Research and Development of Effective Therapies for Patients with Rare Tumors

罕见肿瘤患者有效疗法的研究与开发

• 批准号: 10262708
• 负责人: Brigitte Widemann
• 金额: $ 62.92万
• 依托单位: DIVISION OF CLINICAL 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/10262708
• 关键词: Adolescent; Adult; Advocacy; Advocate; Alveolar Soft Part Sarcoma; Angiogenesis Inhibitors; Award; Biological; Biology; Brain Neoplasms; CCR; COVID-19; Caring; Central Nervous System Neoplasms; Child; Childhood; Childhood Solid Neoplasm; Chordoma; Clinic; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Conduct Clinical Trials; Costello syndrome; Cytotoxic agent; Department of Defense; Development; Developmental Therapeutics Program; Diagnosis; Disease; Disease remission; Division of Cancer Epidemiology and Genetics; Dose; Enrollment; Ensure; Evaluation; Ewings sarcoma; Exhibits; Extramural Activities; FRAP1 gene; Failure to Thrive; Family member; Fostering; Foundations; Funding; General Population; Genes; Genetic Diseases; Genomic approach; Germ-Line Mutation; Glioma; Goals; Heat-Shock Proteins 90; Histology; Human; Incidence; Infrastructure; International; Intramural Research Program; Investigational Therapies; KDR gene; Knowledge; Laboratories; Leadership; Life; MEKs; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical; Molecular; Molecular Genetics; Molecular Target; Multi-Institutional Clinical Trial; NCI Center for Cancer Research; Natural History; Neurofibromatosis 1; Neurofibrosarcoma; New Agents; Noonan Syndrome; Papillary thyroid carcinoma; Pathogenesis; Pathway interactions; Patients; Pediatric Neoplasm; Pediatric Oncology; Pediatric Oncology Group; Pharmacology; Phase; Phase I/II Clinical Trial; Phase I/II Trial; Population; Positioning Attribute; Predisposition; Process; Protocols documentation; Publishing; RET inhibition; Receptor Protein-Tyrosine Kinases; Refractory; Reporting; Research Personnel; Resources; Rhabdomyosarcoma; Risk; Role; Sampling; Sirolimus; Site; Solid Neoplasm; Syndrome; TEK gene; Thyroid Gland; Time; Toxic effect; Translating; Translations; Work; arm; base; bevacizumab; cancer genetics; cancer therapy; cardiofaciocutaneous syndrome; childhood sarcoma; clinical development; congenital heart disorder; design; drug action; drug development; drug discovery; effective therapy; improved; inhibitor/antagonist; leukemia; mTOR Inhibitor; medullary thyroid carcinoma; multi-site trial; novel; osteosarcoma; overexpression; patient engagement; patient population; phase I trial; phase II trial; pre-clinical; rare cancer; research and development; research clinical testing; response; sarcoma; small molecule inhibitor; targeted agent; targeted treatment; therapy development; treatment trial; trial design; tumor; virtual; young adult

The primary objective of this project is to develop new agents for the treatment of cancers and other rare tumors in children and young adults with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. In addition, novel cytotoxic agents are undergoing clinical evaluation. Clinical trials are conducted as single site and multi-site trials. In addition, we are collaborating with the Children's Oncology Group (COG), the sarcoma cooperative group SARC, and the NF Clinical Trials Consortium in the development and conduct of trials. Clinical trials target refractory solid tumors such as Ewing sarcoma or rhabdomyosarcoma, and tumors with no known effective medical therapy such as alveolar soft part sarcoma, medullary thyroid carcinaoma, or malignant peripheral nerve sheath tumors (MPNST). This work is performed through the Pharmacology and Experimental Therapeutics (PET) Section of the NCI POB. Examples of clinical trials ongoing and in development include: 1) Example of collaboration with the Children's Oncology Group (COG): Phase I and II trial of cabozantinib (XL184) for refractory solid tumors and select solid tumor strata. Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases (RTK) including primarily MET, VEGFR2 and RET and to a lesser extent KIT and TIE-2. RET inhibition provided the rationale for our development of cabozantinib for pediatric medullary thyroid carcinoma (MTC). However, cabozantinib also targets RTKs that are overexpressed in a variety of pediatric cancers including, VEGFR2 in pediatric sarcomas, MET in osteosarcoma, glioma, and papillary thyroid carcinoma. We thus collaborated with the COG Phase I/Pilot Consortium in the development of cabozantinib in a phase I trial with an arm specifically for MTC and an arm for refractory solid tumors including brain tumors. Upon completion of this trial based on promising results with several objective responses and prolonged disease stabilization we developed a phase II trial of cabozantinib for several solid tumor strata in collaboration with the COG. The=is trial has nearly completed enrollment. 