Chemotherapy-induced peripheral neuropathy (CIPN) is a devastating consequence of cancer treatment regimens that include neurotoxic chemotherapeutic agents such as cisplatin. CIPN is one of the most common, serious side effects that can lead to dose reductions or early discontinuation of chemotherapy, reducing the efficacy of cancer treatments and significantly impacts the quality of life of the patients due to debilitating neurological symptoms such as pain, tingling sensation, numbness and weakness. Despite the high prevalence and severity of CIPN, currently there is no effective treatment to prevent or reverse CIPN mainly due to the limited understanding of the pathogenic mechanism of CIP...

Read More

Chemotherapy-induced peripheral neuropathy (CIPN) is a devastating consequence of cancer treatment regimens that include neurotoxic chemotherapeutic agents such as cisplatin. CIPN is one of the most common, serious side effects that can lead to dose reductions or early discontinuation of chemotherapy, reducing the efficacy of cancer treatments and significantly impacts the quality of life of the patients due to debilitating neurological symptoms such as pain, tingling sensation, numbness and weakness. Despite the high prevalence and severity of CIPN, currently there is no effective treatment to prevent or reverse CIPN mainly due to the limited understanding of the pathogenic mechanism of CIPN and, therefore, the development of therapeutics is desperately required for improving quality of life in cancer patients and survivors as well as enhance the therapeutic effectiveness of chemotherapy. Based on the previous studies, we develop a hypothesis that the induction of cell cycle activity in dorsal root ganglion sensory neurons, the main cell type affected by chemotherapeutic agents, is a key mechanism causing neurotoxicity in cisplatin-induced CIPN and, thus, targeting this mechanism may provide an effective therapeutic opportunity. Our proposed experiments will rigorously test the hypothesis and therapeutic potential by developing a novel transgenic mouse model and previously well-characterized pharmacology grade cell cycle inhibitors. Both inhibitors have been developed for cancer treatment and their antitumorigenic effect has been confirmed in multiple preclinical and clinical studies. These inhibitors, therefore, would not interfere with the therapeutic effects of chemotherapy when they are used as a combinatorial therapy, indicating the feasibility of our approach for the treatment of CIPN. Thus, the completion of our studies will reveal the pathological mechanism of CIPN and, furthermore, would provide a viable therapeutic approach for CIPN.

Read Less