Thursday, May 9, 2024
5/9/2024
Summary. This is a Type 2 R01 renewal application to continue studying Barrett’s esophagus (BE), a premalignant condition wherein the normal squamous esophageal lining is replaced by a specialized metaplastic columnar epithelium in response to chronic gastroesophageal reflux (GERD). BE patients carry an increased risk of developing esophageal adenocarcinoma (EAC), a rapidly growing, lethal malignancy (5-year survival <20%) whose incidence in the U.S.A. has increased exponentially over the past four decades. The first 5 years of funding by this Academic-Industrial Partnership award have resulted in the creation of a highly successful new company, Capsulomics (also known as Previse), with the development of a fully licensed commercial prognostic product to assess future neoplastic progression risk in BE. The current Type 2 renewal proposal will continue this productive partnership, building on its success while tackling two major clinical dilemmas: 1) The currently accepted marker for EAC risk in BE patients is histologic dysplasia, either high-grade (HGD) or low- grade (LGD). In many centers, confirmed HGD is treated in the same manner as early-stage EAC, i.e., by endoscopic eradication therapy (EET). However, unlike HGD, the predictive value of LGD for cancer risk assessment is weak; moreover, high inter-observer variation in histologic assessment is problematic. Finally, most BE patients never develop LGD or HGD and thus have no means of gauging their progression risk. Thus, accurate, objective, quantitative biomarkers of progression risk in BE will be extremely useful. 2) Early-stage esophageal neoplasia is highly curable; however, most EACs are detected at advanced, incurable stages. Furthermore, only 5% of patients presenting with EAC were previously diagnosed with BE, suggesting that failed BE detection leads to delayed EAC diagnosis. Thus, better early detection of BE and EAC is needed to improve patient outcome. However, the current means of detection, upper GI endoscopy (EGD), is too expensive, invasive, and inaccessible to be practical for population-based screening. Thus, nonendoscopic early BE and EAC detection strategies are needed. We will tackle these challenges by pursuing the following Specific Aims: 1. Analytically and clinically validate and commercialize the EsoPredict methylation assay for personalized BE risk assessment; 1A: Perform an expanded analytical and multicenter clinical validation study of the prognostic assay EsoPredict on FFPE tissue-derived DNAs from 400 patients, incorporating multivariate analyses; 1B: Develop and implement pathways to introduce and establish EsoPredict into clinical practice; 2. Develop, validate, and begin commercialization of the EsoDetect diagnostic assay for nonendoscopic BE diagnosis, using a swallowable-retrievable sponge sampling device; 2A. Build and test a multivariate algorithm on sponge-derived DNAs from 600 patients with various stages of BE neoplasia, incorporating multivariate analyses; 2B. Initiate commercialization of the sponge sample-based EsoDetect assay; and 3. Conduct a prospective study of EsoPredict in tissues and non-endoscopic sponge samples from 350 BE patients, including 260 carried forward from Aim 2.
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