Therapy for NF1-Related Tumors and other Genetic Tumor Predisposition Syndromes

NF1相关肿瘤和其他遗传性肿瘤易感综合征的治疗

• 批准号: 9153674
• 负责人: Brigitte Widemann
• 金额: $ 100.52万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9153674
• 关键词: Adult; Antineoplastic Agents; Award; Biology; CCR; Cancer Therapy Evaluation Program; Characteristics; Child; Childhood; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Data; Department of Defense; Development; Division of Cancer Epidemiology and Genetics; Drug Industry; Drug Kinetics; Endocrine; Enrollment; Evaluation; Extramural Activities; Foundations; Funding; Genetic; Genomics; Goals; Head; Hospitals; Image Analysis; Indiana; Inherited; Institution; Knowledge; Magnetic Resonance Imaging; Malignant Neoplasms; Medical Oncology; Methods; Mission; Modeling; Multicenter Studies; Neoplasms; Neuraxis; Neurofibromatosis 1; Neurofibromatosis 2; Neurofibrosarcoma; Other Genetics; Pathogenesis; Patients; Pediatric Hospitals; Pediatric Oncology; Pediatric Oncology Group; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Plexiform Neurofibroma; Predisposition; Refractory; Research; Research Personnel; Resources; Science; Scientist; Syndrome; Therapeutic; Toxic effect; Translations; Tumor-Associated Process; United States National Institutes of Health; Universities; Woman; Work; assay development; bench to bedside; cancer diagnosis; cancer genetics; cancer therapy; design; drug development; effective therapy; medullary thyroid carcinoma; member; mouse model; neuro-oncology; nonhuman primate; novel; pre-clinical; preclinical study; programs; response; sarcoma; trial design; tumor; young adult

The mission of the Pharmacology & Experimental Therapeutics Section (PETS)* of NCI's Pediatric Oncology Branch (POB) is to develop more effective treatments for children and young adults with refractory cancers and genetic tumor predisposition syndromes (GTPS). Promising novel agents are studied in early clinical trials that evaluate toxicities, activity, pharmacokinetics, and pharmacodynamics. By leveraging unique NIH resources, I have applied the principles of drug development for refractory cancers to neurofibromatosis type 1 (NF1)-related tumors and built the nation's largest comprehensive NF1 clinical trials program directed at plexiform neurofibromas (PN) and malignant peripheral nerve sheath tumors (MPNST). This effort has been expanded to hereditary medullary thyroid carcinoma (MTC) in children and young adults with multiple endocrine neoplasia (MEN) 2B, and other GTPS and rare tumors. Due to distinct characteristics of GTPS, the Section has developed new trial designs, methods of image analysis, and trial endpoints, which allow for more meaningful and safe evaluation of novel agents. For example, our method of automated volumetric MRI analysis of NF1 PN is used in most clinical trials nationwide to centrally (at the NCI) perform response evaluation as primary endpoints The Section uses a highly collaborative approach to accomplish research goals. For the translation of promising preclinical discoveries into clinical trials for refractory cancers, I built a strong collaboration with Dr. Lee Helman as described in team science. Collaboration with the Division of Cancer Treatment and Diagnosis (DCTD) medical oncology team led by Dr. Alice Chen has allowed us to simultaneously enroll pediatric and adult patients, when scientifically meaningful, for example in clinical trials directed at rare sarcomas. For the development of clinical trials for NF1 related tumors, I have extensive and longstanding collaborations with basic extramural investigators, who perform preclinical trials in relevant mouse models of NF1, including Dr. Karen Cichowski (Brigham and Women's Hospital) for MPNST, Dr. Nancy Ratner (Cincinnati Children's Hospital) and Dr. Wade Clapp (Indiana University) for PN, and with the NF Preclinical Trials Consortium. Dr. Karlyne Reilly, a basic scientist with great expertise in NF1 mouse models and a founding member of the NCI Rare Tumor Initiative (RTI), recently joined the efforts of the Section to guide preclinical studies to advance therapies for PN and MPNST. PETS clinical trials are conducted as single- and limited-institution studies, as well as multi-center studies or with cooperative groups [Children's Oncology Group (COG) Phase I/Pilot Consortium, Sarcoma Alliance for Research through Collaboration (SARC), NF Clinical Trials Consortium]. Several of our studies include genomic analyses, for which we have established collaborations with Dr. Paul Meltzer (NCI CCR), Dr. Javed Khan (NCI CCR), and Dr. Douglas Stewart (NCI DCEG). I am working closely with the NCI Cancer Therapy Evaluation Program (CTEP) and the pharmaceutical industry, and have successfully competed for funding to support preclinical collaborations and extramural investigators on clinical trials through Department of Defense (DoD) Clinical Trial Awards (CTA) (n=4), NIH Bench to Bedside awards (n=3), and Children's Tumor Foundation (CTF) awards (n=2). The PETS also provides support to POB, CCR, and NIH investigators for the design of preclinical, clinical, and pharmacokinetic (PK) studies, drug assay development, and analysis of PK data. Central nervous system (CNS) pharmacology of anticancer drugs is studied in collaboration with Dr. Kathy Warren, Head of the Pediatric Neuro-Oncology Section (PNOS), in her non-human primate model.

