Overview

All of our research efforts are directed at improving the length and quality of life for patients affected by inflammatory conditions of the gastrointestinal tract. Along with our colleagues, we have used clinical databases and laboratory modeling to study the general fields of intestinal inflammation, injury repair, and carcinogenesis.  Our work is inspired by clinical interactions with patients affected by the human inflammatory bowel diseases and those patients who experience significant gastrointestinal side effects from radiotherapy-induced bowel injury.   The overarching goal of our research is to identify novel ways to improve life for patients enduring these illnesses. Translating our findings to human relevance is aided by our Division’s DDRCC clinical database, and BioSpecimens repository.

A separate focus of the lab is to explore the role and mechanisms by which probiotic bacteria protect the intestinal epithelium from radiation injury.  The small intestine is highly sensitive to radiation and is a major site of injury during radiation therapy.  Diarrhea as a side effect is the limiting factor in dosing radiation therapy for rectal cancer and other abdominal malignancies. There is a need for agents that could be given before radiation therapy to diminish radiation injury to the small intestine, without decreasing the radiation sensitivity of the tumor.  Our research suggests that certain lactobacillus probiotics or their probiotic-derived products may be useful as a prophylactic strategy to limit intestinal injury to humans during radiation therapy.  Initial funding for this work came from the inaugural Global Probiotic Council’s Young Investigator Award.  We developed and are now initiating a randomized clinical trial to extend this work to humans.  This work is supported by the Longer Life Foundation and a grant from the Siteman cancer center.

 

Major areas of research

Many of our investigations focus on a specific enzyme, Indoleamine 2,3 Dioxygenase (IDO), which has been demonstrated to have a potent immune modulating capacity.  Using experimental models and other laboratory-based approaches we have identified IDO as an important regulator of the intestinal inflammatory response and as a modifier of colitis-associated cancer progression.  IDO expression is increased in both human IBD and colitis models. Blocking this enzyme worsens inflammation, while pharmacologic upregulation of intestinal IDO expression limits inflammation.  Our investigations show that targeting of IDO may have therapeutic potential in both colitis, and colitis-associated cancer.  This work is and has been supported by the National Institutes of Health (NIDDK) and the Crohn’s and Colitis Foundation.

We are also working to define how tryptophan metabolism along the kynurenine pathway can be therapeutically targeted in human IBD and colon cancer.  We previously identified IDO (Indoleamine 2,3 dioxygenase-1) induction as a strategy to promote tolerance and limit inflammation in models of IBD.  We extended this knowledge to two human translational projects examining IDO metabolites as a Crohn’s disease activity biomarker, and IDO gene polymorphisms as a predictor of disease severity.  More recently, we determined that IDO1 also plays a pathogenic role in promoting the progression of colon cancer; an important complication of IBD. Our work indicates that epithelial based tryptophan metabolism, in particular, is important in disease pathogenesis; and developed a new system to test these findings in human-derived spheroid cultures.  These discoveries formed the platform for our current investigations aimed at defining how to most effectively exploit this “immune checkpoint” pathway to target colitis-associated and sporadic colon cancer.

Additionally, we are working to define the role of probiotic bacteria in preventing intestinal mucositis.  Defining host-microbial interactions and identifying how these apply to GI health is a major focus of interest in my basic and clinical research.  We have specifically focused on the unmet need for strategies to prevent GI toxicity from cytotoxic cancer therapy (intestinal mucositis).  We previously demonstrated that exogenous administration of a specific lactobacillus probiotic bacteria, LGG, protects the small intestinal stem cell niche from cytotoxic radiation injury.  Work in the lab is currently directed at defining the probiotic derived product that mediates the effect and defining its signaling mechanisms.  Additionally, we are exploring ways to enhance this probiotic’s cytoprotective efficacy through dietary manipulation and genetic engineering.

Finally, we are now taking this discovery to cancer patients in need.  To do so we developed an IND application with the FDA, navigated regulatory bodies (IRB, NCI cancer center protocol reviews, etc.), and initiated an NCI funded Phase 1 clinical trial which is currently enrolling.  We anticipate extending these findings to a multi-institutional randomized clinical trial with the Alliance for Clinical Trials in Oncology.