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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结-项目2