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

NCI儿科肿瘤学分支（POB）药理学和实验治疗学科（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。在早期临床试验中研究有前途的新药，评估毒性，活性，药代动力学和药效学。通过利用独特的NIH资源，我将难治性癌症药物开发的原则应用于1型神经纤维瘤病（NF 1）相关肿瘤，并建立了全国最大的针对丛状神经纤维瘤（PN）和恶性外周神经鞘瘤（MPNST）的综合NF 1临床试验计划。这项工作已扩大到遗传性甲状腺髓样癌（MTC）的儿童和年轻人多发性内分泌瘤（MEN）2B，和其他GTPS和罕见的肿瘤。由于GTPS的独特特征，该科开发了新的试验设计、图像分析方法和试验终点，从而可以对新药进行更有意义和安全的评价。例如，我们的NF 1 PN的自动体积MRI分析方法用于全国范围内的大多数临床试验，以集中（在NCI）进行反应评价作为主要终点。该部分使用高度协作的方法来实现研究目标。为了将有前景的临床前发现转化为难治性癌症的临床试验，我与Lee Helman博士建立了强有力的合作，如团队科学所述。与由Alice Chen博士领导的癌症治疗和诊断部（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。对于NF 1相关肿瘤的临床试验的开发，我与基本的校外研究人员进行了广泛和长期的合作，他们在NF 1的相关小鼠模型中进行临床前试验，包括Karen Cichowski博士（Brigham and Women's Hospital）的MPNST，Nancy Ratner博士（辛辛那提儿童医院）和Wade Clapp博士（印第安纳州大学）的PN，以及NF临床前试验联盟。Karlyne Reilly博士是一位在NF 1小鼠模型方面具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，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临床试验以单机构和有限机构研究以及多中心研究或与合作组[儿童肿瘤学组（COG）I期/试点联盟、协作研究肉瘤联盟（SARC）、NF临床试验联盟]进行。我们的几项研究包括基因组分析，为此我们与Paul Meltzer博士（NCI CCR），Javed Khan博士（NCI CCR）和道格拉斯斯图尔特博士（NCI DCEG）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，并成功地通过国防部（DoD）临床试验奖（CTA）（n=4），NIH Bench to Bedside奖（n=3）和儿童肿瘤基金会（CTF）奖（n=2）竞争资金，以支持临床前合作和临床试验的校外研究人员。PETS还为POB、CCR和NIH研究者提供临床前、临床和药代动力学（PK）研究设计、药物测定开发和PK数据分析方面的支持。抗癌药物的中枢神经系统（CNS）药理学与儿科神经肿瘤科（PNOS）负责人Kathy Warren博士合作，在她的非人灵长类动物模型中进行研究。

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.