Investigating the Pathogenic Role of Tubulin Post-translational Modifications in CIPN

SUMMARY Chemotherapy induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of oral or intravenous chemotherapy. Approximately 50–90% of patients under chemotherapy are affected by CIPN and bear a high risk of chronicity (approx. 30–40%). Limited symptomatic relief is provided by opioid analgesics, antidepressants, or anticonvulsants. Unfortunately, the pathogenesis of CIPN is still largely unknown. Several different classes of anticancer drugs acting through different antineoplastic mechanisms can induce CIPN. However, sensory impairment is always either the only or predominant adverse effect, suggesting the existence of a common mechanism of pathogenesis. Tubulin is the building block of microtubules and a well-established target for multiple anticancer drugs that can promote CIPN. The contribution of tubulin changes to the onset of CIPN is not well understood but is strongly implicated as the determining factor. Tubulin and microtubules play crucial roles in sensory neuronal functions including the distribution of cargos to distal regions of the nerve, TRP channel activity and regulation of mitochondrial dynamics. The overall hypothesis of this proposal is that CIPN-promoting drugs may share an underlying mechanism of pathogenesis based on modulation of tubulin post-translational modifications at a prodromal stage of the disease. We will further evaluate whether accumulation of delta-2 tubulin, an irreversible modification of a-tubulin, which we recently found to mediate axonal degeneration by the anti-cancer drug bortezomib, plays a common pathogenic role in the neuropathic damage inflicted by unrelated CIPN-promoting drugs. Finally, we will examine the contribution of mitochondrial and TRP channel dysfunction in the axonopathy induced by accumulation of D2 in DRG neurons. Our proposal is based on our published data and the development of robust cellular and preclinical models of CIPN generated by an ongoing collaboration between the PI and Dr. Yalda Moayedi, a co-investigator on this application. Collectively, our studies will provide mechanistic insights into a unifying model of pathogenesis for the development of CIPN based on tubulin modifications and will directly examine the unexplored potential for tubulin-modifying enzymes in drug therapies aimed at preventing axonal injury and neuropathic pain in CIPN. They will also pave the way to analyze the pathogenic role of modified tubulin in the onset of other chemotherapy-related adverse sequelae such as nephrotoxicity or ototoxicity as well as idiopathic or inherited forms of peripheral neuropathy in addition to CIPN.