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Collaborations :: PPG on Esophagus Carcinoma

PI, A. Rustgi
Co-PI, M. Herlyn

2003 - present

Abstract

Esophageal cancer, especially squamous cell cancer, carries with it a dismal prognosis as the preponderance of patients present at late stages, thereby defying traditional chemoradiation therapy. Advances in molecular pathogenesis and therapy will provide a foundation for squamous cell cancers at other sites. This is a competing renewal of the NCI P01entitled "Mechanisms of Esophageal Carcinogenesis" that has made substantial progress in elucidating the molecular mechanisms underlying squamous cell
carcinogenesis with translation to new strategies in therapy. Novel, innovative models have been generated involving 3D organotypic cultures, in vivo bioluminescence imaging in immunodeficient mice and genetically engineered mice that permit recapitulation, for the first time, cardinal genetic features of esophageal squamous cell cancer. New insights have been gained into the esophageal tumor microenvironment, revealing that the interplay between transformed esophageal epithelial cells, mesenchymal stromal fibroblasts and endothelial cells is critical in fostering tumorigenesis. Mechanisms have been identified that underlie resistance to chemoradiation therapy. The experience and expertise of the Project Leaders, in concert with the platforms provided by the Core Facilities, will result in enhancement of the research that would not be possible if the projects were independent of each other. Project 1 (Rustgi, Project Leader) will focus upon the biological roles of the EGFR oncogene and cooperation with p120-catenin and p53 tumor suppressor genes in esophageal carcinogenesis, and the role of activated stromal fibroblasts in augmenting
tumor cell invasion in the microenvironment. Project 2 (Herlyn, Project Leader) defines the relationship between fibroblasts and endothelial cells in the tumor microenvironment, and exploits this information to develop new therapeutics. Project 3 (Diehl, Project Leader) elucidates the manner in which cyclin D1 is regulated and defines the novel role of the Fbx4 mutations in esophageal carcinogenesis, with translation into the development of therapeutic approaches. Four highly successful Core facilities are designed to provide esophageal cancer-specific services for the stimulation of collaborative research: Morphology, Molecular Biology, Biostatistics and Administrative. The Program Project has the unequivocal support of the University of Pennsylvania Cancer Center and Medical School (with robus commitment of new resources) and will continue to foster interdisciplinary research at Penn and nationally which leads to a cooperative understanding of the molecular processes that form and regulate esophageal carcinogenesis.

Project 2: The tumor microenvironment in esophageal squamous cell carcinoma

M. Herlyn, Project Leader

Our long-term objective is to develop new therapies for esophageal squamous cell carcinoma (ESCC) that are based on the unique biological characteristics of this malignancy. Our working hypothesis is that tumor cells establish a dominant relationship with stromal cells to control the formation of a primitive ‘organ’, in which all cellular constituents contribute to tumor cell growth, survival and invasion. We then hypothesize that tumor cell resistance to conventional therapies is due to intrinsic and microenvironmental factors. In preliminary studies we have developed three-dimensional culture models of the normal esophagus and of ESCC tumors that mimic conditions in vivo. These models allow us to dissect the roles for each cell type in a tissue-like context to determine how tumors progress and resist therapeutic drugs. This hypothesis will be pursued by the following interrelated Specific Aims: 1) To determine and define the functional synergy between stromal fibroblasts, endothelial cells, and ESCC cells with a focus upon the interplay between stromal fibroblasts and endothelial cells to nurture the microenvironment for esophageal tumor cells. To that end, tumors represent a finely tuned ‘organ’ in which the malignant cells dominate to drive activation of fibroblasts for matrix and growth factor production. Activated fibroblasts in turn attract endothelial cell and induce their differentiation for vessel formation and provide positive feedback for the tumor cells. We will analyze the secretion of soluble mediators (eg TGFbeta) and the dynamics of cell-cell interactions that together increase the invasive nature of tumors; 2) We will develop strategies to overcome the strong resistance of ESCC cells to current therapy. We believe that the unusual resistance to drugs is due to both microenvironmental and intrinsic cues. We will target the fibroblast-endothelial axis. In the second strategy, we have identified a proteasome inhibitor, Bortezomib, as very active. We will determine how we can enhance it’s efficacy in SCC and plan to use it in combination with radiation and pro-apototic agents. Project 2 is closely integrated with Project 1 (Aims 2 and 3) and Project 3 (Aims 1 and 3), and makes extensive use of the outstanding, cohesive core facilities.