25 Feb Personalized Medicine: Gene Predicts Neuropathy from Vincristine Chemotherapy
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Evans: We are currently curing over 85 percent of children with acute lymphoblastic leukemia (ALL), the most common cancer in children. While we continue to focus on pushing cure rates closer to 100 percent through the development of new treatments, we are also increasingly focused on reducing the acute and chronic side effects of treatment. This is important to improve the quality of life for patients during treatment and as they become adults after being cured, because some side effects can persist for decades after treatment is completed.
One of the medications that every child with acute lymphoblastic leukemia received 30-40 times during their 2+ years of treatment is vincristine. The major side effect of vincristine is peripheral neuropathy (about 25 percent of patients develop this side effect), which can cause loss of sensation, numbness, neuropathic pain and alter their motor skills including manual dexterity, balance and ability to walk properly. This can have very practical consequences, such as writing, using a smart phone, and the use of eating utensils. It can also alter their gait.
Our main finding is we discovered that an inherited variant of the CEP72 gene enhanced the risk and severity of vincristine neuropathy in two groups of patients we studied. Those children who inherited two copies of the high-risk CEP72 gene (one from each parent, about 16 percent of patients) had a significantly higher likelihood (about 3.5-fold) of developing vincristine neuropathy and had a more severe form of neuropathy (about 2.5-fold higher severity).
The CEP72 gene encodes a protein essential for normal microtubule formation in cells—a critical process for cell division. Vincristine inhibits this same cellular process. The inherited form of CEP72 that increases the risk and severity of vincristine neuropathy is associated with lower expression of the CEP72 protein. When coupled with vincristine treatment, CEP72 increases a cell’s sensitivity to vincristine. We were able to reproduce this in the laboratory by lowering CEP72 expression in human neurons made from induced pluripotent stem cells and in human leukemia cells, increasing the sensitivity of both to vincristine. We also showed that the leukemia cells from patients who inherited two copies of the CEP72 risk allele were more sensitive to vincristine, suggesting it may be possible to treat these patients with a lower dose of vincristine to reduce their neuropathy without compromising the treatment of their leukemia—a possibility we plan to test in our next clinical trial at St. Jude.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Evans: If reproduced in additional patients, this finding may lead to a diagnostic test to identify those patients at the highest risk of vincristine-induced neuropathy. If future studies show that these patients can be safely treated with a lower dosage of vincristine to reduce this toxicity without compromising the anticancer effects of vincristine, this may offer a strategy to individualize—personalize—vincristine treatment. We have used this strategy successfully with other medications used to treat leukemia (e.g., adjusting mercaptopurine dosages in patient who inherit TPMT deficiency), which has led to a marked reduction in side effects from mercaptopurine without compromising the efficacy to curative ALL treatment.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Evans: Because vincristine is also used to treat acute lymphoblastic leukemia in adults in addition to many solid tumors in children and adults, it will be important to determine if this inherited difference in CEP72 also influences vincristine neuropathy in those patients. Likewise, if we find that the CEP72 genotype enhances the sensitivity of solid tumors to vincristine, as it does for leukemia, this would offer a strategy to treat these patients with a lower dosage to reduce toxicity without compromising treatment effectiveness. Our upcoming study to assess this strategy in children with acute lymphoblastic leukemia will be an important next step in moving toward personalized therapy based on each patient’s CEP72 genotype.
Association of an Inherited Genetic Variant With Vincristine-Related Peripheral Neuropathy in Children With Acute Lymphoblastic Leukemia
MedicalResearch.com Interview with: William E. Evans, Pharm.D. (2015). Personalized Medicine: Gene Predicts Neuropathy from Vincristine Chemotherapy