Pharmacogenetics of Chemotherapy-Induced Peripheral Neuropathy

Anticancer therapies are commonly prescribed for breast cancer and other solid tumors. While cytotoxic agents are therapeutically efficacious in treatment of many cancers, they often lead to significant toxicities. One of the main non-hematological dose-limiting toxicities for cytotoxic chemotherapies is sensory peripheral neuropathy. Currently, there are no effective therapeutic strategies to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN) due to the lack of understanding in the mechanisms underlying patient susceptibility. This dissertation presents a pharmacogenetic approach to aid in the identification of critical genetic networks that may explain the development of CIPN. With the use of genome-wide association studies conducted from clinical samples of breast cancer patients treated with microtubule-targeting agents, we highlighted the role of sphingosine lipid signaling in microtubule-targeting agent (MTA)-induced peripheral neuropathy (PN). Functional studies using human sensory neurons derived from induced pluripotent stem cells show that inhibiting such pathway attenuates paclitaxel-induced neuronal injury. Additional genes also involved in Rho GTPase signaling were further revealed from a next-generation exome sequencing study on patients treated with MTA chemotherapy. Future efforts are needed to explore how disruption in this signaling pathway develops on the molecular level and subsequently leads to manifestation of CIPN. While these studies have focused on revealing insights of the pathophysiology underlying CIPN, we also investigated the use of early patient-reported symptoms and genome-wide data for the prediction of dose-limiting neuropathy events. We show that early patient-reported outcomes can be used as a tool to predict risk for dose-limiting toxicity events. Future studies aimed at determining whether other types of genomic and clinical information may help improve such predictions. Together, the work presented herein provide novel insights to mechanisms underlying the development of CIPN in efforts to discover novel strategies for CIPN prevention and treatment