2) Example of collaboration with the sarcoma cooperative group SARC and with the DoD sponsored NF Clinical trials Consortium: The mTOR pathway is involved in the progression of human cancers and neurofibromatosis type 1 (NF1) related tumors, and clinical trials with mTOR inhibitors are ongoing for both patient populations. I directed a SARC coordinated multi-institutional clinical trial for patients with refractory sporadic or NF1 related malignant peripheral nerve sheath tumors (MPNST) with the mTOR inhibitor RAD001 in combination with the angiogenesis inhibitor bevacizumab. This trial received funding through a Department of Defense Clinical Trial Award. Based on preclinical work from Dr. Karen Cichowski's laboratory, we also developed a phase I/II clinical trial of the mTOR inhibitor sirolimus in combination with the HSP90 inhibitor ganetespib for adults with refractory sarcomas and MPNST (PI: AeRang Kim, Co-PI: Brigitte Widemann). Both trials were successfully completed for this rare tumor and published. Based on promising preclinical results, we developed a phase II trial combining the mTOR inhibitor sirolimus with a MEK inhibitor, which is open for enrollment (PI: AeRang Kim, Co-PI: Brigitte Widemann). Close collaboration of SARC, the DOD sponsored NF Consortium, and investigators invested in developing effective therapies for MPNST has demonstrated that the timely conduct of histology specific trials is feasible. 3) Example for collaboration with the NCI CCR Developmental Therapeutics Clinic: We are collaborating with Dr. Alice Chen, Director of NCI's Developmental Therapeutics Clinic, by enrolling children with refractory cancers such as alveolar soft part sarcoma, on primarily adult clinical trials directed by her. Similarly, Dr. Chen will evaluate adult patients on Pediatric Oncology Branch trials. This ensures that children and adults with rare tumors get optimal access to targeted therapies. We have developed a pediatric-adult rare tumor protocol with the goal to perform in depth natural history studies in select rare tumors. The NCI POB and my Section have a leadership role in 2 NCI CCR Initiatives: The NCI CCR Rare Tumors Initiative (RTI) fosters focused collaborations between basic and clinical researchers at NCI (CCR and DCEG), as well as extramural investigators. The Rare Tumor Patient Engagement Network (RTPEN), supported by the Cancer Moonshot, aims to connect patients and investigators through shared infrastructure and networks, accelerate the understanding of rare tumors and develop clinical trials for rare tumors through these national and international collaborations of patients, advocates, clinicians, clinical and basic researchers, and other stakeholders. The long-term goal of the RTPEN is to effectively study the biology and clinical course of rare tumors, translate these findings to improve care and treatment and to ensure that all patients have access to clinical trials which may benefit them. In a collaboration with the NCI/DCEG we have developed a rare tumor protocol, which serves CCR and DCEG investigators. The primary objective of this protocol is to engage patients with a set of rare tumors, to study their rare tumor patients and their tumor and biologic samples comprehensively in order to develop better therapies. This rare tumor effort will have extramural collaborators and also engage advocacy groups. The rare tumor protocol is open for enrollment and we are in the process of adding extramural sites. As a subprotocol to the master rare tumor protocol we have developed a protocol for patients with chordoma, which is also open for enrollment. We hosted an inaugural pediatric chordoma clinic in April 2019 and a virtual clinic due to COVID-19 in April 2020, which brought together patients and families, members of the chordoma foundation, and experts in the care of chordoma patients. Additional sub protocols are in development. Finally, we developed a proposal to comprehensively study RASopathies in children and young adults. RASopathies are genetic disorders characterized by germline mutations in RAS pathway genes. These syndromes, such as neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome, and Costello syndrome (CS), have a widely variable incidence (1:1000 NS -1:300,000 CS) are usually first diagnosed in children and exhibit a wide variety of manifestations, including life-threatening congenital heart disease, failure to thrive, and increased risk of development of pediatric cancers such as sarcomas, leukemias, and CNS tumors (up to 42-fold increased risk compared to the general population). No approved medical therapies exist for RASopathies. This is a collaborative effort of the NCI CCR, NCI DCEG as well as extramural investigators and advocacy groups and will include the development of a RASopathy natural history study, the development of treatment trials directed at RASopathy manifestations including tumors associated with RASopathies, and a population genomics approach. This project is described in more detail in Dr. Marielle Yohe's report.

