Grant R21CA206039


The overall goal of this proposal is to establish the safety and tolerability of the probiotic Lactobacillus rhamnosus GG (LGG) as an agent to reduce gastrointestinal (GI) side effects in patients receiving chemoradiation for GI malignancy. The results of the study and its corollary biomarker analyses will be used to guide development of a randomized Phase II placebo-controlled clinical trial to test the efficacy of LGG as a GI protective agent in this same population which is our long-term goal. In the US, cancer originating from the GI tract (rectum, pancreas, stomach and anal canal) is a significant clinical problem with over 110,000 new diagnoses each year. Successful completion of cytotoxic radiation therapy (RT) significantly improves outcomes and cure rates for patients with locally advanced gastrointestinal (GI) malignancies. Despite use of highly focused (RT), patients undergoing pelvic or abdominal RT are at high risk of diarrheal complications from collateral damage to small intestine. Combining RT with chemotherapy adds to the GI toxicity with symptoms that include diarrhea resulting in dehydration and hospitalization. These GI toxicities are a dose-limiting side-effect for cytotoxic therapy which is a significant clinical problem as it leads to reduced efficacy of the cancer treatment regimen. There is currently an unmet need for agents that could protect the normal small intestinal epithelium from collateral damage whereby reducing symptoms of GI toxicity so that patients can receive optimal cancer therapy and a maximized quality of life. New evidence suggests that certain probiotic bacteria may be an innovative approach to reduce cytotoxic therapy-associated GI toxicity. Probiotic bacteria have been used safely as therapy in several GI conditions and offer the advantage of luminal delivery of a locally acting agent. These properties make probiotics a potentially ideal therapy to prevent collateral damage to the normal GI tract during cancer therapy. Using an established experimental model, we found that prophylactic administration of the probiotic LGG effectively reduced cell death and promoted epithelial recovery at doses relevant to humans. Our new preclinical data also indicate that this approach works in fractionated radiation dosing regimens similar to what humans receive during cancer therapy, but importantly does not impact tumor radiosensitivity. This data and detailed analysis of prior clinical trials from outside the US have informed the development of our central hypothesis that "Oral supplementation with the probiotic LGG will reduce treatment-related GI toxicity by protecting the intestinal epithelium in patients receiving cytotoxic therapy for gastrointestinal cancer." Under FDA and IRB approved protocols we will address our central hypothesis to determine the safety and tolerability for LGG as an intestinal protectant in patients receiving RT for GI malignancy in a Phase I study. As a biovalidation aim, we will also establish how novel biomarkers correlate with clinical symptom indices of treatment related GI toxicity. If successful, the significance of this Phase I trial wil enable and guide the initiation of a multi-center, randomized Phase II study to evaluate LGG's efficacy as an intestinal cytoprotectant during therapy for GI malignancy.