Colorectal Cancer Therapies Introduced Through Engineered Native Bacteria - PROJECT SUMMARY/ABSTRACT In 2025, the American Cancer Society projects 154,270 new cases and 52,900 deaths from colorectal can- cer, making it the third most diagnosed and deadly cancer in the U.S. Current prevention strategies—such as surveillance colonoscopy and prophylactic colectomy—are invasive, costly, and poorly adhered to. Systemic chemotherapy, though standard for treatment, is limited by off-target effects, poor tolerability, and long-term complications. Microbial therapies offer targeted, self-renewing delivery and the potential to prevent adenoma- to-cancer progression, but progress has been limited by the transient engraftment of probiotic or lab-adapted strains, which fail to provide sustained tumor interaction or therapeutic delivery. This gap in knowledge reflects the absence of microbial tools and mechanistic insight needed to enable long-term, programmable col- onization in the tumor microenvironment. Additionally, clinical translation of microbial therapies requires ef- fective biocontainment to regulate colonization, persistence, and function, minimizing safety risks. There is a critical need for a microbial chassis that can stably engraft, deliver therapeutic functions over time, be genetically programmable, and be safely cleared after completing its task. Our lab addresses this need with a novel innovation: engineered native bacteria—host-derived E. coli strains that durably colonize the gut, are genetically tractable, and enable controlled luminal function. Our preliminary studies show that these bacteria can perform targeted functions and modulate tumor growth in preclinical models. Our central hypothesis is that engineered native E. coli can durably engraft in the gut to prevent or treat colorectal cancer and be selectively cleared. The overall goal is to develop a microbial platform for durable, targeted delivery of therapeutic molecules to the gut. Over the next five years, we will test this hypothesis through three aims: (1) Test whether engineered native E. coli that modify bile acids can prevent colorectal cancer in high-risk hosts. We will define how sustained microbial delivery of specific bile acid functions alters cancer risk. (2) Engineer native E. coli to activate chemotherapeutics specifically within tumors. This will establish a tumor-targeted precision-microbiome therapy using intratumoral prodrug conversion. (3) Develop a biocon- tainment system enabling selective, non-antibiotic clearance of engrafted strains. This will use an osmo- lality-targeting strategy to enhance safety and control. The expected outcome is a modular, engrafting microbial platform that prevents tumor formation, activates localized chemotherapy, and allows for controlled clearance. This approach has strong translational potential, offering a sustainable, low-toxicity therapy that addresses rising colorectal cancer rates in younger adults and aligns with national goals to reduce chronic disease through precision interventions.
