Program Official

Principal Investigator

Robert S
Bresalier
Awardee Organization

University Of Tx Md Anderson Can Ctr
United States

Fiscal Year
2023
Activity Code
U01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Great Lakes New England Clinical Validation Center

The Great Lakes New England Clinical Validation Center (GLNE CVC), a Clinical Validation Consortium component of the Early Detection Research Network (EDRN) is a highly collaborative group of investigators whose aims to validate biomarkers for the early detection and risk assessment of cancers of the gastrointestinal tract. In this fifth competitive application, the GLNE continues to test the overall hypothesis that a panel of circulating and stool based biomarkers will increase the adherence to colorectal screening and in doing so reduce mortality caused by colorectal cancers. Based on the rising incidence of colorectal cancer (CRC) among adults age <50 in the US, and the low compliance and high mortality in underserved populations, increased emphasis is placed on these populations. The GLNE also proposes to continue its ongoing support of EDRN discovery priorities. We propose to address the following aims: (1) Primary Aim To expand and renew the archive of appropriately preserved stool, serum, plasma, urine, tissue and DNA biospecimens to be used by EDRN investigators for current and future validation and biomarker discovery research with expanded inclusion of subjects with early-onset CRC and underserved populations. This will allow assessment of the utility of individual stool-based, and serum-based biomarkers and biomarker panels for discriminating between individuals without neoplasia (subjects both at average and higher risk for developing colon cancer), and those with colon cancer or screen-relevant neoplasia (cancer plus advanced adenoma), and construction of panels of markers to discriminate between these groups. (2) To perform validation trials of promising biomarkers discovered by EDRN investigators, external collaborating institutions and collaborating EDRN industrial partners for the early detection of colorectal neoplasia. In this context we propose to (a) to clinically validate (via a methods comparison study) the performance of a point-of-care blood- based biomarker panel with the testing of serum/plasma samples obtained in clinics serving low-income and underserved communities and (b) to clinically validate an established 4-plex stool protein panel for early diagnosis of CRC. (3) To follow prospectively subjects enrolled in an established prospective Phase 2 validation trial to identify pre-diagnostic specimens which may be used to develop predictive markers.

