Breakdown of Desmoplasia in Pancreatic Cancer to Enhance Drug Effectiveness

描述（由申请人提供）：胰腺腺癌（PDAC）具有高度促纤维增生性，血管灌注低，导致缺氧，药物输送和有效性差。在PDAC中，结缔组织增生由肿瘤相关成纤维细胞（TAF）驱动，TAF由血管紧张素II（ATII）的几种下游效应物激活。我们已经表明，ATII受体1（AT1R）拮抗剂氯沙坦减少结缔组织增生，并改善PDAC模型中细胞毒性药物的递送和有效性。最近的研究还表明，特定的巨噬细胞亚型在PDAC结缔组织增生的发展和消退中发挥不同的作用。激动剂抗体对CD40的激活增强了PDAC中“具有纤维溶解潜力”的巨噬细胞的浸润，这导致胶原蛋白含量迅速降低。在这里，我们提出，共同靶向巨噬细胞和胶原合成的TAF将导致快速和持续减少结缔组织增生的PDAC模型。在目的1中，我们将测量AT1R阻断剂坎地沙坦、CD40激动剂单克隆抗体FGK 45或坎地沙坦与FGK 45联合对PDAC转基因和原位小鼠模型中的结缔组织增生、胶原重塑、巨噬细胞募集和TAF密度的影响。为了评估巨噬细胞在胶原降解中的作用，我们将联合收割机结合特定巨噬细胞亚群的原位酶谱和免疫荧光。为了证实巨噬细胞在结缔组织增生减少中的作用，我们将用脂质体氯膦酸盐治疗小鼠。在目标2中，我们将确定坎地沙坦和FGK 45如何影响PDAC模型中的血液灌注、血管正常化、药物递送和缺氧。为了确定FGK 45和坎地沙坦如何影响治疗效果，将用细胞毒素处理小鼠。如果这些方法中的任何一种成功，我们的结果将为我们的临床合作者领导的PDAC未来临床试验奠定基础。

DESCRIPTION (provided by applicant): 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.