Understanding and targeting MAPK pathway activation in NF1-deficient malignant peripheral nerve sheath tumor (MPNST)

了解和靶向 NF1 缺陷的恶性周围神经鞘瘤 (MPNST) 中的 MAPK 通路激活

基本信息

批准号：
10657337
负责人：
Ping Chi
金额：
$ 61.7万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657337
关键词：
ATAC-seq Adolescent Adult Alleles Bar Codes Benign Biological Markers Biological Models Biopsy Biopsy Specimen CCR CDKN2A gene Cells Clinical Clinical Treatment Clonal Evolution Combined Modality Therapy Complex Coupled Custom Defect Developmental Therapeutics Program Dose Evaluation Evolution Family Feedback Future Genomics Goals Growth Heterogeneity Human In Vitro Loss of Heterozygosity MAP Kinase Gene MEKs Malignant - descriptor Mediating Memorial Sloan-Kettering Cancer Center Modeling Molecular Molecular Target Mutate Mutation Neoplasm Metastasis Neurofibromatosis 1 Neurofibrosarcoma PDGFRA gene PDGFRB gene Pathway interactions Patients Peripheral Nerve Sheath Neoplasm Phase Phase I/II Clinical Trial Phosphorylation Plexiform Neurofibroma Polycomb Pre-Clinical Model Prognosis Radiation therapy Recommendation Recurrence Research Personnel Resistance Resources Role Safety Sampling Site Soft tissue sarcoma Specimen System Systemic Therapy Technology Up-Regulation cell growth chemotherapy clinical investigation clinical practice design epigenomics in vivo in vivo Model inhibitor inhibitor therapy insight interdisciplinary approach loss of function neoplastic cell next generation sequencing novel novel therapeutics phase I trial pre-clinical preclinical evaluation resistance mechanism response sarcoma single cell analysis single-cell RNA sequencing success therapeutic development therapeutically effective therapy resistant tumor tumor growth tumor heterogeneity

ATAC-seq Adolescent Adult Alleles Bar Codes Benign Biological Markers Biological Models Biopsy Biopsy Specimen CCR CDKN2A gene Cells Clinical Clinical Treatment Clonal Evolution Combined Modality Therapy Complex Coupled Custom Defect Developmental Therapeutics Program Dose Evaluation Evolution Family Feedback Future Genomics Goals Growth Heterogeneity Human In Vitro Loss of Heterozygosity MAP Kinase Gene MEKs Malignant - descriptor Mediating Memorial Sloan-Kettering Cancer Center Modeling Molecular Molecular Target Mutate Mutation Neoplasm Metastasis Neurofibromatosis 1 Neurofibrosarcoma PDGFRA gene PDGFRB gene Pathway interactions Patients Peripheral Nerve Sheath Neoplasm Phase Phase I/II Clinical Trial Phosphorylation Plexiform Neurofibroma Polycomb Pre-Clinical Model Prognosis Radiation therapy Recommendation Recurrence Research Personnel Resistance Resources Role Safety Sampling Site Soft tissue sarcoma Specimen System Systemic Therapy Technology Up-Regulation cell growth chemotherapy clinical investigation clinical practice design epigenomics in vivo in vivo Model inhibitor inhibitor therapy insight interdisciplinary approach loss of function neoplastic cell next generation sequencing novel novel therapeutics phase I trial pre-clinical preclinical evaluation resistance mechanism response sarcoma single cell analysis single-cell RNA sequencing success therapeutic development therapeutically effective therapy resistant tumor tumor growth tumor heterogeneity

