U01CA265719

Engineering Native E. Coli to Detect, Report, and Treat Colorectal Cancer - Project Summary/Abstract

Despite its overall decreasing occurrence, colorectal cancer (CRC) remains the fourth most common cause of cancer deaths in the US. Unfortunately, epidemiological studies demonstrate an alarming increase in incidence in populations below the age of 50, who are not routinely screened. Furthermore, CRC detection is difficult in high-risk groups, including those with a genetic predisposition (e.g. familial adenomatous polyposis), disease traits (e.g. inflammatory bowel disease), or from certain demographics (e.g. Black Americans). Thus, there is a significant need for the development of innovative solutions for the early detection of CRC and the prevention of the transition from adenoma to CRC.

To address this need, our interdisciplinary research team will develop genetically engineered bacteria using synthetic biology approaches to identify early CRC development, monitor and report changes in the adenoma and CRC microenvironment, and prevent cancer progression. To achieve the above objectives, engineered bacteria have to engraft and colonize the hostile luminal environment, sense and distinguish an abnormal environmental signal, compute this signal, and express a reporter or a therapeutic agent. However, appropriate vectors with these features remain lacking, constraining synthetic biology applications for cancer research.

Importantly, CRC is highly associated with E. coli, for which we have many synthetic biology tools. Furthermore, our preliminary proof-of-concept studies have revealed that native E. coli can be engineered to perpetually colonize fully conventional (i.e. non-microbiome depleted) hosts and to execute functions of interest, e.g., deconjugation of luminal bile acids. Deconjugated bile acid and resultant farnesoid X receptor (FXR) agonism can suppress CRC development, indicating a potential therapeutic use of engineered native bacteria.

Building on our strong supportive preliminary results, we will identify native E. coli from healthy, adenoma, and CRC tissues of a genetic model of CRC and engineer them to detect and treat CRC in response to the cancer microenvironment. Furthermore, we will characterize the effects of different tumor environment factors on the colonization and performances of engineered native E. coli in the colon organoid model in an organ-on-chip with the support of mathematical modeling, thereby identifying specific CRC signals for programming the responses of engineered native E. coli as CRC reporters and therapeutics.

Finally, we will engineer native bacteria to detect and attenuate the progression of CRC by quantitatively reporting the level of CRC-related cysteine proteases and selectively inhibiting their activity. The research described in this proposal will generate new, much-needed synthetic biology vectors that can be developed as biosensors and therapeutics of adenoma and CRC, as well as many other diseases. Furthermore, this project will enrich our fundamental knowledge about the CRC-microbiome relationship and elucidate the roles of cysteine proteases in CRC progression and treatment.

San Diego University Of California

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

La Jolla, California 920930983 United States

Single Zip Code

Collaborative Approaches to Engineer Biology for Cancer Applications (U01 Clinical Trial Not Allowed) (RFA-CA-20-054)

Amendment Since initial award the total obligations have increased 1692% from $175,000 to $3,135,340.