Targeting PAK4 for Overcoming Drug Resistance in Pancreatic Cancer

靶向 PAK4 克服胰腺癌耐药性

• 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
• 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

 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。 Ras 基因编码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 中细胞增殖不受控制。尽管 Ras 信号网络已被充分了解，但这些知识无法转化为开发新的抗癌药物。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标的理想结合袋。为了克服这一科学挑战，需要紧急开发新的靶标，无论是来自 Ras 结构本身，还是来自 Kras 的关键直接相互作用伙伴或下游效应器（此处为 p21 激活激酶 4/PAK4）。 PAK 家族成员是 Ras 下游的关键效应子，Ras 充当控制关键细胞过程的调节开关，导致肿瘤侵袭。最近，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非常强的相关性。因此，我们假设 PAK4 蛋白是难以捉摸的 Ras 途径中一个有吸引力的药物候选者，并且它的抑制将通过抑制 PDAC 中 Kras 介导的增殖信号来克服 GEM 耐药性。早期针对 PAK4 的不成功尝试（在非胰腺模型中进行测试）导致 I 型 ATP 竞争性抑制剂 PF-03798309 的开发，但由于通过多药耐药蛋白 (MDR) 导致药物过度外流，导致其不良的药代动力学特征，该药物在一项临床试验中被提前终止。从那时起，就没有认真尝试开发针对这种难以捉摸的蛋白质的更新和更好的抑制剂，因此我们对 PAK4 抑制剂的了解存在空白。为了填补这一科学空白，我们开发了第一个 II 类 PAK4 变构调节剂，该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。在这个高度转化的提案中，我们将描述我们的新型 PAK4 抑制剂针对耐药性 PDAC 的效用。这些研究将有助于理解 PDAC 中 PAK4 依赖性耐药机制。我们的具体目标是： Aim-1：证明 PAK4 是耐药 PDAC 的诊断和治疗生物标志物。 Aim-2：评估原位和公认的转基因胰腺癌中 PAK4 抑制对肿瘤生长的影响 [KrasG12D/+； LSL-Trp53 R172H/+； Pdx-1-Cre]动物模型。影响：我们新发现的 II 型 PAK4 变构调节剂显示出对抗治疗耐药性 PDAC 的活性。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。