Combination of tumor targeted therapy with stroma modulating agent for PDAC

摘要 胰腺导管腺癌（PDAC）是胰腺癌最常见的形式。是 是全球癌症相关死亡的第七大原因，5年生存率 仅占不到9%。胰腺肿瘤治疗中的三个主要问题是： 由于胰腺血液供应有限，抗癌分子的可用性， 对一线药物如吉西他滨耐药和肿瘤间质广泛纤维化。有一个 迫切需要通过同时靶向治疗PDAC的新的有效治疗策略 肿瘤及其微环境。鉴于Myc作为多细胞介导剂的中心作用， 因此，靶向原癌基因的表达是非常必要的 Myc和控制K-Ras介导的胰腺癌耐药。另一方面， 实体瘤的I型胶原致密的细胞外基质严重限制了药物的摄取， 单克隆抗体和纳米治疗剂在胰腺肿瘤中的应用。过度表达的局灶性 粘附激酶（FAK）在胰腺癌的血管生成、纤维化和转移中起作用。 我们假设口服FAK抑制剂（PND 1186）将促进摄取， BRD 4 PROTAC蛋白体的渗透。PROTAC是一类新型的抗癌分子 其选择性地降解靶蛋白而不是仅仅抑制它。 在我们的实验室中发现，BRD 4蛋白水解靶向嵌合体（PROTAC）和FAK抑制剂 - PND 1186在2D和3D中抑制胰腺癌细胞和内皮细胞的生长 文化纳米制剂显示出溶解度和稳定性的显著增强。因此我们 提出了使用BRD 4的长循环白蛋白包被的纳米脂质体的联合疗法 PROTAC和PND 1186（白蛋白体）。建议的SuRE奖的目的是探索 用于胰腺肿瘤特异性递送BRD 4 PROTAC的白蛋白体和PND在肿瘤中的作用 纳米颗粒的吸收。为了实现这一目标，我们提出了两个具体目标：具体目标1。 ARV负载的白蛋白体（AAnano）和PND纳米制剂的系统表征 （PNDnano）.具体目标2。AAnano的抗癌效果、肿瘤摄取和毒性评价 和PNDnano在人胰腺肿瘤异种移植模型中的作用。考虑到缺乏有效的 对于PDAC的治疗，所提出的想法具有显著的临床相关性。

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. It is the seventh leading cause of cancer-related mortality worldwide with the 5-year survival rate standing only at less than 9%. Three major issues in pancreatic tumor treatment are; poor availability of anticancer molecules due to limited blood supply to pancreas, development of resistant to first line agent e.g. Gemcitabine and extensive fibrosis in tumor stroma. There is an urgent need for a novel and effective therapeutic strategy for PDAC via simultaneously targeting tumor and its tumor microenvironment. Given the central role of Myc as a mediator of multiple cell proliferation and survival pathways, it is very essential to target the proto-oncogenic expression of Myc and controlling K-Ras mediated drug resistance in pancreatic cancer. On another side, collagen type I dense extracellular matrix of solid tumor severely restricts the uptake of drug, monoclonal antibodies and nanotherapeutics within pancreatic tumor. Overexpressed focal adhesion kinase (FAK) in pancreatic cancer plays role in angiogenesis, fibrosis and metastasis. We hypothesize that oral delivery of FAK inhibitor (PND1186) will facilitate the uptake and penetration of BRD4 PROTAC albuminosomes. PROTAC is novel class of anticancer molecules which selectively degrades the targeted protein instead of mere inhibiting it. Preliminary studies in our laboratory revealed that BRD4 Proteolysis Targeting Chimera (PROTAC) and FAK inhibitor – PND1186 inhibit the growth of pancreatic cancer cells, and endothelial cells in 2D and 3D culture. Nanoformulation showed significant enhancement in solubility and stability. Thus, we propose a combination therapy using a long circulating albumin coated nanoliposome of BRD4 PROTAC and PND1186 (Albuminosomes). The aim of proposed SuRE award is to explore the albuminosomes for pancreatic tumor specific delivery of BRD4 PROTAC and role of PND in tumor uptake of nanoparticle. To achieve this goal, we propose two specific aims; Specific aim 1. Systematic characterization of ARV-loaded albuminosomes (AAnano) and PND nanoformulation (PNDnano). Specific aim 2. Anticancer efficacy, tumor uptake and toxicity evaluation of AAnano and PNDnano in human pancreatic tumor xenograft model. Considering the scarcity of effective therapy for PDAC, the proposed idea has significant clinical relevance.