Project Details
Description
PROJECT SUMMARY/ABSTRACT
My long-term goal is to improve the toxicity profiles for cancer therapeutics. One-third of cancer patients
treated with the commonly prescribed chemotherapeutic 5-fluorouracil (5-FU) experience severe and life-
threatening toxicity to standard doses of the drug. An appreciable fraction of those patients die—not due to
cancer, but because of side-effects related to treatment. Clinical studies indicate that the majority of patients
who experience severe toxicity to 5-FU are deficient for an enzyme called dihydropyrimidine dehydrogenase
(DPD, DPYD gene); however, only four genetic variants in DPYD have been adequately characterized to be
considered predictive of 5-FU toxicity in clinical studies. My preliminary studies demonstrate that these four
variants explain only a small fraction of severe 5-FU toxicities and have exceedingly limited clinical value
outside of individuals with European ancestry. The primary objective of the studies proposed in this grant
application is to identify additional biomarkers of 5-FU toxicity risk that can be used to individualize 5-FU
dosing with the goal of improving the safety profile for the drug. My overall hypothesis is that expanded
biomarker-based pre-treatment tests will more accurately identify patients with DPD deficiency, as well as the
relative degree to which the DPD function is impaired, enabling more accurate dose optimization. My rationale
is that improved biomarker-based approaches to dose individualization have strong potential to improve the
safety profile for this commonly used therapeutic. Aim #1 will identify risk alleles for severe 5-FU–related
toxicity in understudied populations. Aim #2 will characterize multi-marker haplotype contributions to 5-FU
toxicity. In Aim #3, I will develop an integrated predictive model of 5-FU toxicity using deep machine learning. It
is my expectation that the proposed studies, which will leverage multiple large patient and volunteer data and
specimen collections to address various aspects of my primary hypothesis, will answer key questions that have
vexed pharmacogenetics researchers for decades. In doing so, the proposed studies are expected to identify
clinically relevant biomarkers that can be used to improve the safety profile of 5-FU through dose optimization.
Status | Active |
---|---|
Effective start/end date | 9/1/21 → 8/31/24 |
Funding
- National Cancer Institute: $363,713.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.