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; 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儿科肿瘤学分支（POB）的药理学与实验治疗部分（PET）*的使命是为儿童和年轻人开发更有效的治疗方法，患有难治性癌症和遗传性肿瘤倾向综合征（GTPS）。在评估毒性，活性，药代动力学和药效学的早期临床试验中，研究了有希望的新型药物。通过利用独特的NIH资源，我将耐火癌的药物开发原理应用于1型神经纤维瘤病（NF1）相关肿瘤，并建立了针对Plexiormal Neurofibromas（PN）和恶性外围外围植物sheath sheath sheath tumors（mpns）的全国最大的综合NF1临床试验计划。这项工作已扩展到具有多种内分泌肿瘤（MEN）2B的儿童和年轻人中的遗传性甲状腺癌（MTC），以及其他GTPS和其他稀有肿瘤。由于GTP的独特特征，该部分开发了新的试验设计，图像分析方法和试验终点，从而可以对新型药物进行更有意义，安全的评估。例如，在全国大多数临床试验中，使用了NF1 PN自动体积MRI分析的方法，用于集中（在NCI上）进行响应评估，作为主要终点，该部分使用高度协作的方法来实现研究目标。为了将有前途的临床前发现转化为耐火罐癌症的临床试验，我正与团队科学中所述，与Lee Helman博士建立了强有力的合作。由爱丽丝·陈（Alice Chen）博士领导的癌症治疗和诊断（DCTD）医学肿瘤学团队的合作，使我们能够同时入学儿科和成年患者，例如科学意义，例如，参与针对稀有肉瘤的临床试验。为了开发NF1相关肿瘤的临床试验，我与基本的外壁外研究人员进行了广泛而长期的合作，他们在相关的NF1鼠标模型中进行了临床前试验，包括Karen Cichowski博士（Brigham and妇女医院）MPNST与MPNST，NANCY RATNER（CINCINATI CLABS）（CINCINATI CLAPP）（CINCINATI）和Indiala Acline Cllin Acrop for P. Prima and Prima for p. Prima and for p.财团。 Karlyne Reilly博士是一位基础科学家，在NF1小鼠模型中拥有丰富的专业知识，也是NCI稀有肿瘤倡议（RTI）的创始成员，最近加入了该部分的努力，指导临床前研究，以推动PN和MPNST的疗法。宠物的临床试验作为单机构研究，多中心研究或合作组[儿童肿瘤学小组（COG）I/PILOT联盟，肉瘤协作联盟（SARC），NF临床试验联盟[SARC）]。我们的几项研究包括基因组分析，我们与Paul Meltzer博士（NCI CCR），Javed Khan博士（NCI CCR）和Douglas Stewart博士（NCI DCEG）建立了合作。我正在与NCI癌症治疗评估计划（CTEP）和制药行业紧密合作，并成功地争夺资金，以支持临床前合作和临床试验的临床校外研究人员（DOD）临床试验奖（CTA）（CTA）（CTA）（cta）（n = 4）（n = 4），NIH BEC TO TO BECHESS to BEDISE AFCHADES AAFADADARADS（N = 3），n = 3 = 3 = 3 = 3），tamor's Mays（cf）。宠物还为POB，CCR和NIH研究者提供了支持，以设计临床前，临床和药代动力学（PK）研究，药物测定开发以及PK数据分析。抗癌药物的中枢神经系统（CNS）药理学与儿科神经肿瘤科（PNOS）（PNOS）的负责人Kathy Warren博士在其非人类灵长类动物模型中进行了研究。