Breakdown of Desmoplasia in Pancreatic Cancer to Enhance Drug Effectiveness

描述（由申请人提供）：胰腺腺癌（Pancreatic adenocarticoma, pdac）是高度粘连性的，表现为低血管灌注，导致缺氧，药物传递和有效性差。在PDAC中，结缔组织形成是由肿瘤相关成纤维细胞（TAFs）驱动的，TAFs被血管紧张素II （ATII）的几种下游效应物激活。我们已经证明，在PDAC模型中，ATII受体1 （AT1R）拮抗剂氯沙坦可以减少结缔组织增生，提高细胞毒性药物的递送和有效性。最近的研究也表明，特定的巨噬细胞亚型在PDAC粘连增生的发生和消退中起着不同的作用。通过激动剂抗体激活CD40，增强了“具有纤维溶解潜能”的巨噬细胞在pdac中的浸润，从而导致胶原含量迅速减少。在这里，我们提出TAFs共同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Aim 1中，我们将测量AT1R阻滞剂坎地沙坦、CD40受体兴奋剂单克隆抗体FGK45或坎地沙坦联合FGK45对转基因和原位PDAC小鼠模型中结扎形成、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，我们将结合原位酶谱法和特定巨噬细胞亚群的免疫荧光。为了证实巨噬细胞在减少结缔组织增生中的作用，我们将用氯膦酸脂质体治疗小鼠。在Aim 2中，我们将确定坎地沙坦和FGK45如何影响PDAC模型中的血液灌注、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，小鼠将接受细胞毒治疗。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PDAC的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.