Combination of tumor targeted therapy with stroma modulating agent for PDAC

肿瘤靶向治疗与基质调节剂联合治疗 PDAC

基本信息

批准号：
10629924
负责人：
Ketankumar D. Patel
金额：
$ 16.4万
依托单位：
ST. JOHN'S UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-12 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629924
关键词：
3-Dimensional Address Albumins Antineoplastic Agents Apoptosis Award Biological Assay Blood Vessels Body Weight Cancer Etiology Cell Culture Techniques Cell Line Cell Proliferation Cell Survival Cells Cessation of life Circulation Coculture Techniques Collagen Type I Combined Modality Therapy Deposition Desmoplastic Development Drug Delivery Systems Drug Kinetics Drug resistance Emerging Technologies Endothelial Cells Environment Evaluation Extracellular Matrix Fibroblasts Fibrosis Focal Adhesion Kinase 1 Formulation Fostering Goals Growth Hematology Hepatotoxicity Human Hyaluronic Acid Immune checkpoint inhibitor Immunohistochemistry In Vitro Intravenous Investigation KRAS2 gene Kinetics Laboratories Liposomes Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator Mentors Metabolism Methods Microsomes Mission Monoclonal Antibodies Nanotechnology Nature Neoplasm Metastasis Oncogenic Oncoproteins Oral Pancreas Pancreatic Ductal Adenocarcinoma Pathogenesis Pathway interactions Patients Penetration Pharmaceutical Preparations Plasma Play Prognosis Proliferating Protac Proteins Research Research Methodology Research Proposals Resistance Resistance development Role Science Side Solid Neoplasm Solubility Students Survival Rate Testing Toxic effect Training Tumor Angiogenesis Tumor Markers Tumor Volume United States National Institutes of Health Universities Vascular blood supply Western Blotting Xenograft Model angiogenesis anti-cancer anticancer activity c-myc Genes cancer cell cancer type chimeric antigen receptor T cells clinically relevant combinatorial curative treatments cytotoxicity density design effective therapy gemcitabine graduate student human disease improved in vivo indexing innovative technologies kinase inhibitor liposomal formulation liposome vector mortality nanoformulation nanoliposome nanomedicine nanomolar nanoparticle nanotherapeutic neoplastic cell novel overexpression pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic neoplasm pharmacologic racial diversity recruit targeted delivery targeted treatment technology platform therapeutically effective three dimensional cell culture three-dimensional modeling translational approach tumor tumor growth tumor microenvironment tumor xenograft ubiquitin-protein ligase undergraduate student uptake

项目摘要

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.

抽象的胰腺导管腺癌（PDAC）是最常见的胰腺癌形式。以 5 年生存率计算，是全球癌症相关死亡的第七大原因胰腺肿瘤治疗的三大问题是：由于胰腺的血液供应有限，抗癌分子的可用性，开发对一线药物（例如吉西他滨）具有耐药性，并且肿瘤基质中存在广泛的纤维化。迫切需要通过同时靶向治疗 PDAC 的新颖有效的治疗策略考虑到 Myc 作为多细胞介质的核心作用。增殖和生存途径中，靶向原癌表达非常重要 Myc 和控制 K-Ras 介导的胰腺癌耐药性。实体瘤的I型胶原致密细胞外基质严重限制了药物的摄取，胰腺肿瘤内过表达的单克隆抗体和纳米疗法。胰腺癌中的粘附激酶（FAK）在血管生成、纤维化和转移中发挥作用。我们认为口服 FAK 抑制剂 (PND1186) 将促进吸收和 BRD4 PROTAC 蛋白体的渗透 PROTAC 是一类新型抗癌分子。它选择性地降解目标蛋白质而不是仅仅抑制它。我们实验室发现BRD4蛋白水解靶向嵌合体（PROTAC）和FAK抑制剂 – PND1186 抑制胰腺癌细胞以及 2D 和 3D 内皮细胞的生长因此，纳米制剂的溶解度和稳定性显着增强。提出使用长循环白蛋白包被的 BRD4 纳米脂质体的联合疗法 PROTAC 和 PND1186（白蛋白体）拟议的 SuRE 奖项的目的是探索用于胰腺肿瘤特异性递送 BRD4 PROTAC 的蛋白体以及 PND 在肿瘤中的作用为了实现这一目标，我们提出了两个具体目标：负载 ARV 的蛋白体 (AAnano) 和 PND 纳米制剂的系统表征 (PNDnano)。具体目标2. AAnano的抗癌功效、肿瘤摄取和毒性评价。考虑到在人胰腺肿瘤异种移植模型中缺乏有效性。对于 PDAC 的治疗，所提出的想法具有重要的临床意义。