U54CA274374

Understanding Adenoma Progression: Interplay Among Tissue Microenvironment, Clonal Architecture, and Gut Microbiome - Summary

Colorectal cancer (CRC) affects approximately 145,000 people per year in the US and is the third most common cause of cancer-related deaths. CRC arises from early lesions that are precancerous, namely colon adenomas and serrated sessile lesions (SSL). Colon adenomas account for 80-85% of the precancerous lesions and progress to CRC through an early adenoma-advanced adenoma-CRC sequence. In light of the well-characterized clinical natural history of adenomas, we plan to study them as early lesions and determine the mechanisms involved in the formation and progression of these precancerous lesions.

Notably, only a few early adenomas will progress to advanced adenomas (AA), and even fewer will progress to CRC. Our group and others have shown that mutations alone are not sufficient to cause adenoma initiation and/or progression in the majority of cases. There are likely multiple nonautonomous mechanisms that cooperate with DNA alterations in the adenomas to cause progression, and these mechanisms are likely operative in discrete subsets of affected individuals. We and others have observed alterations, such as tissue senescence, high cancer driver gene mutation loads, aberrant DNA methylation patterns, and dysbiotic gut microbiomes, in the normal colon of people with advanced adenomas and CRC patients. We have termed normal colons with these features "primed colons" and propose that these features are plausible mechanisms that affect adenoma initiation and progression.

Based on these observations and our prior studies, we hypothesize that early lesion progression requires a suite of hallmark behaviors and that these behaviors are induced by adenoma autonomous factors (e.g., cancer driver gene mutations) and adenoma nonautonomous factors from the "primed colon" or adenoma microenvironment. Our proposed studies will integrate basic and translational cancer research projects to iteratively examine the direct causal relationships and interactions of adenomas, the colon "primed" microenvironment, and host-systemic factors as "co-organizers" of adenoma initiation and/or progression.

The specific aims are:

AIM 1) To determine the adenoma cell autonomous molecular factors that distinguish nonadvanced adenomas from advanced adenomas and regulate nonadvanced adenoma progression. (Projects 1 and 2)

AIM 2) To determine the adenoma nonautonomous factors from the "primed" colon and the adenoma microenvironment that associate with advanced human colon adenomas and regulate adenoma progression. These factors will include the following "primed" colon states: 1. Senescence state; 2. Cancer driver gene mutation burden; 3. Gut microbiome state; 4. Colon methylome, and 5. Colon immune activity state. (Projects 1-3)

AIM 3) To determine how adenoma autonomous and nonautonomous factors from the adenoma microenvironment and the "primed" colon cooperate to drive adenoma formation and progression. (Projects 1-3)

Fred Hutchinson Cancer Center

TO REDUCE CANCER RISK, INCIDENCE, MORBIDITY, AND MORTALITY AND ENHANCE QUALITY OF LIFE IN CANCER SURVIVORS THROUGH AN ORDERLY SEQUENCE FROM RESEARCH ON INTERVENTIONS AND THEIR IMPACT IN DEFINED POPULATIONS TO THE BROAD, SYSTEMATIC APPLICATION OF THE RESEARCH RESULTS THROUGH DISSEMINATION AND DIFFUSION STRATEGIES. PRIMARY EMPHASIS IS ON THE INCLUSION OF CANCER PREVENTION AND CONTROL INTERVENTION(S) IN ANY PROPOSED STUDY. CANCER PREVENTION AND CANCER CONTROL RESEARCH STUDIES ARE CLASSIFIED INTO ONE OF FIVE PHASES: (1) HYPOTHESIS DEVELOPMENT, (2) METHODS DEVELOPMENT AND TESTING, (3) CONTROLLED INTERVENTION TRIALS TO ESTABLISH CAUSE-AND-EFFECT RELATIONSHIPS, (4) RESEARCH IN DEFINED POPULATIONS, AND (5) DEMONSTRATION AND IMPLEMENTATION STUDIES. PRIMARY INTERESTS ARE IN RESEARCH ON CANCER CONTROL INTERVENTIONS IN PHASES 2 THROUGH 5, AND ON CANCER PREVENTION RESEARCH IN ALL PHASES. CANCER PREVENTION AND CONTROL PROGRAMS INCLUDE THOSE IN THE FOLLOWING AREAS: (1) CANCER EPIDEMIOLOGY, (2) CANCER COMMUNICATIONS, (3) NUTRITION, DIET, AND PHYSICAL ACTIVITY, (4) SCREENING AND EARLY DETECTION IN HEALTH CARE DELIVERY, (5) BIOBEHAVIORAL MECHANISMS, (6) TOBACCO CONTROL, (7) HEALTH DISPARITIES RESEARCH, (8) SUPPORTIVE CARE AND SURVIVORSHIP, (9) HEALTH SERVICES AND OUTCOMES RESEARCH, AND (10) SURVEILLANCE RESEARCH. CANCER CONTROL USES SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS TO ENGAGE DOMESTIC SMALL BUSINESS CONCERNS IN FEDERAL RESEARCH AND DEVELOPMENT THAT HAS POTENTIAL FOR COMMERCIALIZATION. THE GOALS OF THE SBIR & STTR PROGRAMS ARE TO STIMULATE TECHNOLOGICAL INNOVATION, INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF FEDERAL RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERALLY FUNDED RESEARCH AND DEVELOPMENT, AND FOSTER PARTICIPATION BY SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE STTR PROGRAM REQUIRES THE SMALL BUSINESS CONCERN TO FORMALLY COLLABORATE WITH A RESEARCH INSTITUTION IN PHASE I AND PHASE II OF THE PROGRAM.

93.399 - Cancer Control

National Cancer Institute (NCI) [HHS - NIH]

Washington United States

State-Wide

Translational and Basic Science Research in Early Lesions (TBEL) (U54 Clinical Trial Not Allowed) (RFA-CA-21-054)

Amendment Since initial award the total obligations have increased 240% from $1,692,618 to $5,762,006.