Targeting PAK4 for Overcoming Drug Resistance in Pancreatic Cancer

靶向 PAK4 克服胰腺癌耐药性

基本信息

批准号：
8890492
负责人：
Asfar S Azmi
金额：
$ 19.93万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8890492
关键词：
ABCB1 gene ABCG2 gene Adenocarcinoma Cell Animal Model Antineoplastic Agents Automobile Driving Binding Biological Assay Biological Markers Cancer Etiology Cell Line Cell Proliferation Cell model Cell physiology Cells Cessation of life Characteristics Chemicals Clinical Clinical Trials Code Collaborations Consensus Cytoskeleton Development Diagnostic Disease Drug Efflux Drug Targeting Drug resistance Environment Family Family member Future Genes Goals Guanosine Triphosphate Phosphohydrolases Heterogeneity Human Investigation Knowledge Letters Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modality Modeling Molecular Multi-Drug Resistance Mutate Mutation Neoplasm Metastasis Nuclear Oncogenes Oncogenic Outcome P-Glycoproteins Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Permeability Pharmaceutical Preparations Play Proteins RAS genes RNA Interference Recruitment Activity Residual Tumors Resistance Role Set protein Signal Transduction Small Interfering RNA Structure Systems Biology Testing Therapeutic Toxicity Tests Transgenic Mice Transgenic Organisms Translating Withdrawal base cohort design efficacy testing epithelial to mesenchymal transition gemcitabine genetic resistance inhibitor/antagonist link protein novel novel therapeutics p21 activated kinase pharmacokinetic characteristic preclinical study public health relevance ras Proteins resistance mechanism rho rho GTP-Binding Proteins small hairpin RNA small molecule stem success therapeutic target therapy resistant tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease in urgent need of newer molecularly targeted drugs. Aberrations in the Kras oncogene for long have been appreciated to be a major driver of this disease. Ras genes code for a set of proteins that are instrumental in cellular signaling, and when mutated, permit uncontrolled cellular proliferation in PDAC. Even though, the Ras signaling network has been well understood, however this knowledge could not be translated into developing new cancer drugs. This is primarily because Ras proteins lack the ideal binding pockets that usually serve as attractive targets for small molecule drugs. To overcome this scientific challenge, newer targets, either from the Ras structure itself, or from critical direct interacting partners or downstream effectors of Kras (here the p21 activated kinase 4/PAK4) need to be urgently exploited. The PAK family members are key effectors downstream of Ras, which act as regulatory switches that control critical cellular processes, leading to tumor aggressiveness. Recently, studies have shown amplification of PAK4 gene in large PDAC patient cohorts. Our investigations in gemcitabine (GEM) resistant PDAC models showed a very strong correlation between PAK4 over-expression and drug resistance. Therefore we hypothesize that PAK4 protein is an attractive druggable candidate in the elusive Ras pathway and its inhibition will overcome GEM resistance by suppressing Kras mediated proliferative signaling in PDAC. Earlier unsuccessful attempts to target PAK4 (tested in non-pancreatic models) resulted in the development of a Type I ATP competitive inhibitor PF-03798309 that was prematurely discontinued based on a single clinical trial in view of its undesirable pharmacokinetic characteristics due to excessive drug efflux through multi-drug resistance proteins (MDRs). Since then there have been no serious attempts to develop newer and superior inhibitors against this elusive protein, and thus there is a void in our knowledge in relation to PAK4 inhibitors. Filling this scientific void we have developed the first in class Type II allosteric modulators of PAK4 that show selective activity in resistant pancreatic cancer. Most importantly, unlike PF-03798309, our Type II PAK4 allosteric modulators are not substrates to multi-drug resistance (MDR) proteins. In this highly translational proposal, the utility of our novel PAK4 inhibitors against resistant PDAC will be delineated. These studies will help in the understanding of PAK4 dependent resistance mechanisms in PDAC. Our specific aims are: Aim-1: Demonstrate that PAK4 is a diagnostic and therapeutic biomarker for resistant PDAC. Aim-2: Evaluate the impact on tumor growth of PAK4 inhibition in orthotopic and well recognized pancreatic cancer transgenic [KrasG12D/+; LSL-Trp53 R172H/+; Pdx-1-Cre] animal models. Impact: Our newly discovered Type II PAK4 allosteric modulators show activity against therapy resistant PDAC. The outcome of our proposed pre-clinical studies will enable us to have a focused design, toxicity and efficacy testing of PAK4 allosteric modulators in PDAC.

描述（由申请人提供）：胰腺导管腺癌（PDAC）是一种致命的疾病，迫切需要更新的分子靶向药物。长期以来，Kras 癌基因的异常被认为是这种疾病的主要驱动因素。一组在细胞信号传导中发挥作用的蛋白质，当突变时，会导致 PDAC 中的细胞增殖不受控制。尽管 Ras 信号传导网络已被充分了解，但这些知识无法转化。这主要是因为 Ras 蛋白缺乏通常作为小分子药物有吸引力的靶点的理想结合袋，为了克服这一科学挑战，需要来自 Ras 结构本身或来自关键的直接相互作用伙伴的新靶点。或 Kras 的下游效应器（此处为 p21 激活激酶 4/PAK4）需要紧急开发。PAK 家族成员是 Ras 下游的关键效应器，它们充当控制关键细胞过程的调节开关，导致肿瘤侵袭性。研究表明，PAK4 基因在大型 PDAC 患者群体中出现扩增，我们对吉西他滨 (GEM) 耐药性 PDAC 模型的研究表明，PAK4 过度表达与耐药性之间存在很强的相关性，因此我们认为 PAK4 蛋白是一种有吸引力的药物候选者。难以捉摸的 Ras 通路及其抑制将通过抑制 PDAC 中 Kras 介导的增殖信号来克服 GEM 耐药性，早期针对 PAK4 的失败尝试（在非胰腺模型中进行了测试）导致了这一结果。 I 型 ATP 竞争性抑制剂 PF-03798309 的开发，由于其因多药耐药蛋白 (MDR) 导致药物外流过多而产生不良药代动力学特征，基于单一临床试验，该抑制剂被提前终止。我们认真尝试开发针对这种难以捉摸的蛋白质的更新、更优越的抑制剂，因此我们在 PAK4 抑制剂方面的知识存在空白，为了填补这一科学空白，我们开发了同类首个抑制剂。 PAK4 的 II 型变构调节剂在耐药性胰腺癌中表现出选择性活性最重要的是，与 PF-03798309 不同，我们的 II 型 PAK4 变构调节剂不是多药耐药 (MDR) 蛋白的底物。我们将描述针对耐药性 PDAC 的新型 PAK4 抑制剂，这些研究将有助于理解 PDAC 中 PAK4 依赖性耐药机制。目标 1：证明 PAK4 是耐药 PDAC 的诊断和治疗生物标志物；目标 2：评估原位和公认的转基因胰腺癌 [KrasG12D/+；LSL-Trp53 R172H/； +；Pdx-1-Cre] 动物模型：我们新发现的 II 型 PAK4 变构调节剂显示出对抗治疗耐药的活性。 PDAC。我们提出的临床前研究的结果将使我们能够对 PDAC 中的 PAK4 变构调节剂进行集中设计、毒性和功效测试。