In the U.S., the incidence of esophageal adenocarcinoma (EAC) is rising more rapidly than other cancer, increasing 350% in the last 30 years. Most cases of EAC are preceded by Barrett's esophagus (BE), observed in 2-5% of the population. Although only 0.5% of individuals with BE develop EAC annually, it is widely agreed that the rate of EAC for BE patients with high-grade dysplasia (HGD) approaches 5-8%. Thus, current guidelines recommend routine endoscopic surveillance for HGD followed by eradication of HGD lesions. A major challenge is that current white light (WL) endoscopic surveillance requires invasive and cumbersome random biopsies since HGD arising within BE is often patchy and indistinguishable from non-dysplastic mucosa. Thus, the vast majority of patients with non-dysplastic BE undergo unnecessary surveillance with biopsies. Moreover, this strategy is insensitive, with up to 40% of patients with HGD harboring additional foci of undetected EAC and does not permit real-time identification of dysplasia for immediate treatment. These inherent limitations of our current surveillance approach underscores the need for novel endosopic imaging methods which can detect, in real time and in situ, HGD with high sensitivity. Our overall goal is to advance technologies that we have developed utilizing near infrared fluorescent (NIRF) endoscopic imaging of novel optical probes activated selectively in dysplasia by cathepsin B (CTSB) proteases. In the prior funding period, we have made considerable progress in the development of this approach for more sensitive, real time detection of colorectal neoplasia. We have also demonstrated selective upregulation of CTSB in small HGD lesions within background, CTSB-negative non-dysplastic BE. Thus, we now propose to translate these innovative CTSB-selective probes for the detection of HGD in BE using mouse models which closely mimic human disease and human BE tissue samples which have been histologically and genomically characterized. We will leverage this preclinical work into a Phase l/ll clinical trial in patients with BE. If successful, this technology could fundamentally change our approach to the early detection and real time localization of HGD in BE, a critical area of unmet need for the prevention of EAC.
In the next year, an estimated 16,980 U.S. men and women will be diagnosed with esophageal adenocarcinoma (EAC) and 14,710 will die of the disease. Current endoscopic surveillance of Barrett's esophagus, the only known precursor for EAC, is cumbersome and insensitive. Thus, there is a clear imperative to develop novel approaches for early detection of high-grade dysplasia within background BE.
|Ananthakrishnan, Ashwin N; Du, Mengmeng; Berndt, Sonja I et al. (2015) Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies. Cancer Epidemiol Biomarkers Prev 24:198-205|
|Song, Mingyang; Gong, Jian; Giovannucci, Edward L et al. (2015) Genetic variants of adiponectin and risk of colorectal cancer. Int J Cancer 137:154-64|
|Lochhead, Paul; Chan, Andrew T; Nishihara, Reiko et al. (2015) Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol 28:14-29|
|Inamura, Kentaro; Yamauchi, Mai; Nishihara, Reiko et al. (2015) Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma. Ann Surg Oncol 22:1226-35|
|Serrano, César; Wang, Yuexiang; Mariño-Enríquez, Adrián et al. (2015) KRAS and KIT Gatekeeper Mutations Confer Polyclonal Primary Imatinib Resistance in GI Stromal Tumors: Relevance of Concomitant Phosphatidylinositol 3-Kinase/AKT Dysregulation. J Clin Oncol 33:e93-6|
|Rosenthal, Michael H; Kim, Kyung Won; Fuchs, Charles S et al. (2015) CT predictors of overall survival at initial diagnosis in patients with stage IV colorectal cancer. Abdom Imaging 40:1170-6|
|Arteaga, Carlos L; Engelman, Jeffrey A (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25:282-303|
|Wu, Chen; Kraft, Peter; Stolzenberg-Solomon, Rachael et al. (2014) Genome-wide association study of survival in patients with pancreatic adenocarcinoma. Gut 63:152-60|
|Ma, Tianle; Jang, Eun Jeong; Zukerberg, Lawrence R et al. (2014) Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous polyposis (FAP) syndrome. Surg Endosc 28:2349-56|
|Blaszkowsky, L S; Ryan, D P; Szymonifka, J et al. (2014) Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer. Ann Oncol 25:121-6|
Showing the most recent 10 out of 259 publications