CCSG Supplement: Early-Stage Surgeon Scientist (ESSP)

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Linked publications, trials & patents

Abstract

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-21-100. Abstract Patients with locally advanced rectal cancers face a difficult treatment course involving neoadjuvant 5-FU based doublet or triplet chemotherapy, chemoradiotherapy therapy, and eventual surgical resection. While rates of neoadjuvant chemotherapy induce a complete regression of tumors in a significant subset of patients (30-40%), and is associated with significantly improved long term survival, responses remain heterogeneous with both local and distant failures. Recently, we and others have demonstrated specific bacterial taxa within rectal cancers are associated with a diminished response to neoadjuvant therapy. These bacteria have been shown to lead to the inactivation of common chemotherapeutics and have the ability to form an immune exclusionary environment within rectal cancers. While these microbial communities can be modulated in preclinical models leading to improved response and tumor control; there is a significant gap in our understanding of the ability to modulate these microbes in a clinical setting. Intriguingly, clearance of a common deleterious bacterium Fusobacterium nucleatum (Fn) through 5-FU based chemotherapy has been shown to improve recurrence free survival in a cohort of rectal cancer patients. To understand the influence of these microbes in rectal cancer, we propose to study banked and prospectively collected tissue from a feasibility study of the ability of metronidazole to selectively clear deleterious anaerobes, such as Fn, and the effect this has to augment 5-FU Fn killing. This will be coupled with translational studies of both the tumor immune microenvironment comparing the tumors of patients able to achieve durable complete responses as compared to those with persistent viable tumor post neoadjuvant therapy. Finally, we will study the spatial immune and bacterial profile of the tumors of patients that either do or do not clear tumoral Fn to better understand barriers to clearing these deleterious anaerobes and potentially improve outcomes and increase inclusion of watch and wait protocols in the near future. We hypothesize this study will identify active immune infiltrates correlate with response to neoadjuvant chemotherapy while inactive or absent immune infiltrates will correlate with the presence of high-risk microbes and a lack of response