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Tumor-intrinsic and Paracrine Roles of Endoglin in Pancreatic Cancer

Sponsored by National Cancer Institute

$376.7K Funding
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ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy featuring early metastasis late onset ofsymptoms and notorious resistance to existing therapies. A critically elusive aspect of this disease relates tothe tumors which are often hypovascularized relative to other solid cancers manifesting in poor perfusion andimpaired drug delivery. In preliminary studies we discovered that endoglin normally an endothelial-specificTGF-beta coreceptor required for angiogenesis is expressed as two variants in pancreatic cancer cells- thewildtype which supports tumor-intrinsic growth and chemoresistance; and a novel splice variant with distinctstructural features that gets secreted to inhibit tumor vascularization. To understand their interplay in thetumor microenvironment we have generated a variety of cellular and pharmacologic reagents to interrogatethe underlying mechanisms and their therapeutic potential. We propose to define novel paracrinemechanisms of TGF-beta signaling that suppress PDAC vascularization (Aim 1); and identify tumor-intrinsicendoglin pathways as critical therapeutic targets in PDAC (Aim 2); and determine the endoglin variants asdistinct spatiotemporal targets during disease progression (Aim 3). Results from these studies will define TGF-beta-based mechanisms critical for PDAC tumor growth and vascularization and deliver clinically relevantdata for improved patient-based therapeutics.