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.

项目摘要/摘要抑制肿瘤对放疗仍然是改善诊断患者预后的关键障碍本地高级，无法切除的癌症。细胞对电离辐射（IR）的敏感性由细胞内控制和细胞外因子。为了克服肿瘤辐射，敏感性肿瘤细胞的药物对电离使用辐射（IR）。非靶向的细胞毒性化学疗法与放射疗法同时进行证明癌症患者的肿瘤控制得到改善和总体存活。但是，由于这个范式转移方法发生在1980年代，在分子发展中缺乏令人震惊的进展有针对性的放射敏化方法。改善IR的治疗比率与系统地结合可以通过两种一般方法来实现递送的药物，1）使用阻止DNA损伤修复的药物反应2）选择性地将放射敏化药物赋予肿瘤。这两种方法是正交的实现相同最终目标的技术，以增加IR诱导的肿瘤杀死，同时减少正常组织毒性。为了解决这两个基本的癌症治疗问题，我们专注于目标发现和肿瘤选择性药物输送车。关于目标发现，我们最近的研究非典型的CRAF功能导致我们发现了PAK在DNA损伤修复中的意外作用，对IR的敏感性。 PAK由I和II组中的六个激酶组成。重要的是，Pak是参与肿瘤发生，肿瘤攻击性和患者存活的过程中心。应对肿瘤选择性药物输送，我们正在开发药物共轭的可激活细胞穿透宠物（ACPP）基于细胞外肿瘤蛋白酶活性，有选择地将有效的放射增敏剂传递到肿瘤中。 ACPP 由药物共轭的多阳离子细胞穿透性肽和自身抑制性聚苯故肽组成通过柔性肽接头彼此分离。该肽接头被蛋白酶特别裂解富含细胞外肿瘤微环境。当ACPP完好无损时，药物共轭细胞穿透性肽被多支肽肽中和（即以“促毒物”状态持有），以便该药物无法访问其细胞内目标。肿瘤微环境蛋白酶清除ACPP并释放药物共轭细胞穿透肽，然后被肿瘤细胞吸收。我们建议的目标是为了了解PAK如何控制放射线，然后从理论上可以用靶向PAK来利用这一点在AIM 1中，我们将普遍确定I组和II组管理的机制 IR抗性。在AIM 2中，我们将实际测试用小分子进行放射敏化肿瘤的能力 PAK抑制剂。在AIM 3中，我们将测试靶向ACPP的肿瘤是否增加了共轭PAK的治疗比率抑制剂。我们的方法在DNA损伤目标发现和肿瘤中都具有互补的创新选择性药物输送。结合这些方法将为摆脱非目标而奠定基础细胞毒性放射敏化对生物标志物驱动的分子辐射敏化。