Principal Investigator

Matthew D
Stachler
Awardee Organization

University Of California, San Francisco
United States

Fiscal Year
2024
Activity Code
R37
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Optimization and validation of a biomarker panel for risk stratification in Barrett's esophagus

Intestinalization of the esophagus, termed Barrett’s esophagus (BE), is thought to develop in response to chronic acid and bile reflux and carries great clinical significance because it is the precursor to esophageal adenocarcinoma (EAC). The incidence of BE is quite high, estimated to be found in at least 1:100 people. While relatively few with BE progress to cancer there is great importance to being able to detect and treat those at risk of progression as EAC is an aggressive cancer with potential for early spread. Efforts to screen for high-risk disease in those with BE have, to date, not been very successful. Therefore, there is profound need to define the process by which BE progresses into EAC, to develop biomarkers to diagnose early progression and assess progression risk in BE tissues as well as to develop novel therapies for treatment. The objective of this R01 proposal is to investigate the ability of biomarkers to identify BE patients at high risk of progression. Using results from two externally funded genomic studies in non-dysplastic BE (NDBE) and BE with low-grade dysplasia (LGD) and previously published results, we will compare biomarkers and determine an optimized combination for risk stratification in two prospective cohorts including patients with NDBE or LGD. We will then validate our risk stratification assay in an independent US cohort. Finally, we will compare our genomic biomarker panel results in paired biopsy and brush samples. A unique collaboration between the PI Dr. Stachler, expert gastroenterologist (Dr. J Bergman), a talented computational biologist (Dr. CZ Zhang), and an expert biostatistician (Dr. K Zwinderman) along with key collaborators allows a truly innovated study to be performed. This will be accomplished using an unprecedented collection of clinically derived samples, a highly optimized targeted sequencing panel, and novel computational approaches that allow a wide array of information to be determined in a cost effective, clinically relevant manor. Aim 1: Identify a set of genomic biomarkers highly predictive of progression in biopsies from a prospective cohort of patients diagnosed with NDBE and LGD and assess whether the addition of methylation-based biomarkers improves stratification. For clinical implementation all biomarkers should be compared head to head in order to determine an optimized combination of biomarkers for risk stratification. Aim 2: Validate the risk stratification assay in a multi-institutional cohort of patients with a baseline diagnosis of NDBE or LGD. For clinical implementation, it is vital to validate any risk stratification assay on completely independent cohorts looking at clinically relevant time points. Aim 3: Determine if brush-based sampling devices improve biomarker detection over standard endoscopic biopsies. Broad sampling of the BE epithelium may allow for increased rates of detection for genomic or methylation biomarkers, therefore we will determine if samples from a brushed based device can better risk stratify patients compared to standard biopsies.

Publications

  • Qurat-Ul-Ain, Frei NF, Khoshiwal AM, Stougie P, Odze R, Camilleri-Broet S, Ferri L, Duits LC, Bergman J, Stachler MD. Feasibility Study Utilizing NanoString's Digital Spatial Profiling (DSP) Technology for Characterizing the Immune Microenvironment in Barrett's Esophagus Formalin-Fixed Paraffin-Embedded Tissues. Cancers. 2023 Dec 18;15. (24). PMID: 38136440
  • Chatterjee A, Azevedo-Martins JM, Stachler MD. Interleukin-33 as a Potential Therapeutic Target in Gastric Cancer Patients: Current Insights. OncoTargets and therapy. 2023 Aug 10;16:675-687. doi: 10.2147/OTT.S389120. eCollection 2023. PMID: 37583706
  • Rubenstein JH, Stachler MD. TSP-9: A Barrett's Esophagus Biomarker Better Than Pathologists? Gastroenterology. 2023 Nov;165(5):1106-1107. Epub 2023 Sep 1. PMID: 37659675
  • Stachler MD. Bridging the Gap between Diseases of the Stomach and Lower Esophagus. Cancer discovery. 2023 Jun 2;13(6):1291-1293. PMID: 37264822