Clinical Research Directory

Pharmacogenomic and Circulating Biomarkers for CDK4/6 Inhibitors

The goal of this research study is to reduce adverse effects of anti-cancer medications known as kinase inhibitors, while preserving their therapeutic benefits. There have been major advances in the way cancers are treated. A class of drugs known as kinase inhibitors have proven to be highly effective for the treatment of cancers, including lung, kidney, gastrointestinal, and breast cancers. However, kinase inhibitor medications are well known for having unpredictable side effects. The body breaks down (metabolizes) medications such as kinase inhibitors using an enzyme known as cytochrome P450 3A4 (CYP3A4). CYP3A4 is the most important drug metabolizing enzyme in humans due to the fact that it is involved in the metabolism of nearly half of all prescribed medications and almost all of the currently prescribed kinase inhibitors. Among patients, there can be nearly 400 times difference in how efficiently CYP3A4 metabolizes drugs. Remarkably, very little is known about the role of genetic differences in CYP3A4 and a gene known as pregnane X receptor (PXR). PXR serves as a sensor for drugs in the body and helps to regulate how much CYP3A4 is made. Currently, there are no predictive biomarkers, whether in genes (genomic) or circulating in blood (endogenous) that could aid treating oncologists with regards predicting adverse effects or suboptimal response to this important class of anticancer drugs. The goal is to carry out DNA sequencing for genetic changes in CYP3A4 and PXR to assess differences in enzyme activity of not only common, but also rare genetic variants. CYP3A4 activity will be determined in participants blood samples based on break down products of the drug tamoxifen as well as cholesterol, the latter called 4β-hydroxycholesterol, both known to be influenced by the CYP3A4 enzyme. Since cholesterol is naturally made in the body, comparing blood cholesterol to 4β-hydroxycholesterol levels will be a biomarker of CYP3A4 metabolic activity that can be measured in anyone. Furthermore, circulating CYP3A4 messenger RNA from human blood will be measured as another independent marker of CYP3A4 gene expression. A model will be generated that includes these biomarkers of CYP3A4 expression and function, as well as genetic variation in CYP3A4 and PXR, that will aid in better identifying which patients may be at risk for loss of benefit or toxicity from kinase inhibitor therapy. This model will be evaluated in 100 breast cancer patients undergoing chemotherapy with kinase inhibitors, namely cyclin-dependent kinases CDK4 and CDK6 inhibitor (abemaciclib, ribociclib or palbociclib), as such kinase inhibitors are widely prescribed for breast cancer and are known to be broken down by CYP3A4.

Trial of Preemptive Pharmacogenetics in Underserved Patients

This proposed research is relevant to human health because preemptive clinical pharmacogenetic testing may improve the personalization of drug therapy which should improve patient outcomes. Better understanding of the effectiveness and feasibility of preemptive clinical pharmacogenetic testing will inform when and how this innovative healthcare technology is implemented into clinical care. To ensure equitable dissemination in all patient populations, such data is also needed in racial minorities and other traditionally underserved populations. The combined proposed research are relevant to the parts of the NIH's mission pertaining to protecting and improving health and developing scientific human resources that will ensure the Nation's capability to prevent and treat disease.

Pharmacogenetic Testing at Community Pharmacy

The purpose of this study is to assess the clinical impact of reducing treatment failure rates after using genetic information targeting CYP2C19 in validating escitalopram prescription. 5 pharmacies in the canton of Vaud (Lausanne, Switzerland) will participate in the study. The study will also explored the ability to perform the test in community pharmacy, physician and pharmacist approval of prescription changes, patient acceptance of the test and dose changes, the economic impact of the test, the association between genetic polymorphisms and therapeutic failures and the degree of satisfaction, barriers and facilitators by stakeholders.