Project 2: Targeted Therapies for Malignant Peripheral Nerve Sheath Tumors

项目2：恶性周围神经鞘瘤的靶向治疗

• 批准号: 8932163
• 负责人: STEPHEN X SKAPEK
• 金额: $ 48.55万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932163
• 关键词: Accounting; Address; Adult; Antineoplastic Agents; Biological Markers; Biology; CDK4 gene; CXCR4 gene; Cell Proliferation; Cell Surface Receptors; Cells; Child; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Complication; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Development; Diagnosis; Disease; Dose; Drug resistance; Excision; Foundations; Functional Imaging; G-Protein-Coupled Receptors; Gene Expression; Genetic; Genetic Engineering; Genetic study; Genetically Engineered Mouse; Germ Lines; Glucose; Goals; HIV; Human; Image; Individual; Ionizing radiation; Knowledge; Laboratory Study; Laboratory mice; Left; Life; Link; Malignant Neoplasms; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; NF1 Gene Inactivation; NF1 gene; Neurofibromatoses; Neurofibromatosis 1; Neurofibrosarcoma; New Agents; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Penetrance; Peripheral Nerve Sheath Neoplasm; Pharmaceutical Preparations; Pharmacodynamics; Phase; Pilot Projects; Plexiform Neurofibroma; Positioning Attribute; Positron-Emission Tomography; Pre-Clinical Model; Premalignant; Primary Neoplasm; Radiosurgery; Reproduction spores; Research; Schedule; Specimen; Speed; Therapeutic; Therapeutic Agents; Translations; Tumor Biology; Unresectable; Work; base; chemotherapy; clinically relevant; fighting; imaging biomarker; improved; in vivo Model; inhibitor/antagonist; insight; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel therapeutics; pre-clinical; preclinical study; response; response marker; sarcoma; soft tissue; stem; targeted treatment; therapeutic target; tool; tumor; tumor growth

PROJECT SUMMARY – PROJECT 2 The primary goal of this project is to develop better therapy for children with neurofibromatosis and malignant peripheral nerve sheath tumor (MPNST), the major life-threatening complication of neurofibromatosis. Sadly, children (and adults) with this aggressive soft tissue sarcoma are rarely cured if the tumor is large or has spread throughout the body. Further, the application of intensive chemotherapy, ionizing radiation, and surgery has done little to improve this dismal outcome. By leveraging robust pre-clinical models of neurofibromatosis, we are poised to erase major problems associated with MPNST. Our key insights stem from genetically engineered mouse models that recapitulate many facets of the human conditions. Their use has revealed two key “vulnerabilities” in MPNST: the cell surface receptor CXCR4, and Cyclin D1, which drives cell proliferation by activating Cyclin-dependent kinases 4 and 6 (CDK4/6). Our complementary molecular and genetic studies show that impeding CXCR4 or Cyclin D1-associated CDK4/6 blocks cell proliferation and tumor growth in both mouse and human MPNST. Fortunately, drugs that block CXCR4 and CDK4/6 are already available for use in children and adults. Plerixafor, a CXCR4 inhibitor originally developed to fight HIV, is available and has already been used in children. Palbociclib was developed as a CDK4/6 inhibitor for breast cancer and other malignancies that are linked to genetic amplification of Cyclin D1. It, too, has been utilized as an anti-cancer agent. Neither drug has been systematically applied to patients with neurofibromatosis and MPNST. To speed the translation from our pre-clinical models illuminating CXCR4 and CDK4/6 as therapeutic targets to the effective use of plerixafor and palbociclib in children with neurofibromatosis and MPNST, we must close several gaps. First, we must leverage our pre-clinical models to optimize dose/schedule for these agents. Second, we must develop robust pathological and imaging biomarkers to confirm that these agents can reach their therapeutic target in an individual patient. And third, we must carry out a “Phase 0” clinical trial to confirm that the optimized dose/schedule and response biomarkers can be applied to neurofibromatosis patients with MPNST. Accomplishing this will pave the way toward definitive clinical trials of these new agents for children with this disease.

项目概要-项目2 该项目的主要目标是为儿童神经纤维瘤病和恶性肿瘤开发更好的治疗方法。 周围神经鞘瘤（MPNST），神经纤维瘤病的主要危及生命的并发症。可悲的是， 患有这种侵袭性软组织肉瘤的儿童（和成人）如果肿瘤很大或 遍布全身此外，强化化疗、电离辐射和手术的应用 对改善这一惨淡的结果几乎毫无作用。 通过利用强大的神经纤维瘤病临床前模型，我们准备消除主要问题 与MPNST相关。我们的关键见解来自基因工程小鼠模型， 人类状况的许多方面。它们的使用揭示了MPNST中的两个关键“漏洞”： 表面受体CXCR 4和通过激活细胞周期蛋白依赖性激酶驱动细胞增殖的细胞周期蛋白D1 4和6（CDK 4/6）。我们互补的分子和遗传学研究表明，阻碍CXCR 4或细胞周期蛋白 D1相关的CDK 4/6阻断小鼠和人MPNST中的细胞增殖和肿瘤生长。 幸运的是，阻断CXCR 4和CDK 4/6的药物已经可用于儿童和成人。 Plerixafor是一种最初开发用于对抗HIV的CXCR 4抑制剂，现已上市，并已用于 孩子Palbociclib是一种CDK 4/6抑制剂，用于乳腺癌和其他恶性肿瘤， 与细胞周期蛋白D1基因扩增有关。它也被用作抗癌剂。这两种药物都没有 系统应用于神经纤维瘤病和MPNST患者。 为了加速从我们的临床前模型（阐明CXCR 4和CDK 4/6作为治疗靶点）到 普乐沙福和哌柏西利在神经纤维瘤病和MPNST儿童中的有效使用，我们必须密切关注 几个差距。首先，我们必须利用我们的临床前模型来优化这些药物的剂量/时间表。 其次，我们必须开发出强大的病理和成像生物标志物，以证实这些药物可以达到 他们的治疗目标在一个病人身上。第三，我们必须进行“0期”临床试验， 优化的剂量/时间表和反应生物标志物可以应用于患有神经纤维瘤病的患者， MPNST。完成这项工作将为这些新药物的儿童临床试验铺平道路 与这种疾病。