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项目摘要

Project Abstract Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft tissue sarcomas that occur in distinct clinical settings: neurofibromatosis 1 (NF1)-associated (45%), sporadic (45%) or radiotherapy (RT)-associated (10%). MPNSTs metastasize early and are resistant to radiotherapy and systemic chemotherapy and have poor prognosis. Irrespective of the clinical settings, MPNSTs share the same molecular pathway inactivation in NF1 (>90%, hence NF1-deficient), Polycomb repressive complex 2 (PRC2), and CDKN2A through biallelic genetic alterations, suggesting that they can be molecularly targeted similarly. NF1- deficient plexiform neurofibroma responds well to MEK inhibitor (MEKi) treatment clinically; however, NF1- deficeint MPNSTs arising from plexiform neurofibromas are universally resistant to MEKi, suggesting intrinsic resistance in the more aggressive form of peripheral nerve sheath tumors. Using MPNST patient tumor samples and preclinical MPNST models, we have uncovered that PRC2-loss leads to PDGRA upregulation; MEKi treatment resulted in feedback upregulation of PDGFRB irrespective of the PRC2 status. The convergence of the PDGFR pathway activation by different mechanisms points to a novel therapeutic opportunity to target the PDGFR pathway to overcome MEKi resistance in MPNST. Combination of a novel PDGFRA/B inhibitor, ripretinib with a MEKi leads to synergistic growth inhibition of MPNST in vitro and in vivo. We hypothesize that PDGFRA/B pathway activation represent a central resistance mechanism to MEKi and combined targeting of the PDGFR and MAPK pathways with ripretinib (pan-PDGFRA/B inhibitor) and binimetinib (MEKi) may present an effective therapeutic strategy in NF1-deficient MPNST. Here, we propose to investigate the tumor heterogeneity and cellular plasticity involved in tumor evolution and adaptive resistance to binimetinib and combination of ripretinib and binimetinib, using well-defined preclinical MPNST in vitro and in vivo model systems and single-cell analysis including single cell RNA-seq (scRNA-seq) and a novel barcoding system. Additionally, we propose a collaborative clinical investigation between CCR/NCI (Drs. Widemann/Shern) and MSKCC (Dr. Chi) to conduct a proof-of-concept phase I/II study of the combination of ripretinib and binimetinib in patients with NF1-deficient MPNST. In this trial, we will assess and optimize the evaluation of MAPK pathway inhibition to the ripretinib/binimetinib combination therapy using traditional ERK phosphorylation and newly established custom Pea3-family ETS-regulated MAPK signature. Further, we will also investigate the tumor heterogeneity and cellular plasticity in tumor evolution and resistance mechanisms to the ripretinib/binimetinib combination using targeted NGS, scRNA-seq and integrative analysis. The proposal leverages the synergistic expertise and resources at MSKCC and CCR/NCI. We believe that these studies will generate mechanistic insight of therapeutic resistance and provide the pivotal clinical and translational information for future definitive trials, with the potential to change the clinical practice in MPNST.

项目摘要恶性周围神经鞘肿瘤（MPNST）代表一组高度侵略性的软组织在不同的临床环境中发生的肉瘤：神经纤维瘤病1（NF1）相关（45％），零星（45％）或放疗（RT）相关（10％）。 MPNST早日转移，对放射疗法有抵抗力和全身性化学疗法且预后差。无论临床环境如何，MPNST共享相同的分子 NF1（> 90％，因此缺乏NF1），PolyComb抑制复合物2（PRC2）和通过双重遗传改变的CDKN2A，表明它们可以分子类似地靶向。 NF1- 缺乏丛状神经纤维瘤对MEK抑制剂（MEKI）的反应良好。但是，NF1- 由丛状神经纤维瘤引起的缺陷MPNST普遍抵抗Meki，这表明固有以更具侵略性的外周神经鞘肿瘤的抗性。使用MPNST患者肿瘤样品和临床前MPNST模型，我们发现PRC2损失会导致PDGRA上调。梅基治疗导致PDGFRB的反馈上调，与PRC2状态无关。融合通过不同机制激活的PDGFR途径指向针对目标的新型治疗机会 PDGFR途径克服MPNST中的MEKI抗性。新型PDGFRA/B抑制剂Ripretinib的组合 MEKI导致MPNST体外和体内的协同增长抑制。我们假设这一点 PDGFRA/B途径激活代表了MEKI的中央电阻机制并组合用ripretinib（PAN-PDGFRA/B抑制剂）和Binimetinib靶向PDGFR和MAPK途径（MEKI）可能会在NF1缺乏的MPNST中提出有效的治疗策略。在这里，我们建议研究参与肿瘤进化和的细胞可塑性和使用明确定义的临床前，对二米替尼的自适应耐药性以及ripretinib和binimetinib的组合 MPNST在体外和体内模型系统和单细胞分析，包括单细胞RNA-SEQ（SCRNA-SEQ）和一个新颖的条形码系统。此外，我们提出了CCR/NCI之间的协作临床研究（Widemann/Shern博士）和MSKCC（Chi博士）进行概念验证阶段I/II的组合研究 NF1缺陷MPNST患者的Ripretinib和Binimetinib的。在此试验中，我们将评估和优化使用传统ERK评估对Ripretinib/Binimetinib组合疗法的MAPK途径抑制磷酸化和新建立的自定义PEA3-元素ETS调节的MAPK签名。此外，我们会的还研究肿瘤的异质性和细胞可塑性在肿瘤演化和抗性机制中使用靶向NGS，SCRNA-SEQ和综合分析的Ripretinib/Binimetinib组合。提案利用MSKCC和CCR/NCI的协同专业知识和资源。我们相信这些研究将产生治疗性抗性的机械洞察力，并提供关键的临床和翻译未来确定试验的信息，有可能改变MPNST的临床实践。