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/II 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.
| Danai, Laura V; Babic, Ana; Rosenthal, Michael H et al. (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600-604 |
| Grasso, Catherine S; Giannakis, Marios; Wells, Daniel K et al. (2018) Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov 8:730-749 |
| Corcoran, Ryan B; André, Thierry; Atreya, Chloe E et al. (2018) Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer. Cancer Discov 8:428-443 |
| Song, Mingyang; Wu, Kana; Meyerhardt, Jeffrey A et al. (2018) Fiber Intake and Survival After Colorectal Cancer Diagnosis. JAMA Oncol 4:71-79 |
| Babic, A; Schnure, N; Neupane, N P et al. (2018) Plasma inflammatory cytokines and survival of pancreatic cancer patients. Clin Transl Gastroenterol 9:145 |
| Lopes-Ramos, Camila M; Kuijjer, Marieke L; Ogino, Shuji et al. (2018) Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism. Cancer Res 78:5538-5547 |
| Van Blarigan, Erin L; Ou, Fang-Shu; Niedzwiecki, Donna et al. (2018) Dietary Fat Intake after Colon Cancer Diagnosis in Relation to Cancer Recurrence and Survival: CALGB 89803 (Alliance). Cancer Epidemiol Biomarkers Prev 27:1227-1230 |
| Patra, Krushna C; Kato, Yasutaka; Mizukami, Yusuke et al. (2018) Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol 20:811-822 |
| Katona, Bryson W; Yurgelun, Matthew B; Garber, Judy E et al. (2018) A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet Med 20:1324-1327 |
| Jeon, Jihyoun; Du, Mengmeng; Schoen, Robert E et al. (2018) Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors. Gastroenterology 154:2152-2164.e19 |
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