Molecular Strategies to Block Peripheral Neuropathy in Mouse Models of Vincristine Neurotoxicity
Martha Bhattacharya, Ph.D.
- McDonnell Pediatric Cancer Center
2/1/2012 - 7/31/2014
Pediatric brain cancer patients are routinely prescribed chemotherapy including the drug vincristine. While vincristine is effective in disrupting cell division and halting tumor growth, it comes with the serious side effect of peripheral nerve damage. This damage can cause loss of motor and sensory function as well as intense pain. Nerve damage from vincristine occurs because this drug interferes with the axonal compartment of neurons, causing these axons to swell, fragment, and ultimately degenerate. We have identified a number of critical molecular pathways used by vincristine and other chemotherapy drugs to cause axonal damage. An exciting possibility is that inhibiting one or more of these newly discovered axonal degeneration pathways during vincristine treatment will mitigate the toxic effects of vincristine on peripheral nerves. For proteins without known effector pathways, we will investigate their mechanism in order to identify steps amenable to inhibition. For more well-studied proteins, we will test available, clinically-tested inhibitors in mouse models of peripheral neuropathy to assess whether these agents might be put to use concurrently with chemotherapeutics to protect nerves. This work will enhance our mechanistic understanding how peripheral neuropathy develops in pediatric and adult cancer patients following exposure to chemotherapy drug and how this can be prevented. Since the timing of vincristine administration to pediatric cancer patients is known in advance and the neuronal insult is transient, treatment to block axonal degeneration would hold great promise. These results could be applied to the care of cancer patients within the next 5 – 10 years.