Elucidation and therapeutic exploitation of PAK mediated radioresistance

PAK 介导的放射抗性的阐明和治疗利用

基本信息

批准号：
10302259
负责人：
Sunil J Advani
金额：
$ 36.14万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-18 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302259
关键词：
Address Affect Antibody-drug conjugates Attention Biosensor Cancer Histology Cancer Patient Cells Clinical Cytotoxic Chemotherapy DNA Damage DNA Repair Data Diagnosis Drug Delivery Systems Drug Sensitization Drug usage Family Foundations Goals Heterogeneity Human Ionizing radiation Label Link MEKs Malignant Neoplasms Mediating Methods Modeling Molecular Molecular Target Morbidity - disease rate Mus Nonmetastatic Normal tissue morphology Oncogenes Organ Pathway interactions Patient-Focused Outcomes Patients Peptide Hydrolases Peptide antibodies Peptides Pharmaceutical Preparations Pharmacology Phosphorylation Phosphotransferases Play Process Prodrugs Radiation Tolerance Radiation therapy Radiation-Sensitizing Agents Radiosensitization Resistance Role Schedule Serine Shock Signal Pathway Signal Transduction Techniques Technology Testing Therapeutic Therapeutic Index Toxic effect Translating Treatment Efficacy Tumor Cell Line Tumor Tissue Unresectable Work base biomarker-driven cancer cell cancer survival cancer therapy cell killing chemotherapy clinical translation clinically relevant curative treatments cytotoxic delivery vehicle extracellular flexibility genetic approach homologous recombination improved improved outcome inhibitor innovation insight kinase inhibitor molecular targeted therapies neoplastic cell novel novel therapeutics p21 activated kinase p21-activated kinase 1 patient derived xenograft model peptide drug radiation resistance radioresistant response side effect small molecule subcutaneous tool tumor tumor microenvironment tumor xenograft tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT Tumor resistance to radiotherapy remains a critical barrier to improving outcomes for patients diagnosed with locally advanced, unresectable cancers. Cellular sensitivity to ionizing radiation (IR) is governed by intracellular and extracellular factors. To overcome tumor radioresistance, drugs that sensitize tumor cells to ionizing radiation (IR) are used. Non-targeted cytotoxic chemotherapies given concurrently with radiotherapy have demonstrated improved tumor control and overall survival in cancer patients. However, since this paradigm shifting approach occurred in the 1980's there has been a shocking lack of progress in developing molecularly targeted radiosensitization approaches. Improving the therapeutic ratio of IR in combination with systemically delivered drugs can be achieved by two general approaches, 1) using drugs that block DNA damage repair responses 2) delivering radiosensitizing drugs selectively to tumors. These two methods are orthogonal techniques to achieve the same end goal of increasing IR induced tumor kill while reducing normal tissue toxicities. To address both of these fundamental cancer therapy problems, we have focused on target discovery and tumor selective drug delivery vehicles. With regards to target discovery, our recent studies on non-canonical CRAF functions led to our discovery of an unexpected role for PAK in DNA damage repair and sensitivity to IR. PAK is comprised of a family of six kinases subdivided in Group I and II. Importantly, PAK are involved in process central to oncogenesis, tumor aggressiveness and patient survival. To tackle tumor selective drug delivery, we are developing drug conjugated activatable cell penetrating peptides (ACPP) to selectively deliver potent radiosensitizers to tumors based on extracellular tumor protease activity. ACPP consist of a drug conjugated polycationic cell penetrating peptide and an autoinhibitory polyanionic peptide separated from each other by a flexible peptide linker. This peptide linker is specifically cleaved by proteases enriched in the extracellular tumor microenvironment. While ACPP is intact, the drug conjugated cell penetrating peptide is neutralized (i.e. held in a “pro-drug” state) by the polyanionic peptide so that the drug cannot gain access to its intracellular target. Tumor microenvironment proteases cleave ACPP and release the drug conjugated cell penetrating peptide, which is then taken up by tumor cells. The goals of our proposal are to gain insight into how PAK governs radioresistance and then therapeutically exploit this with targeted PAK inhibitors. In Aim 1, we will genetically determine the mechanisms through which Group I and II PAKs govern IR resistance. In Aim 2, we will pharmacologically test the ability to radiosensitize tumors with small molecule PAK inhibitors. In Aim 3, we will test if tumor targeted ACPP increase the therapeutic ratio of conjugated PAK inhibitors. Our approach has complementary innovations in both DNA damage target discovery and tumor selective drug delivery. Combining these approaches will lay a foundation for moving away from non-targeted cytotoxic radiosensitization to biomarker driven molecularly guided radiosensitization.

项目概要/摘要肿瘤对放疗的耐药性仍然是改善诊断为癌症的患者预后的一个关键障碍局部晚期、不可切除的癌症细胞对电离辐射 (IR) 的敏感性由细胞内控制。和细胞外因子，以克服肿瘤放射抗性，使肿瘤细胞对电离敏感的药物。与放射治疗同时进行的非靶向细胞毒性化疗。然而，由于这种模式，改善了癌症患者的肿瘤控制和总体生存率。方法的转变发生在 20 世纪 80 年代，令人震惊的是，在开发分子生物学方面却缺乏进展。靶向放射增敏方法与全身治疗相结合提高 IR 的治疗率。可以通过两种一般方法来实现，1）使用阻止 DNA 损伤修复的药物反应2）选择性地将放射增敏药物递送至肿瘤这两种方法是正交的。技术来实现相同的最终目标，即增加 IR 诱导的肿瘤杀伤力，同时减少正常组织为了解决这两个基本的癌症治疗问题，我们重点关注目标。在靶点发现方面，我们最近的研究涉及肿瘤选择性药物递送载体。非规范 CRAF 功能使我们发现 PAK 在 DNA 损伤修复和 PAK 由六种激酶组成，分为 I 组和 II 组。参与肿瘤发生、肿瘤侵袭性和患者生存的核心过程。选择性药物递送，我们正在开发药物偶联的可激活细胞穿透肽（ACPP）根据细胞外肿瘤蛋白酶活性选择性地将有效的放射增敏剂递送至肿瘤。由药物缀合的聚阳离子细胞穿透肽和自抑制聚阴离子肽组成通过柔性肽连接体彼此分开。该肽连接体被蛋白酶特异性切割。当 ACPP 完整时，药物结合细胞，富集在细胞外肿瘤微环境中。穿透肽被聚阴离子肽中和（即保持在“前药”状态），使得药物无法进入其细胞内靶标，肿瘤微环境蛋白酶会裂解 ACPP 并释放药物结合的细胞穿透肽，然后被肿瘤细胞吸收我们建议的目标是。深入了解 PAK 如何控制放射抗性，然后通过靶向 PAK 进行治疗性利用在目标 1 中，我们将从基因角度确定 I 组和 II 组 PAK 的控制机制。在目标 2 中，我们将从药理学角度测试小分子对肿瘤放射增敏的能力。在目标 3 中，我们将测试肿瘤靶向 ACPP 是否可以提高缀合 PAK 的治疗率。我们的方法在 DNA 损伤靶点发现和肿瘤方面具有互补的创新。结合这些方法将为摆脱非靶向给药奠定基础。细胞毒性放射增敏到生物标志物驱动的分子引导放射增敏。