Toxic Toll

Ph.D. Candidate's Study Shows Persistent Gut Toxicity from Newer Breast Cancer Chemotherapy Drug

December 16 — A UH College of Pharmacy Ph.D. candidate's study indicating persistent gut toxicity associated with use of a breast cancer chemotherapy drug approved three years ago was recognized with a Best Abstract Award from the Lone Star Regional Chapter of the Society of Toxicology. 

The project by Ph.D. candidate Gabriel Tao, working under the supervision of Associate Professor Romi Ghose, Ph.D., was focused on the pan-HER tyrosine kinase inhibitor drug neratinib, which received FDA approval in 2017 for HER2-positive breast cancer treatment. During the drug's phase III clinical trial, approximately 96 percent of patients reported experiencing diarrhea. In addition, subsequent retrospective studies by other researchers have indicated that the drug didn't have a significant impact on quality of life and its use was not cost effective based on side effects and economic costs. 

Tao's work was carried out using mouse models divided into an undosed control group, a second group receiving an oral dose of neratinib once daily for 18 days, and a third group receiving the same oral dose once daily for 12 days. In the latter two groups, persistent gastrointestinal damage in the form of intestinal ulcers, damage to the projections of the intestinal lining where nutrients are absorbed, and inflitration of inflammatory cells into the colon.

Further analysis revealed an increase in proinflammatory cytokines — small molecule enzymes involved in cell signaling — and a reduction in the expression of a key enzyme involved in the metabolism of the drug. These factors contribute to accumulation of the drug in the GI tract and high risk of diarrhea in patients.

Tao was originally scheduled to present his project at the 2020 Society of Toxicology 59th Annual Meeting & ToxExpo in March, with the support of a SOT Graduate Student Travel Award, but the meeting was later converted to virtual format due to concerns over the COVID-19 pandemic. In addition, he was invited to co-chair one of the poster sessions, " Safety Assessment: Pharmaceutical—Drug Development." Following the virtual national meeting, Tao was invited to make an oral presentation of his project at the Lone Star Chapter's meeting.