A microtubule centric approach to tackling Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) occurs as a serious side effect to treatment using antineoplastic agents, often forcing discontinuation of an otherwise successful therapy.

Despite decades of work on drug development, and the availability of several drugs with different modes of action, CIPN continues to be a vexing problem.

A major reason for this is our lack of mechanistic understanding of the nerve degeneration process, which involves cytoskeletal, mitochondrial, and ion-channel gating dysfunctions.

CIPN sets in from the longest of axons that innervate the limbs, suggesting that the axonal microtubule skeleton, which is responsible for long-distance transport, may be a causative element in the degeneration pathway.

Given that many chemotherapeutic drugs target microtubules, we thus hypothesize that CIPN originates from perturbations of microtubule homeostasis.

Based on the recent demonstration that alterations to post-translational modifications (PTMs) of microtubules induce peripheral nerve degeneration, we will now determine the role of these PTMs in CIPN.

The mechanistic understanding we gain from this work will also be used to develop novel assays which will enable better screening of drugs for their potential to cause CIPN.

If PTM do indeed modulate CIPN, drugs targeting tubulin-modifying enzymes may provide novel strategies to alleviate CIPN.