NCI儿科肿瘤科(POB)的药理学和实验治疗科(PETS)*的使命是为患有难治性癌症和遗传性肿瘤易感综合征(GTPS)的儿童和年轻人开发更有效的治疗方法。有希望的新药在早期临床试验中被研究，评估毒性、活性、药代动力学和药效学。通过利用NIH独特的资源，我将难治性癌症的药物开发原则应用于1型神经纤维瘤病(NF1)相关肿瘤，并建立了全国最大的针对丛状神经纤维瘤(PN)和恶性周围神经鞘瘤(MPNST)的综合NF1临床试验计划。这项工作已经扩展到儿童和患有多发性内分泌肿瘤(MAN)2B的年轻人的遗传性髓样甲状腺癌(MTC)，以及其他GTPS和罕见肿瘤。由于GTPS的独特特点，该科开发了新的试验设计、图像分析方法和试验终点，从而能够对新制剂进行更有意义和更安全的评价。例如，我们的NF1 PN的自动体积MRI分析方法被用于全国大多数临床试验，作为主要终点集中(在NCI)执行响应评估该科使用高度协作的方法来实现研究目标。为了将有希望的临床前发现转化为难治性癌症的临床试验，我与李·赫尔曼博士建立了强大的合作关系，正如《团队科学》中所描述的那样。与由Alice Chen博士领导的癌症治疗与诊断科(DCTD)医学肿瘤学团队的合作使我们能够在具有科学意义的情况下同时招募儿科和成人患者，例如针对罕见肉瘤的临床试验。在NF1相关肿瘤的临床试验开发方面，我与基础的校外调查人员有着广泛而长期的合作，他们在NF1的相关小鼠模型上进行临床前试验，包括MPNST的Karen Cichowski博士(布里格姆妇女医院)、Nancy Ratner博士(辛辛那提儿童医院)和Wade Clapp博士(印第安纳大学)，以及与NF临床前试验联盟的合作。Karlyne Reilly博士是一位在NF1小鼠模型方面拥有丰富专业知识的基础科学家，也是NCI罕见肿瘤倡议(RTI)的创始成员之一，他最近加入了该部门的工作，指导临床前研究，以推进PN和MPNST的治疗。PETS临床试验作为单机构和有限机构研究以及多中心研究或与合作小组[儿童肿瘤学小组(COG)第一阶段/试点联盟、肉瘤协作研究联盟(SARC)、NF临床试验联盟]进行。我们的几项研究包括基因组分析，我们已经与NCI CCR的Paul Meltzer博士、NCI CCR的Javed Khan博士和NCI DCEG的Douglas Stewart博士建立了合作关系。我与NCI癌症治疗评估计划(CTEP)和制药行业密切合作，并通过国防部(DoD)临床试验奖(CTA)(n=4)、NIH工作台到床边奖(n=3)和儿童肿瘤基金会(CTF)奖(n=2)成功地争取到资金，以支持临床前合作和外部调查人员进行临床试验。PETS还为POB、CCR和NIH研究人员提供支持，以设计临床前、临床和药代动力学(PK)研究、药物分析开发和PK数据分析。在她的非人灵长类动物模型中，与儿科神经肿瘤科(PNOS)主任凯西·沃伦博士合作研究了抗癌药物的中枢神经系统(CNS)药理学。