Publications

  • Zackular JP, Rogers MA, Ruffin MT 4th, Schloss PD. The human gut microbiome as a screening tool for colorectal cancer. Cancer prevention research (Philadelphia, Pa.). 2014 Nov;7(11):1112-21. Epub 2014 Aug 7. PMID: 25104642
  • Brenner DE, Rennert G. Fecal DNA biomarkers for the detection of colorectal neoplasia: attractive, but is it feasible? Journal of the National Cancer Institute. 2005 Aug 3;97(15):1107-9. PMID: 16077063
  • Turgeon DK, Brenner DE. Fecal DNA-Based Detection of Colorectal Neoplasia. Current colorectal cancer reports. 2007 Oct;3(4):171-177. PMID: 26078729
  • Li H, Vanarsa K, Zhang T, Soomro S, Cicalese PA, Duran V, Dasari S, Lee KH, Pedroza C, Kisiel JB, Qin H, Bresalier RS, Chia N, Mohan C. Comprehensive aptamer-based screen of 1317 proteins uncovers improved stool protein markers of colorectal cancer. Journal of gastroenterology. 2021 Jul;56(7):659-672. Epub 2021 Jun 12. PMID: 34117903
  • Wang M, Block TM, Steel L, Brenner DE, Su YH. Preferential isolation of fragmented DNA enhances the detection of circulating mutated k-ras DNA. Clinical chemistry. 2004 Jan;50(1):211-3. PMID: 14709652
  • Kaczor-Urbanowicz KE, Saad M, Grogan TR, Li F, Heo YJ, Elashoff D, Bresalier RS, Wong DTW, Kim Y. Performance of Salivary Extracellular RNA Biomarker Panels for Gastric Cancer Differs between Distinct Populations. Cancers. 2022 Jul 26;14. (15). PMID: 35892889
  • Yurgelun MB, Goel A, Hornick JL, Sen A, Turgeon DK, Ruffin MT 4th, Marcon NE, Baron JA, Bresalier RS, Syngal S, Brenner DE, Boland CR, Stoffel EM. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer prevention research (Philadelphia, Pa.). 2012 Apr;5(4):574-82. Epub 2012 Jan 18. PMID: 22262812
  • Normolle D, Ruffin MT, Brenner D. Design of early validation trials of biomarkers. Cancer informatics. 2005;1(1):25-31. PMID: 19305629
  • Wang Y, Taylor JM. A measure of the proportion of treatment effect explained by a surrogate marker. Biometrics. 2002 Dec;58(4):803-12. PMID: 12495134
  • Li C, Simeone DM, Brenner DE, Anderson MA, Shedden KA, Ruffin MT, Lubman DM. Pancreatic cancer serum detection using a lectin/glyco-antibody array method. Journal of proteome research. 2009 Feb;8(2):483-92. PMID: 19072160
  • Tuck MK, Chan DW, Chia D, Godwin AK, Grizzle WE, Krueger KE, Rom W, Sanda M, Sorbara L, Stass S, Wang W, Brenner DE. Standard operating procedures for serum and plasma collection: early detection research network consensus statement standard operating procedure integration working group. Journal of proteome research. 2009 Jan;8(1):113-7. PMID: 19072545
  • Krishnan K, Aoki T, Ruffin MT, Normolle DP, Boland CR, Brenner DE. Effects of low dose aspirin (81 mg) on proliferating cell nuclear antigen and Amaranthus caudatus labeling in normal-risk and high-risk human subjects for colorectal cancer. Cancer detection and prevention. 2004;28(2):107-13. PMID: 15068834
  • Cooper GS, Markowitz SD, Chen Z, Tuck M, Willis JE, Berger BM, Brenner DE, Li L. Evaluation of Patients with an Apparent False Positive Stool DNA Test: The Role of Repeat Stool DNA Testing. Digestive diseases and sciences. 2018 Jun;63(6):1449-1453. Epub 2018 Mar 7. PMID: 29516325
  • Ruffin MT, Normolle DP, Evelegh MJ, Baron JA, Bresalier RS, Marcon NE, Syngal S, Turgeon DK, Tuck MK, Brenner DE. Rectal mucosal quantitative galactose oxidase-Schiff reaction as an early detection biomarker for colorectal cancer: comparison to fecal occult stool blood test. Cancer biomarkers : section A of Disease markers. 2011;8(2):109-12. PMID: 21896998
  • Yue T, Maupin KA, Fallon B, Li L, Partyka K, Anderson MA, Brenner DE, Kaul K, Zeh H, Moser AJ, Simeone DM, Feng Z, Brand RE, Haab BB. Enhanced discrimination of malignant from benign pancreatic disease by measuring the CA 19-9 antigen on specific protein carriers. PloS one. 2011;6(12):e29180. Epub 2011 Dec 29. PMID: 22220206
