A specific genetic variant of the VAC14 gene may be involved in the development of peripheral neuropathy following taxane administration, a group of drugs commonly used for breast, ovary, lung, or prostate cancer treatment.
The findings were described in the study “Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of VAC14 Polymorphism That Increases Risk of Docetaxel-Induced Neuropathy,” and published in the journal Clinical Cancer Research.
Periphery neuropathy is a condition that develops as a result of damage to the peripheral nervous system (the vast network of nerve cells that transmit information between the brain and the remaining parts of the body) and is a common side effect of taxane treatment. Patients who experience this condition suffer from muscle weakness, numbness, and become abnormally sensitive – often feeling pain in response to a stimulus that does not cause pain.
To prevent unnecessary toxicity and maximize taxane efficacy, researchers at the Moffitt Cancer Center, in Tampa, Fla., studied specific mutations that could predict a patient’s risk of experiencing neuropathy induced by taxane treatment, allowing for a more personalized treatment.
The investigators analyzed the DNA of 623 men who had castrate-resistant metastatic prostate cancer and participated in a randomized Phase 3 trial that included docetaxel in the treatment regimen, in order to identify genetic variations known as single nucleotide polymorphism (SNP) – a type of mutation in which a single nucleotide is switched by another. The authors found that 8% of the study’s participants experienced grade 3-plus neuropathy, and they identified a specific SNP in the VAC14 gene that was highly associated with peripheral neuropathy development upon docetaxel administration.
To confirm the association, the research team knocked down VAC14 with an RNA silencing approach in peripheral neuronal cells. The results demonstrated that VAC14 depleted neurons were more sensitive to docetaxel, as measured by reduced neuronal branches, suggesting that the VAC14 genetic variant should be further validated as a potential risk factor for docetaxel-induced neuropathy and to determine if patients should be referred for individual treatment.
“The genetic variant of VAC14 identified in this study could be useful for understanding the mechanism of docetaxel-induced neuropathy and may be informative for avoiding docetaxel treatment in patients at elevated neuropathy risk,” said Howard McLeod, medical director of the DeBartolo Family Personalized Medicine Institute at Moffitt, in a press release. “This also offers new drug development strategies to improve the outcomes for cancer patients.”