Preclinical Testing of Targeted Therapies for Neurofibromas

神经纤维瘤靶向治疗的临床前测试

• 批准号: 7645813
• 负责人: David W Clapp
• 金额: $ 61.93万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645813
• 关键词: Preclinical; Testing; Targeted; Therapies; Neurofibromas

DESCRIPTION (provided by applicant): Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1). NF1 encodes a GTPase activating protein (GAP) for p21ras (Ras) called neurofibromin, and studies by us and others have shown that the Ras signaling pathways are hyperactive in cells from NF1 patients. Neurofibromas are pathognomonic tumors that collectively affect 95% of NF1 patients. Neurofibromas are composed of Schwann cells, endothelial cells, fibroblasts, degranulating, inflammatory mast cells, and pericytes/vascular smooth muscle cells (VSMCs). Utilizing genetically engineered mice, Zhu et al (Science, 2002), found that haploinsufficiency of Nf1 in cells in the tumor microenvironment was required for development of neurofibromas. Our group previously provided the first genetic, cellular, and biochemical evidence that haploinsufficiency of Nf1 alters Ras activity and cell fates in mast cells. We have now shown that Nf1 mast cells release a diverse number of growth factors and other molecules in response to stimulation via c-kit ligand and that these growth factors and molecules collectively promote angiogenesis, the alteration of extracellular matrix and cell growth. In both Nf1 murine models and primary cells from NF1 patients, we have now identified haploinsufficient phenotypes in endothelial cells (ECs), VSMCs and fibroblasts that collectively promote neoangiogenesis, collagen synthesis and alter the extracellular matrix. Further, we have identified key growth factors and biochemical pathways that regulate the haploinsufficient gains-in-function in each of these lineages and verified that the murine model closely recapitulates the human disease phenotypes. Identification of these multiple Nf1 cellular phenotypes and development of in vitro and in vivo model systems provide us a platform to test compounds alone or in combination that inhibit key Ras effector kinases and growth factor receptors in neurofibromin deficient cells as a strategy to treat existing plexiform neurofibromas. Importantly, many of the kinases and molecular targets that we have discovered in neurofibromin deficient cells have also been identified in the treatment of more common cancers and provide us the opportunity to use existing preclinical compounds and phase 1-3 drugs that were developed for other uses. Therefore, in this application, we are focusing on compounds that have already beenextensively evaluated by pharmaceutical scientists in other model systems, thus allowing us to efficiently pursue multiple therapeutic targets. Finally, using a combination of PET and CT imaging, we now have the ability to image the development, growth, and metabolism of plexiform neurofibromas in genetically engineered mice in vivo as a function of time.

描述（由申请人提供）：NF1肿瘤抑制基因中的突变导致1型神经纤维瘤病（NF1）。 NF1编码称为Neurofiromin的P21RA（RAS）的GTPase激活蛋白（GAP），我们和其他人的研究表明，NF1患者的细胞中RAS信号通路是多活跃的。神经纤维瘤是病原体肿瘤，共同影响95％的NF1患者。神经纤维瘤由雪旺细胞，内皮细胞，成纤维细胞，脱粒，炎性肥大细胞和周细胞/血管平滑肌细胞（VSMC）组成。 Zhu等人（Science，2002）利用基因工程的小鼠，发现肿瘤微环境中NF1的单倍症是神经纤维瘤发展所必需的。我们的小组先前提供了第一个遗传，细胞和生化证据，即NF1的单倍不足会改变肥大细胞中的RAS活性和细胞命运。现在，我们已经表明，NF1肥大细胞通过C-KIT配体响应刺激而释放了多种生长因子和其他分子，并且这些生长因子和分子共同促进了血管生成，细胞外基质和细胞生长的改变。在NF1鼠模型和NF1患者的原代细胞中，我们现在已经确定了内皮细胞（ECS），VSMC和成纤维细胞中的单倍型表型，这些表型统一促进了新血管生成，胶原蛋白合成并改变细胞外基质。此外，我们已经确定了关键的生长因子和生化途径，这些因素和生化途径可以调节每个谱系中的单倍函数，并确认鼠模型密切概括了人类疾病表型。鉴定这些多个NF1细胞表型以及体外和体内模型系统的开发为我们提供了一个单独或组合测试化合物的平台，可抑制关键的RAS效应激酶和神经纤维蛋白缺陷细胞中的生长因子受体作为治疗现有的PLEXISTION神经纤维瘤的策略。重要的是，我们在神经纤维蛋白缺乏细胞中发现的许多激酶和分子靶标在治疗更常见的癌症中也已经鉴定出来，并为我们提供了使用现有的临床前化合物和开发用于其他用途的1-3期药物的机会。因此，在此应用中，我们专注于其他模型系统中药物科学家已经对已经进行了延展性评估的化合物，从而使我们能够有效地追求多个治疗靶标。最后，使用PET和CT成像的组合，我们现在可以在体内在基因工程小鼠中成像丛状神经纤维瘤的发育，生长和代谢作为时间的函数。