Combination Therapy for Pancreatic Cancer

摘要： 胰腺癌是最致命的癌症之一，也是导致癌症死亡的第四大原因。 在美国。吉西他滨(GEM)与紫杉醇(PTX)或NAB-紫杉醇(纳米粒)的组合 (NP)白蛋白结合PTX，Abraxane®)是局部复发或转移性前列腺癌的一线治疗方法之一。 然而，在临床上仅显示出有限的益处。此外，这种治疗与显著的 毒性。前列腺癌的特点是存在致密的间质，这可能限制相对有效的穿透。 大型核动力源。另一方面，游离宝石迅速从血液循环中消除，也 被脱氨酶迅速失活的。因此，迫切需要开发符合以下条件的小型核燃料 能够保护药物，并有效地促进肿瘤的蓄积和渗透。我们最近展示了 GEM与POEg-co-PVD聚合物的偶联使其粒径从160降至 13 nm。由此产生的纳米载体，名为PGEM，在肿瘤聚集和渗透方面非常有效。 作为一种GEM前药，PGEM体内抗肿瘤活性显著增强。此外，PGEM具有很高的 有效地将GEM与另一种疏水药物，如CCR2拮抗剂PF-04136309(PF)共传递。 Flow研究显示，经PGEM处理后，CD8+T细胞应答增加。但是我们也观察到， 髓系来源的抑制细胞(MDSCs)数量增加。机械学研究表明， 经PGEM处理后的CCL2和CCL7。已知CCL2和CCL7作用于肿瘤细胞上的CCR2和 免疫细胞通过直接作用于肿瘤细胞和促进肿瘤侵袭转移 免疫抑制细胞的招募。我们的初步数据显示，PF被掺入PGEM NPs中 导致了PANC02模型的显著改进。更重要的是，这种治疗导致了一场激烈的 肿瘤免疫微环境的改善，与抗PD-1治疗相结合是个好兆头。 这一应用的重点是基于PF/PGEM治疗的进一步改进和表征。一个 还将开发改进的PGEM(PGEMi)，以提高PF和PGEM在肿瘤中的生物利用度 纸巾。本申请将追求三个具体目标：目标1将开发和表征PGEMi和 PF/PGEMi的生物物理和体外生物学特性。目标2将定义肿瘤的穿透性 PGEMi的效率，以及pF/pGEMi在小鼠和人前列腺癌模型中的PK和生物分布 PDX模型。AIM 3将研究PF/PGEMi在各种PCa中的毒性分布和治疗效果 模特们。这项研究的完成可能会导致开发一种新的、改进的联合疗法， 将推进前列腺癌的治疗。

ABSTRACT: Pancreatic cancer (PCa) is one of the deadliest forms of cancers and the fourth leading cause of cancer deaths in the United States. Combination of gemcitabine (GEM) and paclitaxel (PTX) or Nab-paclitaxel (nanoparticle (NP) albumin-bound PTX, Abraxane®) is one of the first-line treatments for locally recurrent or metastatic PCa. However, only limited benefits have been shown in clinic. In addition, this treatment is associated with significant toxicity. PCa is characterized by the presence of dense stroma that may limit effective penetration of relatively large-sized NPs. On the other hand, free GEM is rapidly eliminated from the blood circulation and is also subjected to rapid inactivation by deaminase. Therefore, there is an urgent need to develop small NPs that are capable of protecting the drugs and are effective in tumor accumulation and penetration. We have recently shown that conjugation of GEM to POEG-co-PVD polymer led to a significant decrease in the particle size from 160 to 13 nm. The resulting nanocarrier, named PGEM, was highly effective in tumor accumulation and penetration. As a GEM prodrug, PGEM showed significantly improved antitumor activity in vivo. In addition, PGEM is highly effective in codelivery of GEM and another hydrophobic drug such as PF-04136309 (PF), a CCR2 antagonist. Flow study showed that PGEM treatment also led to increased CD8+ T cell response. However, we also observed increased numbers of myeloid-derived suppressor cells (MDSCs). Mechanistic study showed upregulation of CCL2 and CCL7 following treatment with PGEM. CCL2 and CCL7 are known to act on CCR2 on tumor cells and immune cells and promote tumor invasion and metastasis through both direct impact on tumor cells and recruitment of immunosuppressive cells. Our preliminary data showed that incorporation of PF into PGEM NPs led to significant improvement in PANC02 model. More importantly this treatment resulted in a drastic improvement in tumor immune microenvironment, which boded well with combination with anti-PD-1 treatment. This application is focused on further improvement and characterization of PF/PGEM-based therapy. An improved PGEM (PGEMi) will also be developed to improve the bioavailability of both PF and PGEM in tumor tissues. Three specific aims will be pursued in this application: Aim 1 will develop and characterize PGEMi and PF/PGEMi with respect to biophysical and in vitro biological properties. Aim 2 will define the tumor penetration efficiency of PGEMi, and the PK and biodistribution of PF/PGEMi in murine and human PCa models including PDX model.Aim 3 will investigate the toxicity profile and the therapeutic efficacy of PF/PGEMi in various PCa models. Completion of this study may lead to the development of a new and improved combination therapy that will advance the treatment of PCa.