Preventing Adverse Patient Responses to Cancer Chemotherapeutics
Abstract
Scientific Objective and Rationale: Metastatic colorectal cancer patients are often treated with the drug irinotecan. It’s been known for many years that the collection of microbes (“microbiome”) living in the guts of some patients can interact with this drug and metabolize it in a way that leads to severe diarrhea. We recently discovered that certain individuals are more active gut metabolizers of irinotecan, and we hypothesize that these individuals are more at risk for severe diarrhea when they are treated with irinotecan. The scientific objective of this proposal is to pioneer non-invasive pre-therapy analysis of patient gut microbiomes to reliably identify high-risk patients before they are treated, thus providing their physicians an early warning that will prevent severe diarrhea. Career Goals in Cancer Research: The overall goal of Principal Investigator (PI) Kelly’s lab is to alleviate patient suffering and improve patient outcomes by giving doctors the ability to better target cancer treatments for individual patients. The Peer Reviewed Cancer Research Program (PRCRP) Career Development Award will advance PI Kelly’s career focus on colorectal cancer by providing her crucial funds and mentoring support to work with cancer doctors and their patients to demonstrate that her approach can improve colorectal cancer treatment, a Fiscal Year 2017 PRCRP Topic Area, via pre-therapy analysis. Her research plan is based on solid preliminary data demonstrating that particular microbiome features can predict high irinotecan metabolism. She will thus examine the microbiomes of colorectal cancer patients who are taking irinotecan to identify specific microbes and specific proteins that are responsible for high metabolism of the drug and use this information to predict, for future patients, whether they will respond favorably to treatment with irinotecan. PI Kelly’s career development plan includes work with senior cancer researcher and immunologist Dr. Sridhar Mani, who will facilitate her interactions with clinicians and will help her navigate any roadblocks encountered during her work. This Career Development Award will also allow PI Kelly to attend a workshop designed to help basic scientists bring their work into the clinic. She will benefit substantially from networking opportunities at this workshop, with the Albert Einstein Cancer Center, and when presenting her work at internationally attended microbiology and cancer research conferences. Applicability: The initial patients whom PI Kelly’s work will help are metastatic colorectal cancer patients taking drug regimens that include irinotecan. The proposed work will help these patients by identifying those at heightened risk for adverse responses to irinotecan that are driven by the microbes that live in their guts. Based on our results from this proposal, a feasible clinical application in a 5-year timeframe is microbiome pre-therapy analysis for all metastatic colorectal cancer patients taking irinotecan. We anticipate this pre-therapy analysis will alleviate patient suffering and decrease hospital costs associated with the severe adverse events that can accompany irinotecan administration. There are no risks associated with fecal sampling for pre-therapy analysis. A potential risk of the analysis itself are false positives and false negatives, that is, wrongly predicting a patient will suffer an adverse response when they actually do not and wrongly predicting that a patient will not suffer an adverse response when they do. Our proposed work will address these concerns by calculating our false positive and false negative rates and using only highly informative microbiome features for our predictions. In the future, we hope to manipulate patient microbiomes such that patients are moved into a low-risk category for adverse responses before they are ever treated with irinotecan. Finally, PI Kelly’s proposed pre-therapy analysis is not limited to irinote
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810112
Entities
People
- Libusha Kelly
Organizations
- Albert Einstein College of Medicine
- United States Army