Gut Microbiome as a Predictor of Response to Chemotherapy in Metastatic Colorectal Cancer
Abstract
The current project is focused on Colorectal cancer which has been identified by the Congress as one of the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas. Additionally, this project is focused on better understanding and thereby improving the treatment of metastatic colorectal cancer, which is Area of Emphasis for FY19 PRCRP. Colon and rectal cancer (CRC) is the second most common cause of cancer related deaths in United States. Our military personnel and Veterans bear significant brunt of this formidable disease. Most patients with CRC die of metastases. Despite decades of research, cytotoxic chemotherapy continues to be the first line of treatment of metastatic colon and rectal cancer (mCRC). However, the patients with mCRC respond variably to cytotoxic chemotherapy, with about 20% only having stable disease (i.e., no shrinkage but no progression) and a third progressing despite chemotherapy. However, no predictors/tests have been identified till date which can help predict whether patients will respond to chemotherapy or not. Hence, patients are started on chemotherapy, and only after about 4-6 months it becomes apparent whether the patient will benefit from chemotherapy or not. Thus, there is a striking need to identify predictors of response to chemotherapy, so that valuable time is not lost in treating patients with chemotherapy which they will not benefit from. We are surrounded by bacteria. In fact, a large number of bacteria live in our intestines, a niche known as gut microbiome. Not all bacteria are harmful and many living in our intestines have vital functions and help us live a healthy life. However, our recent studies in animal models of cancer suggest that some of the gut bacteria may actually promote cancer growth, and inhibiting the bacterial growth by, for instance, antibiotics, can inhibit the tumor growth. In fact, our studies also suggest that modifying the bacterial species in our gut microbiome can increase the effectiveness of chemotherapy. In the current grant proposal, we are building on our initial studies and evaluating our concepts in patients suffering from mCRC. Based on our preliminary data we have hypothesized that the composition of gut microbial bacteria helps predict response of mCRC to chemotherapy (i.e., patients who respond well to chemotherapy have a certain gut microbiome composition, when compared to those who progress despite chemotherapy). Thus, evaluation of the gut microbiome will help us identify the patients who will not respond to chemotherapy and for whom alternative strategies need to be evaluated. In the second part of the current proposal, using animal studies, we will assess if gut microbiome modulation can help increase the efficacy of chemotherapy. This hypothesis is based on our preliminary data which reveals that modulation of gut microbiome sensitizes colon cancer cells to chemotherapy. For this, we will generate human gut microbiome AVATAR mice, where the gut microbiome of patients, who are resistant to chemotherapy (identified in Specific Aim 1) will be transplanted into germ-free mice, followed by implantation of the colon tumors in them. These AVATAR mice will be used to evaluate whether gut microbiome modulation by antibiotics, pre-biotics or pro-biotics can increase the efficacy of chemotherapy. Successful execution of these studies will lead to two benefits: (1) proposed studies will lead to generation of a gut microbiome composition signature, where presence of certain bacteria in the gut microbiome will predict response or resistance to chemotherapy. This signature can be identified during the duration of the proposed study (4 years) followed by validation in another 4 years. Thus, within a decade from initiation of this project, this signature could help select effective chemotherapy for patients with mCRC. (2) The proposed studies will also decipher if gut microbiome can be modulated to make the chemotherap
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010740
Entities
People
- Nipun Merchant
Organizations
- United States Army
- University of Miami