Dissecting and targeting oncogenic functions of PAK4 in high-risk rhabdomyosarcoma

剖析和靶向 PAK4 在高风险横纹肌肉瘤中的致癌功能

基本信息

批准号：
10577174
负责人：
Jason Yustein
金额：
$ 37.14万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-06 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577174
关键词：
3-Dimensional Address Adolescent Advanced Malignant Neoplasm Alternative Splicing Biochemical Biology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Child Clinical Treatment Clinical Trials Combined Modality Therapy Cytotoxic Chemotherapy Data Development Disease Drug Combinations Drug Screening Equipment and supply inventories Evaluation Ewings sarcoma Family Genes Genetic Genetically Engineered Mouse Goals Guanosine Triphosphate Phosphohydrolases Histology Human Immune Immune checkpoint inhibitor Informatics Knock-out Knowledge MAP Kinase Gene Malignant Skeletal Muscle Neoplasm Mediating Metastatic Neoplasm to the Lung Mission Modeling Molecular Molecular Profiling Monitor Mus Mutation NF1 gene Oncogenic Operative Surgical Procedures Pathway interactions Patient-Focused Outcomes Patients Phenotype Phosphatidylinositols Phosphotransferases Pre-Clinical Model Protein Isoforms Protein Kinase Protein Splicing Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Public Health RAS inhibition RNA Splicing Radiation Ras Signaling Pathway Receptor Protein-Tyrosine Kinases Receptor Signaling Regimen Regulation Relapse Reporter Research Resistance Resources Rhabdomyosarcoma Role SN-38 Secondary to Serine Signal Pathway Signal Transduction Soft tissue sarcoma Survival Rate Therapeutic Therapeutic Intervention Toxic effect Treatment Protocols United States National Institutes of Health anti-PD-1 bioluminescence imaging checkpoint inhibition chemotherapy childhood sarcoma clinical application clinically relevant combinatorial differential expression efficacy evaluation functional genomics high risk improved in vivo in vivo Model inhibitor innovation insight mutant new therapeutic target novel novel therapeutic intervention novel therapeutics p21 activated kinase pharmacologic phosphoproteomics pre-clinical preclinical evaluation proteogenomics proteomic signature selective expression targeted agent targeted treatment therapy resistant transcriptomics tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Overall, survival rates for RMS are approximately 65-70%. However, despite intensification of chemotherapeutic regimens, long-term outcomes for patients with metastatic or relapsed rhabdomyosarcoma remain extremely poor, with overall survival rates between 20-30%. Thus, alternative targeted therapies are essential for improving patient outcomes. Our proposal will address a significant gap in the knowledge and treatment of high-risk rhabdomyosarcoma. RMS tumors have frequent mutations in the RAS/NF1 pathway and perturbations in the receptor tyrosine kinases (RTK)/RAS/phosphoinositide 3-kinase (PI3K) signaling axis, which are associated with high-risk conditions. The p21-activated kinases (PAK) family of serine/threonine kinases intersects the oncogenic signaling by RTK and RAS-activated pathways. Downstream PAK signaling regulates metastatic phenotypes and resistance to therapeutics, thus making them attractive targets for advanced cancers. Based upon extensive informatic, functional genomic, biochemical interactome and pharmacological data we have evidence that PAK4 regulates intrinsic and extrinsic mechanisms, including alternative splicing(AS) and immune modulatory signals, that contributes to RMS progression. In addition, using high-throughput combination drug screens we identified mechanistically rational and clinically applicable synergistic therapeutic regimens with PAK4 inhibition. The overarching goals of our proposal are to gain critical molecular insights into novel PAK4-mediated mechanisms and further investigate the therapeutic potential of targeting PAK4 in RMS. We will examine PAK4’s role as a novel regulator of AS and PAK4-mediated downstream transcriptomic and proteomic signatures that contribute to RMS progression through the use of our extensive inventory of highly relevant human and syngeneic murine pre-clinical models. We hypothesize PAK4 regulates critical intrinsic and extrinsic molecular signatures vital for RMS progression, and PAK4 inhibitors in combination with rational targeted agents can provide effective novel therapeutic regimens for these high-risk patients. We propose three independent, yet innovative and novel complementary aims to address this hypothesis. Aim1. Evaluation of PAK4 as a novel splicing regulating protein kinase and its direct effects on downstream signaling in RMS. Aim 2. Role of PAK4 in modulating the tumor microenvironment and identification of therapeutic applications using relevant murine pre-clinical models of RMS developed in our lab. Aim3. Investigate the therapeutic potential of inhibiting PAK4 in combination with mechanistically rational targeted agents using innovative ex vivo 3D lung metastasis models and in vivo orthotopic and metastatic RMS models. Completion of these studies will provide novel molecular insights into RMS biology and impact RMS therapy by providing new therapeutic strategies that can be quickly moved towards clinical trials for the treatment of relapsed or metastatic RMS.

项目概要/摘要横纹肌肉瘤（RMS）是儿童和青少年中最常见的软组织肉瘤。然而，尽管加强了化疗，RMS 的存活率仍约为 65-70%。治疗方案中，转移性或复发性横纹肌肉瘤患者的长期结果仍然非常严重总体生存率在 20-30% 之间，因此，替代靶向治疗对于改善病情至关重要。我们的建议将解决高风险知识和治疗方面的重大差距。横纹肌肉瘤的 RAS/NF1 通路频繁发生突变，并且 RAS/NF1 通路受到干扰。受体酪氨酸激酶 (RTK)/RAS/磷酸肌醇 3-激酶 (PI3K) 信号轴，与丝氨酸/苏氨酸激酶的 p21 激活激酶 (PAK) 家族与致癌物质相交。 RTK 和 RAS 激活途径的信号传导调节转移表型。和对治疗的抵抗力，从而使它们成为晚期癌症的有吸引力的目标。信息学、功能基因组、生化相互作用组和药理学数据，我们有证据表明 PAK4 调节内在和外在机制，包括选择性剪接（AS）和免疫调节信号，此外，使用高通量组合药物筛选，我们发现了有助于 RMS 进展的因素。机制合理且临床适用的 PAK4 抑制协同治疗方案。我们提案的总体目标是获得对新型 PAK4 介导机制的关键分子见解并进一步研究 PAK4 在 RMS 中的治疗潜力。 AS 和 PAK4 介导的下游转录组和蛋白质组特征的新型调节剂，有助于通过使用我们广泛的高度相关的人类和同基因小鼠库存来促进 RMS 进展我们探索了 PAK4 调节关键的内在和外在分子特征。 RMS进展，PAK4抑制剂与合理的靶向药物联合可以提供有效的新型我们为这些高危患者提出了三种独立但创新的治疗方案。互补的目的是解决这一假设。 Aim1。激酶及其对 RMS 下游信号传导的直接影响目标 2. PAK4 在调节肿瘤中的作用。使用相关的 RMS 小鼠临床前模型研究微环境并确定治疗应用我们的实验室开发了 Aim3 来研究抑制 PAK4 的治疗潜力。使用创新的离体 3D 肺转移模型和体内的机械合理的靶向药物原位和转移 RMS 模型的完成将为我们提供新的分子见解。 RMS 生物学并通过提供可快速推进的新治疗策略来影响 RMS 治疗治疗复发或转移性 RMS 的临床试验。