Breakdown of Desmoplasia in Pancreatic Cancer to Enhance Drug Effectiveness

描述(申请人提供)：胰腺癌(PDAC)是高度促结缔组织增生性疾病，表现为低血管灌注，导致缺氧，药物输送和疗效差。在PDAC中，促结缔组织增生是由肿瘤相关成纤维细胞(TAFs)驱动的，TAFs由血管紧张素II(ATII)的几个下游效应分子激活。我们已经证明ATII受体1(AT1R)拮抗剂氯沙坦可减少PDAC模型中的促结缔组织增生，并改善细胞毒剂的输送和有效性。最近的研究还表明，特定的巨噬细胞亚型在PDAC结缔组织增生症的发生和消退中发挥着不同的作用。CD40被激动剂抗体激活后，增强了巨噬细胞在PDAC中的渗透，从而导致胶原含量的迅速减少。在这里，我们认为TAFs联合靶向巨噬细胞和胶原合成将导致PDAC模型中结缔组织增生的快速和持续减少。在目标1中，我们将检测AT1R阻滞剂坎地沙坦、CD40激动剂单抗FGK45或坎地沙坦与FGK45联合使用对转基因和原位PDAC小鼠模型中促结缔组织增生、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，我们将结合特定巨噬细胞亚群的原位酶谱和免疫荧光。为了确认巨噬细胞在减少促结缔组织增生中的作用，我们将用氯屈膦酸脂质体治疗小鼠。在目标2中，我们将确定坎地沙坦和FGK45如何影响我们的PDAC模型的血液灌流、血管正常化、药物输送和缺氧。为了确定FGK45和坎地沙坦如何影响治疗效果，将对小鼠进行细胞毒素治疗。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未来PDAC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.