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（由适用提供）：胰腺导管腺癌（PDAC）是一种致命的疾病，迫切需要新的分子靶向药物。长期以来，KRAS癌基因的畸变已被认为是这种疾病的主要驱动力。 RAS基因代码为一组在细胞信号传导中发挥作用的蛋白质，并且在突变时允许PDAC中不受控制的细胞增殖。尽管RAS信号网络已经很好地理解，但是这些知识不能转化为开发新的癌症药物。这主要是因为RAS蛋白缺乏理想的结合口袋，通常是小分子药物的吸引力。为了克服这一科学挑战，需要紧急探索来自RAS结构本身的较新目标，或者是从关键的直接相互作用伙伴或KRAS的下游效应（此处p21激活的激酶4/pak4）都需要紧急探索。 PAK家族成员是RAS下游的关键作用，它充当控制关键细胞过程的调节开关，从而导致肿瘤侵袭性。最近，研究表明，大型PDAC患者队列中PAK4基因的扩增。我们在吉西他滨（GEM）抗性PDAC模型中进行的研究表明，PAK4过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ELSECTION RAS途径中的一种有吸引力的药物候选者，其抑制作用将通过抑制PDAC中的KRAS介导的增殖信号传导来克服GEM耐药性。较早的尝试靶向PAK4的尝试（在非胰腺模型中进行了测试）导致I型ATP竞争性抑制剂PF-03798309的发展，该抑制剂PF-03798309的发展是基于单个临床试验过早停用的，鉴于其由于多种药物的不良药代动力学特征而导致过多的药物通过多种驱动力蛋白质（Multi-drug oftim ofti-drugance protee）（Mdrs protee）（Mdrs protee）（Mdrs prote）（MDRS）。从那时起，就没有认真地尝试针对这种难以捉摸的蛋白质开发新的和优越的抑制剂，因此我们的知识在与PAK4抑制剂有关的知识中存在空隙。在填补这一科学空隙的情况下，我们开发了PAK4 II类变构调节剂中的第一个，该调节剂在耐药性胰腺癌中显示了选择性活性。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性（MDR）蛋白的底物。在这个高度翻译的建议中，将描绘出我们新颖的PAK4抑制剂对抗性PDAC的实用性。这些研究将有助于理解PDAC中PAK4依赖性抗性机制。我们的具体目的是：AIM-1：证明PAK4是抗性PDAC的诊断和治疗生物标志物。 AIM-2：评估对原位且公认的胰腺癌转基因抑制PAK4抑制的影响[KRASG12D/+； LSL-TRP53 R172H/+; PDX-1-CRE]动物模型。影响：我们新发现的II型PAK4变构调节剂显示抗治疗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PAK4变构调节剂进行重点设计，毒性和有效性测试。