  • Gupta S, Lieberman D, Anderson JC, Burke CA, Dominitz JA, Kaltenbach T, Robertson DJ, Shaukat A, Syngal S, Rex DK. Recommendations for Follow-Up After Colonoscopy and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. The American journal of gastroenterology. 2020 Mar;115(3):415-434. PMID: 32039982
  • Rho JH, Mead JR, Wright WS, Brenner DE, Stave JW, Gildersleeve JC, Lampe PD. Discovery of sialyl Lewis A and Lewis X modified protein cancer biomarkers using high density antibody arrays. Journal of proteomics. 2014 Jan 16;96:291-9. Epub 2013 Nov 1. PMID: 24185138
  • Stoffel EM, Turgeon DK, Stockwell DH, Zhao L, Normolle DP, Tuck MK, Bresalier RS, Marcon NE, Baron JA, Ruffin MT, Brenner DE, Syngal S, Great Lakes-New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. Missed adenomas during colonoscopic surveillance in individuals with Lynch Syndrome (hereditary nonpolyposis colorectal cancer). Cancer prevention research (Philadelphia, Pa.). 2008 Nov;1(6):470-5. PMID: 19138994
  • Tian Y, Denda-Nagai K, Tsukui T, Ishii-Schrade KB, Okada K, Nishizono Y, Matsuzaki K, Hafley M, Bresalier RS, Irimura T. Mucin 21 confers resistance to apoptosis in an O-glycosylation-dependent manner. Cell death discovery. 2022 Apr 11;8(1):194. PMID: 35410995
  • Brenner DE, Hawk E. Trials and tribulations of interrogating biomarkers to define efficacy of cancer risk reductive interventions. Cancer prevention research (Philadelphia, Pa.). 2013 Feb;6(2):71-3. Epub 2013 Jan 18. PMID: 23333813
  • Schwegler EE, Cazares L, Steel LF, Adam BL, Johnson DA, Semmes OJ, Block TM, Marrero JA, Drake RR. SELDI-TOF MS profiling of serum for detection of the progression of chronic hepatitis C to hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2005 Mar;41(3):634-42. PMID: 15726646
  • Stoffel EM, Turgeon DK, Stockwell DH, Normolle DP, Tuck MK, Marcon NE, Baron JA, Bresalier RS, Arber N, Ruffin MT, Syngal S, Brenner DE, Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying. Cancer prevention research (Philadelphia, Pa.). 2008 Dec;1(7):507-13. PMID: 19139000
  • Su YH, Wang M, Brenner DE, Norton PA, Block TM. Detection of mutated K-ras DNA in urine, plasma, and serum of patients with colorectal carcinoma or adenomatous polyps. Annals of the New York Academy of Sciences. 2008 Aug;1137:197-206. PMID: 18837947
  • Gupta S, Lieberman D, Anderson JC, Burke CA, Dominitz JA, Kaltenbach T, Robertson DJ, Shaukat A, Syngal S, Rex DK. Recommendations for Follow-Up After Colonoscopy and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2020 Mar;158(4):1131-1153.e5. Epub 2020 Feb 7. PMID: 32044092
  • Krishnan K, Brenner DE. Prostaglandin inhibitors and the chemoprevention of noncolonic malignancy. Gastroenterology clinics of North America. 2001 Dec;30(4):981-1000. PMID: 11764539
  • Baxter NT, Ruffin MT 4th, Rogers MA, Schloss PD. Microbiota-based model improves the sensitivity of fecal immunochemical test for detecting colonic lesions. Genome medicine. 2016 Apr 6;8(1):37. PMID: 27056827
  • Hannigan GD, Duhaime MB, Ruffin MT 4th, Koumpouras CC, Schloss PD. Diagnostic Potential and Interactive Dynamics of the Colorectal Cancer Virome. mBio. 2018 Nov 20;9. (6). PMID: 30459201
  • Bresalier RS, Grady WM, Markowitz SD, Nielsen HJ, Batra SK, Lampe PD. Biomarkers for Early Detection of Colorectal Cancer: The Early Detection Research Network, a Framework for Clinical Translation. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020 Dec;29(12):2431-2440. Epub 2020 Apr 16. PMID: 32299850
  • Rho JH, Ladd JJ, Li CI, Potter JD, Zhang Y, Shelley D, Shibata D, Coppola D, Yamada H, Toyoda H, Tada T, Kumada T, Brenner DE, Hanash SM, Lampe PD. Protein and glycomic plasma markers for early detection of adenoma and colon cancer. Gut. 2018 Mar;67(3):473-484. Epub 2016 Nov 7. PMID: 27821646
  • Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ, Lok AS. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in american patients. Hepatology (Baltimore, Md.). 2003 May;37(5):1114-21. PMID: 12717392
