SUMMARY
- Early detection of colorectal and other gastrointestinal neoplasms. Research has focused especially on the development and clinical validation of novel screening tools which are noninvasive or minimally invasive.
- Identification and evaluation of informative tumor markers in stool, blood, and other biological sources with respect to screening, diagnostic, or prognostic applications.
Specific Projects
- Identification and validation of novel exfoliated markers in stool for the screen-detection of colorectal neoplasia. This is an NIH-funded project (R01 CA 71680) to explore a range of neoplasm-specific markers based on recovered fecal colonocytes and colonocyte constituents (proteins, DNA, other). Assay development and early phase clinical validation studies are underway.
- Multicenter study to compare a novel DNA-based stool test against conventional approaches to colorectal cancer screening. Funded by NIH (UO1 CA 89389). Participating sites include Mayo Clinic Rochester and centers within the North Central Cancer Treatment Group.
- Use of Methylated DNA markers for the detection of aerodigestive cancers. Tissue specific markers will be identified for each major aerodigestive cancer and incorporated into assay panels that will be validated for both stool and serum applications. This novel approach promises an economic and user-friendly strategy for screen-detection of both colorectal and supracolonic aerodigestive cancers. Funding is provided by a private foundation grant (Oswald Investigation).
- Detection of supracolonic aerodigestive cancers by assay of DNA alterations in stool. An assay that targets point mutations on K-ras, APC, and p53, a microsatellite marker Bat-26, and long (nonapoptotic) DNA is employed. Funding is from EXACT Labs.
- Assay of novel tumor-derived markers in blood in the diagnosis and staging of colorectal neoplasia. Assays include immunocapture of circulating colonocytes followed by RT-PCR and the above-mentioned EXACT assay to detect mutant/altered DNA in serum. Multiple patient groups will be studied.
- Identification and evaluation of differentially expressed genes as diagnostic targets for colorectal neoplasia. Overexpressed genes from cancers and adenomas are identified by subtractive hybridization and evaluated as candidate screening markers (by RT-PCR or assay of encoded protein) on tissue and stool across patient groups. Funding will be provided by industry and Mayo Foundation.
- Chemoprevention of colorectal adenomas by ursodeoxycholic acid. Clinical trial (PI Mark Larson, [Ahlquist coinvestigator]). Funded by Axcan and Mayo Foundation.
Technologies Used
This program is translational in nature and comprises both laboratory and clinical based elements.
For the lab-based components: Techniques to isolate malignant cells from stool and blood (immunocapture, flow cytometry, density gradient centrifugation), to assess gene expression (RT-PCR), to assay for DNA alterations (CR-based methods), and to isolate/quantify proteins (immunochemical, mass spectometry) are employed.
For the clinical components: Access to our large patient population provides high volume procurement of biological materials. Clinical, laboratory, and pathology databases are capitalized on for subject identification and characterization.
Significance of Research
There is a clinical imperative and enormous opportunity to reduce the toll of morbidity and mortality caused by colorectal cancer and the other prevalent aerodigestive cancers through more effective and efficient preventive strategies. Collectively, these malignancies account for more than half of all cancer deaths. Early detection of premalignant adenomas and curable-stage cancers is currently hampered by limitations in the performance of available screening tools which, like fecal blood testing, are insensitive and nonspecific or, like colonoscopy, too expensive and invasive. There is a strong biological and clinical rationale to target exfoliated markers in stool and blood to detect colorectal and supracolonic aerodigestive neoplasms. Assay of such markers by various molecular and immunochemical techniques promises to substantially improve the diagnostic accuracy of screening, and the non-invasive nature of this approach should enhance patient compliance as well. Implementation of such tools could translate into a substantially improved cancer control effort.