Administrative Supplements to Participate in the NCI Early-stage Surgeon Scientist Program (ESSP)

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PROJECT SUMMARY ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as "NOT- CA-21-100." Esophageal cancer (EC) is the sixth most common cause of cancer deaths worldwide, with 5- year survival of 20%. The two primary subtypes of EC, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), demonstrate markedly different sensitivities to standard-of-care neoadjuvant regimens, including chemotherapy and chemoradiation prior to esophagectomy, and adjuvant immunotherapy protocols for residual disease. Given their differential sensitivities to treatment, there is a critical need to identify the unique vulnerabilities of ESCC and EAC and develop tailored treatment regimens for each histology, which historically have been treated as a single disease. The transcription factor p63 is a marker of squamous cell differentiation, and our preliminary data have shown that it is highly expressed in ESCC cell lines and absent in EAC cell lines. P63 is a known regulator of cellular metabolism, with established roles in promoting glycolysis and redox homeostasis in both embryonic development and squamous cell tumors, while the absence of p63 results in glucose intolerance and metabolic syndrome. We aim to determine the role of p63 in defining metabolic programs that underlie ESCC and EAC histologies in order to define their unique metabolic vulnerabilities and identify novel therapeutic targets, towards a more personalized treatment approach for esophageal cancers. Through the proposed Specific Aims and Career Development Plan, we will quantify the flux through metabolic pathways that define ESCC and EAC and determine their dependence on p63 isoform expression, correlating these results with markers of squamous and glandular differentiation. Furthermore, we will validate these results against metabolome profiles of treatment-naïve ESCC and EAC tissue samples. In Aim 2, we will define direct and indirect metabolic targets of p63 isoforms in esophageal cancer cell lines and organoids using CUT-and-RUN and transcriptomics analyses, and integrate these datasets using multi-omics approaches to define the metabolic network downstream of p63. Studies will be performed in 2D and 3D cultures using established cell lines and patient- derived organoids, as well as patient-derived biopsy samples, and utilize functional genomics, high throughput metabolomics, and multi-omics integration in novel 3D culture models that recapitulate the native architecture and physiology of human esophagus and esophageal cancers. The results of these studies will provide novel insight into the unique metabolic vulnerabilities of ESCC and EAC that underlie their sensitivity and resistance phenotypes, and will provide the basis for future studies to establish new metabolic targets for treatment of this deadly disease.