R01CA252042

Discovery and Verification of Methylated Circulating Tumor DNA Markers for the Detection of Colorectal Cancer in Subjects Under 50 Years of Age - Abstract

In recent years, the incidence of colorectal cancer (CRC) under the age of 50 years has increased significantly, and population-based screening is currently not offered to persons under 50 years. Consequently, persons with early-onset (<50 years) CRC (EOCRC) more frequently present with symptomatic disease at advanced stages (III/IV), resulting in greater loss of life in young cases.

In 2020, the U.S. Preventive Services Task Force recommended the age for CRC screening by colonoscopy or fecal tests be reduced to 45 years. However, the uptake of screening by these methods in all screen-eligible populations is low, including in those <50 years who are genetically at high risk, so adherence in the asymptomatic population <50 years is also likely to be low. Also, over half of EOCRC occur in persons under <45 years of age, where no such screening would be offered.

A minimally invasive, blood-based screening test for EOCRC would provide a cost-effective and patient-friendly option for triaging and identifying those warranting a follow-up colonoscopy, while increasing screening adherence in the younger population.

Cancer-specific methylated DNA biomarkers are highly suited for population-based cancer screening via the detection of circulating tumor DNA (ctDNA) in blood plasma because they are more prevalent across patients with a given cancer type than tumor mutations and are more stable (nuclease-resistant) in plasma. The methylated SEPT9 plasma ctDNA test, "mSEPT9" (Epi proColon V2.0, Epigenomics), is FDA-approved for CRC screening in persons aged =50 years who decline colonoscopy and fecal tests. This test urgently needs to be assessed in persons <50 years to determine its suitability for the detection of EOCRC. Even so, a multi-marker test is likely to have superior sensitivity to a single-marker test.

Thus, the objectives of our study are to identify and confirm a panel of methylated ctDNA markers for the plasma-based detection of EOCRC and to compare the diagnostic performance of this panel to the mSEPT9 test in persons <50 years of age.

In Aim 1, we will identify the most prevalent differentially-methylated (tumor vs. normal) DNA markers in CRC cases <50 years by performing deep methyl-Seq across 4.2 million CpG sites in paired primary tumor vs. normal colon tissues from EOCRC cases and leukocytes from healthy controls (to filter out non-specific markers). The identified markers will be validated in independent sample series. For the top-ranked markers, we will then develop methylation-specific real-time PCR assays with high analytical sensitivity and test these in pooled plasma from metastatic CRC cases (to select markers producing the strongest signals) and healthy controls (to eliminate any producing low-level non-specific signals) to finalize the marker panel.

In Aim 2, we will evaluate the diagnostic performance characteristics of the mSEPT9 test vs. the multi-marker panel test in plasma from colonoscopy-verified CRC cases and controls <50 years.

This study will yield a multi-marker methylated ctDNA panel with improved diagnostic performance over the single-marker mSEPT9 test for cost-effective, blood-based CRC screening in asymptomatic persons <50 years of age.

H. Lee Moffitt Cancer Center And Research Institute Hospital

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]

Tampa, Florida 336129416 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-24-254)

Amendment Since initial award the total obligations have increased 383% from $685,529 to $3,311,889.