  • Baron JA. Screening for cancer with molecular markers: progress comes with potential problems. Nature reviews. Cancer. 2012 Apr 12;12(5):368-71. PMID: 22495319
  • Qiu Y, Patwa TH, Xu L, Shedden K, Misek DE, Tuck M, Jin G, Ruffin MT, Turgeon DK, Synal S, Bresalier R, Marcon N, Brenner DE, Lubman DM. Plasma glycoprotein profiling for colorectal cancer biomarker identification by lectin glycoarray and lectin blot. Journal of proteome research. 2008 Apr;7(4):1693-703. Epub 2008 Feb 27. PMID: 18311904
  • Poneros JM, Faye AS, Barr Fritcher EG, Sen A, Anandasabapathy S, Bresalier RS, Marcon N, Turgeon DK, Appelman H, Normolle D, Morrison LE, Brenner DE, Halling KC. A Multicenter Study of a Fluorescence In Situ Hybridization Probe Set for Diagnosing High-Grade Dysplasia and Adenocarcinoma in Barrett's Esophagus. Digestive diseases and sciences. 2017 May;62(5):1216-1222. Epub 2017 Mar 6. PMID: 28265829
  • Su YH, Wang M, Aiamkitsumrit B, Brenner DE, Block TM. Detection of a K-ras mutation in urine of patients with colorectal cancer. Cancer biomarkers : section A of Disease markers. 2005;1(2-3):177-82. PMID: 17192038
  • Miller CT, Moy JR, Lin L, Schipper M, Normolle D, Brenner DE, Iannettoni MD, Orringer MB, Beer DG. Gene amplification in esophageal adenocarcinomas and Barrett's with high-grade dysplasia. Clinical cancer research : an official journal of the American Association for Cancer Research. 2003 Oct 15;9(13):4819-25. PMID: 14581353
  • Shaukat A, Marsh TL, Crockett SD, Syngal S, Bresalier RS, Brenner DE. Low Prevalence of Screen-Detected Colorectal Cancer in an Average-Risk Population: The New Normal. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022 Nov;20(11):2650-2652.e1. Epub 2021 Sep 20. PMID: 34547437
  • Rennert G, Kislitsin D, Brenner DE, Rennert HS, Lev Z. Detecting K-ras mutations in stool from fecal occult blood test cards in multiphasic screening for colorectal cancer. Cancer letters. 2007 Aug 18;253(2):258-64. Epub 2007 Mar 8. PMID: 17349741
  • Bresalier RS, Byrd JC, Tessler D, Lebel J, Koomen J, Hawke D, Half E, Liu KF, Mazurek N, Great Lakes-New England Clinical and Epidemiology Center of the Early Detection Research Network. A circulating ligand for galectin-3 is a haptoglobin-related glycoprotein elevated in individuals with colon cancer. Gastroenterology. 2004 Sep;127(3):741-8. PMID: 15362030
  • Su YH, Wang M, Brenner DE, Ng A, Melkonyan H, Umansky S, Syngal S, Block TM. Human urine contains small, 150 to 250 nucleotide-sized, soluble DNA derived from the circulation and may be useful in the detection of colorectal cancer. The Journal of molecular diagnostics : JMD. 2004 May;6(2):101-7. PMID: 15096565
  • Cooper GS, Markowitz SD, Chen Z, Tuck M, Willis JE, Berger BM, Brenner DE, Li L. Performance of multitarget stool DNA testing in African American patients. Cancer. 2018 Oct 1;124(19):3876-3880. Epub 2018 Sep 7. PMID: 30193399
  • Yu M, O'Leary RM, Kaz AM, Morris SM, Carter KT, Chak A, Chandar A, Willis JE, Moinova HR, Markowitz SD, Brenner DE, Anandabapasathy S, Westerhoff M, Wong CJ, Shaheen NJ, Chen Y, Barnholtz-Sloan JS, Grady WM. Methylated B3GAT2 and ZNF793 Are Potential Detection Biomarkers for Barrett's Esophagus. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015 Dec;24(12):1890-7. Epub 2015 Nov 6. PMID: 26545406
  • Baxter NT, Koumpouras CC, Rogers MA, Ruffin MT 4th, Schloss PD. DNA from fecal immunochemical test can replace stool for detection of colonic lesions using a microbiota-based model. Microbiome. 2016 Nov 14;4(1):59. PMID: 27842559

Clinical Trials

Study Name Clinical Trial ID
Evaluation of Stool Based Markers for the Early Detection of Colorectal Cancers and Adenomas NCT00843375
Preliminary Longitudinal Validation of Biomarkers Predictive of Barrett's Esophagus NCT00844077