Targeting PAK4 for Overcoming Drug Resistance in Pancreatic Cancer

靶向 PAK4 克服胰腺癌耐药性

• 批准号: 9023516
• 负责人: Asfar S Azmi
• 金额: $ 16.68万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023516
• 关键词: ABCB1 gene; ABCG2 gene; Adenocarcinoma Cell; Animal Model; Automobile Driving; Binding; Biological Assay; Cancer Etiology; Cell Line; Cell Proliferation; Cell model; Cell physiology; Cells; Cessation of life; Characteristics; Chemicals; Clinical; Clinical Trials; Code; Collaborations; Consensus; Cytoskeleton; Development; Disease; Drug Efflux; Drug Targeting; Drug resistance; Environment; Family; Family member; Future; Genes; Goals; Guanosine Triphosphate Phosphohydrolases; 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; diagnostic biomarker; efficacy testing; epithelial to mesenchymal transition; gemcitabine; genetic resistance; inhibitor/antagonist; link protein; novel; novel anticancer drug; novel therapeutics; overexpression; 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; targeted agent; targeted treatment; therapeutic biomarker; therapy resistant; three dimensional cell culture; tumor; tumor growth; tumor heterogeneity

 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(申请人提供)：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癌基因的异常一直被认为是这种疾病的主要驱动因素。RAS基因编码一组蛋白质，这些蛋白质在细胞信号转导中起作用，当发生突变时，允许PDAC中的细胞不受控制地增殖。尽管RAS信号网络已经被很好地理解，但是这种知识不能被转化为开发新的抗癌药物。这主要是因为RAS蛋白缺乏理想的结合口袋，而这些口袋通常是小分子药物的诱人靶点。为了克服这一科学挑战，迫切需要开发新的靶点，要么来自RAS结构本身，要么来自关键的直接相互作用伙伴或Kras下游效应因子(这里是p21激活的激酶4/PAK4)。PAK家族成员是RAS下游的关键效应者，RAS充当调控开关，控制关键的细胞过程，导致肿瘤侵袭性。最近，研究表明PAK4基因在大量的PDAC患者队列中扩增。我们在吉西他滨(GEM)耐药的PDAC模型中的研究表明，PAK4的过度表达与耐药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通路中一个有吸引力的候选药物，它的抑制将通过抑制Kras介导的PDAC增殖信号来克服GEM耐药。早期针对PAK4的失败尝试(在非胰腺模型中测试)导致了I型三磷酸腺苷竞争性抑制剂PF-03798309的开发，鉴于其不良的药代动力学特征，由于通过多药耐药蛋白(MDR)过量的药物外排，该药基于一项临床试验而过早停用。从那时起，没有人认真尝试开发针对这种难以捉摸的蛋白质的新的和更好的抑制剂，因此，我们对PAK4抑制剂的了解是空白的。填补了这一科学空白，我们已经开发出第一个第二类PAK4变构调节剂，它在耐药胰腺癌中显示出选择性活性。最重要的是，与PF-03798309不同，我们的II型PAK4型变构调节剂不是多药耐药(MDR)蛋白的底物。在这项高度翻译的提案中，我们将描述我们的新型PAK4抑制剂对抗耐药PDAC的效用。这些研究将有助于理解PDAC中PAK4依赖的耐药机制。我们的具体目标是：目的-1：证明PAK4是耐药PDAC的诊断和治疗生物标志物。目的-2：在原位和公认的胰腺癌转基因[KrasG12D/+；LSL-Trp53 R172H/+；PDX-1-CRE]动物模型中，评价抑制PAK4对肿瘤生长的影响。影响：我们新发现的II型PAK4型变构调节剂显示出对抗耐药PDAC的活性。我们拟议的临床前研究的结果将使我们能够在PDAC中对PAK4变构调节剂进行有重点的设计、毒性和有效性测试。

项目成果

F-BOX proteins in cancer cachexia and muscle wasting: Emerging regulators and therapeutic opportunities.

• DOI: 10.1016/j.semcancer.2016.01.002
• 发表时间: 2016-02
• 期刊: Seminars in cancer biology
• 影响因子: 14.5
• 作者: Sukari A;Muqbil I;Mohammad RM;Philip PA;Azmi AS
• 通讯作者: Azmi AS

The Role of microRNAs in the Diagnosis and Treatment of Pancreatic Adenocarcinoma.

• DOI: 10.3390/jcm5060059
• 发表时间: 2016-06-16
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Diab M;Muqbil I;Mohammad RM;Azmi AS;Philip PA
• 通讯作者: Philip PA

The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities.

• DOI: 10.1080/14737140.2018.1417844
• 发表时间: 2018-03
• 期刊: Expert review of anticancer therapy
• 影响因子: 3.3
• 作者: Tesfaye AA;Kamgar M;Azmi A;Philip PA
• 通讯作者: Philip PA

Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma.

新型的P21激活激酶4（PAK4）变构调节剂克服胰腺导管腺癌中的耐药性和干性。

• DOI: 10.1158/1535-7163.mct-16-0205
• 发表时间: 2017-01
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Aboukameel A;Muqbil I;Senapedis W;Baloglu E;Landesman Y;Shacham S;Kauffman M;Philip PA;Mohammad RM;Azmi AS
• 通讯作者: Azmi AS

Targeting the Nuclear Export Protein XPO1/CRM1 Reverses Epithelial to Mesenchymal Transition.

• DOI: 10.1038/srep16077
• 发表时间: 2015-11-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Azmi AS;Muqbil I;Wu J;Aboukameel A;Senapedis W;Baloglu E;Bollig-Fischer A;Dyson G;Kauffman M;Landesman Y;Shacham S;Philip PA;Mohammad RM
• 通讯作者: Mohammad RM