GrantR01CA
Tumor-intrinsic and paracrine roles of endoglin in pancreatic cancer
- Activity
- R01
- Institute
- CA
- Fiscal years
- 2023–2026
- Amount counted
- $1,485,340
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Abstract public domain (NIH RePORTER)
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy featuring early metastasis, late onset of symptoms, and notorious resistance to existing therapies. A critically elusive aspect of this disease relates to the tumors which are often hypovascularized relative to other solid cancers, manifesting in poor perfusion and impaired drug delivery. In preliminary studies, we discovered that endoglin, normally an endothelial-specific TGF-beta coreceptor required for angiogenesis, is expressed as two variants in pancreatic cancer cells- the wildtype, which supports tumor-intrinsic growth and chemoresistance; and a novel splice variant with distinct structural features that gets secreted to inhibit tumor vascularization. To understand their interplay in the tumor microenvironment, we have generated a variety of cellular and pharmacologic reagents to interrogate the underlying mechanisms and their therapeutic potential. We propose to define novel paracrine mechanisms of TGF-beta signaling that suppress PDAC vascularization (Aim 1); and identify tumor-intrinsic endoglin pathways as critical therapeutic targets in PDAC (Aim 2); and determine the endoglin variants as distinct 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 relevant data for improved patient-based therapeutics.
Public health relevance public domain (NIH RePORTER)
PROJECT NARRATIVE Pancreatic cancer is one of the most lethal malignancies with poor long-term survival due to its delayed onset of symptoms and notorious resistance to existing chemotherapy and radiation. Hence, there is an unmet urgent need for better early diagnosis, screening and treatment methods. Here our project investigates a protein uniquely expressed in pancreatic tumors and released into patient blood, which we will test as a biomarker and therapeutic target.