic, and efficacy analyses of an optimized combinatorial regimen of paclitaxel and a pharmacologic S100A9 inhibitor with simultaneous assessment of protection from PIPN and antitumor properties in established experimental models of breast cancer and NSCLC. It is expected that these studies will shed new light on the etiology of PIPN and provide a rationale for the future implementation of a novel targeted intervention strategy to prevent this debilitating side effect.