129IN - Antiemetics: A window to translational medicine

Date 30 September 2012
Event ESMO Congress 2012
Session ESMO-MASCC Joint symposium: Integration between medical oncology and supportive care: Two sides of the same coin
Topics Supportive Care
Translational Research
Presenter Steven Grunberg
Authors S. Grunberg
  • Hematology/oncology Unit, University of Vermont, 05405 - Burlington/US

Abstract

The concepts of targeted therapy, molecular pharmacology, and population genetics are not new to the field of clinical antiemetic care. The most basic principle of antiemetic care is to identify and target neurotransmitter/neurotransmitter receptor pairs within the emetic reflex arc that can be suppressed without causing severe disruption of physiologic function. Early research focused on dopamine (D2) receptors led to effective antiemetics but also resulted in significant antidopaminergic toxicity. Identification of serotonin (5HT3) receptor pathways with similar emetogenic activity provided a target that could be effectively suppressed without antidopaminergic toxicity. Appreciation of the role of neurokinin (NK-1) receptors in delayed emesis complements previous knowledge and allows for more effective suppression of emesis throughout the period of emetic risk. More recently genetic mutations that alter these neural pathways as well as the metabolic pathways of antiemetic agents have been appreciated. Over-expression of the CYP 2D6 pathway increases metabolism of some serotonin antagonist antiemetics and has been shown to decrease the efficacy of these agents. A mutation in the 5-HT3B subunit of the serotonin (5HT3) receptor itself can also alter sensitivity to emetogenic chemotherapy and to antiemetic agents. Appreciation of the role of genotype and phenotype in the response of different ethnic groups to therapy has now allowed correlation of lessons from population science with clinical treatment. A study from Malaysia comparing Chinese, Malay, and Indian populations receiving similar chemotherapy and similar antiemetics has demonstrated an increased emetic response in the Chinese population. A study from the United States similarly demonstrated increased emetic response in a Chines population compared to a Caucasian population. Whole genome analysis to identify differences between these ethnic groups may therefore lead back to genetic foci of interest that will in turn affect the clinical science of antiemetic protection. Such translational and multidisciplinary efforts increase knowledge of the basic mechanisms of disease and treatment while simultaneously improving patient quality of life.

Disclosure

S. Grunberg: I have served as a consultant to Helsinn, Merck, Tesaro, AP Pharma, and Prostrakan. I also am a stockholder in and have received honoraria from Merck.