Pancreatic adenocarcinomas (PDACs) are highly desmoplastic and exhibit low vascular perfusion, which leads to hypoxia, and poor drug delivery and effectiveness. In PDAC, desmoplasia is driven by tumor-associated fibroblasts (TAFs), which are activated by several downstream effectors of angiotensin II (ATII). We have shown that the ATII receptor 1 (AT1R) antagonist losartan reduces desmoplasia and improves the delivery and effectiveness of cytotoxic agents in PDAC models. Recent studies have also suggested that specific macrophage subtypes play differential roles in the development and resolution of PDAC desmoplasia. The activation of CD40 by an agonist antibody enhances the infiltration of macrophages "with a fibrolytic potential" in PDACs, which produces a rapid reduction in collagen content. Here, we propose that co-targeting macrophages and collagen synthesis by TAFs will lead to a rapid and sustained reduction in desmoplasia in PDAC models.
In Aim 1, we will measure the effects of the AT1R blocker candesartan, the CD40 agonist monoclonal antibody FGK45 or candesartan combined with FGK45 on desmoplasia, collagen remodeling, macrophage recruitment, and TAF density in transgenic and orthotopic mice models of PDAC. To assess the role of macrophages in collagen degradation we will combine in-situ zymography and immunofluorescence of specific macrophage subpopulations. To confirm the role of macrophages in desmoplasia reduction we will treat mice with liposomal clodronate.
In Aim 2 we will determine how candesartan and FGK45 affect blood perfusion, vascular normalization, drug delivery, and hypoxia in our PDAC models. To establish how FGK45 and candesartan affect therapeutic effectiveness, mice will be treated with cytotoxics. If any of these approaches is successful, our results will form the foundation for future clinical trials in PDAC led by our clinical collaborators.

Public Health Relevance

The collagen-rich desmoplasia in pancreatic ductal adenocarcinomas (PDAC) reduces vascular perfusion, and the delivery and effectiveness of cytotoxic agents. Thus it is imperative to develop matrix modifiers that will reduce desmoplasia and enhance vascular perfusion and drug uptake. We will determine in transgenic mice with PDAC if a CD40 agonist antibody combined with the angiotensin II receptor blocker candesartan can reduce reduce desmoplasia, and improve vascular perfusion and therapeutic effectiveness. We will also elucidate the mechanisms leading to reduce desmoplasia and improvement in vascular perfusion.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Muszynski, Karen
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Massachusetts General Hospital
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