This renew/al Project arose from the discovery made in our current Project 3 that collagen-rich desmoplastic tissue compresses blood vessels in tumors. Pancreatic adenocarcinomas (PDACs) are highly desmoplastic and exhibit low vascular perfusion, which leads to poor oxygenation and drug delivery, hypoxia-induced drug resistance and increased tumor aggressiveness. In PDAC, desmoplasia is driven by tumor-associated fibroblasts (TAFs), which are activated by several downstream effectors of Angiotensin II (ATM). ATII signaling stimulates TAFs to produce collagen through TSP1-dependent TGFB1 activation, MEK/ERK activation and SDF1a/CXCR4 expression in PDAC. foreover, the SDF1a/CXCR4 pathway promotes the recruitment of bone marrow-derived cells (e.g., granulocytes), which secrete pro-fibrotic molecules such as TGFB1 or produce collagen themselves. We hypothesize that by promoting desmoplasia, the TSP1/TGFB1 MEK/ERK and SDF1cx/CXCR4 pathways promote poor vascular perfusion, which limits the efficacy of cytotoxics in PDAC. Based on our preliminary data, we propose that specific blockade of these pathways-or of the master regulator ATM receptor 1 (AT1R)-reduces desmoplasia and increases perfusion, drug delivery and oxygenation in PDAC.
In Aim 1, we will compare the effects ofthe AT1R blockers losartan and telmisartan on desmoplasia in PDAC and determine their effects on the expression/activity of TSP1, TGFB1, SDFIa and ERK. We will then examine the effects of the direct blockade of TGFB1, MEK and CXCR4 on desmoplasia.
In Aim 2 we will determine how ATIR or TGFB1, MEK and CXCR4 blockers affect blood perfusion, vascular normalization, drug delivery and hypoxia in our PDAC models. Finally, in Aim 3 we will utilize the best matrix modifiers identified in Aims 1 and 2 to enhance the therapeutic efficacy of small (5FU and oxaliplatin) and large (Abraxane) therapeutics in PDAC (Aim 3). If any of these approaches is successful, our results will form the foundation for future clinical trials in PDAC led by our clinical collaborators.
The limited efficacy of cytotoxic agents in pancreatic cancer patients is linked in part to poor drug delivery. In our proposed studies we will test novel approaches to enhance the delivery and efficacy of cytotoxic agents using approved agents. If successful, these studies can be rapidly translated into the clinic as a novel treatment strategy for patients with pancreatic cancer.
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