该项目的主要目标是开发治疗儿童和年轻人癌症和其他罕见肿瘤的新药，重点是基于目前对人类癌症分子发病机制的了解，采取更合理、更有针对性的药物开发方法。基于药物的作用机制和靶点在儿童癌症中的重要性，正在针对成人癌症进行临床开发的新型分子靶向药物将应用于儿童癌症。此外，新型细胞毒剂正在接受临床评估。临床试验分为单中心试验和多中心试验。此外，我们还与儿童肿瘤学组 (COG)、肉瘤合作组 SARC 和 NF 临床试验联盟合作开发和开展试验。临床试验针对难治性实体瘤，如尤文肉瘤或横纹肌肉瘤，以及尚无有效药物治疗的肿瘤，如腺泡软组织肉瘤、甲状腺髓样癌或恶性周围神经鞘瘤（MPNST）。这项工作是通过 NCI POB 的药理学和实验治疗学 (PET) 部门进行的。正在进行和正在开发的临床试验示例包括： 1) 与儿童肿瘤学组 (COG) 合作的示例：卡博替尼 (XL184) 用于难治性实体瘤和选定实体瘤层的 I 期和 II 期试验。卡博替尼是一种多种受体酪氨酸激酶 (RTK) 的小分子抑制剂，主要包括 MET、VEGFR2 和 RET，以及较小程度的 KIT 和 TIE-2。 RET 抑制为我们开发用于儿童甲状腺髓样癌 (MTC) 的卡博替尼 (cabozantinib) 提供了理论基础。然而，卡博替尼还针对在多种儿科癌症中过度表达的 RTK，包括儿科肉瘤中的 VEGFR2，骨肉瘤、神经胶质瘤和甲状腺乳头状癌中的 MET。因此，我们与 COG I 期/试点联盟合作，在 I 期试验中开发卡博替尼，其中一个专门用于 MTC 的手臂和一个用于难治性实体瘤（包括脑肿瘤）的手臂。在这项试验完成后，基于几个客观反应和长期疾病稳定的有希望的结果，我们与 COG 合作开发了卡博替尼用于多个实体瘤层的 II 期试验。该试验已接近完成注册。 2）与肉瘤合作组织SARC和DoD赞助的NF临床试验联盟合作的例子：mTOR通路参与人类癌症和1型神经纤维瘤病（NF1）相关肿瘤的进展，mTOR抑制剂的临床试验正在进行中对于这两个患者群体。我指导了一项 SARC 协调的多机构临床试验，针对难治性散发性或 NF1 相关的恶性周围神经鞘瘤 (MPNST) 患者，使用 mTOR 抑制剂 RAD001 联合血管生成抑制剂贝伐珠单抗。该试验通过国防部临床试验奖获得了资助。基于 Karen Cichowski 博士实验室的临床前工作，我们还开展了 mTOR 抑制剂西罗莫司与 HSP90 抑制剂 ganetespib 联合治疗成人难治性肉瘤和 MPNST 的 I/II 期临床试验（PI：AeRang Kim，Co-PI：布丽吉特·维德曼）。针对这种罕见肿瘤的两项试验均已成功完成并发表。基于有希望的临床前结果，我们开发了一项将 mTOR 抑制剂西罗莫司与 MEK 抑制剂相结合的 II 期试验，该试验现已开放招募（PI：AeRang Kim，Co-PI：Brigitte Widemann）。 SARC、国防部赞助的 NF 联盟以及投资开发 MPNST 有效疗法的研究人员的密切合作表明，及时进行组织学特异性试验是可行的。 3) 与 NCI CCR 发育治疗诊所合作示例：我们与 NCI 发育治疗诊所主任 Alice Chen 博士合作，招募患有难治性癌症（如肺泡软组织肉瘤）的儿童，进行由她指导的主要成人临床试验。同样，陈博士将评估儿科肿瘤科试验中的成年患者。这确保患有罕见肿瘤的儿童和成人获得最佳的靶向治疗机会。我们开发了一种儿童-成人罕见肿瘤方案，旨在对选定的罕见肿瘤进行深入的自然史研究。 NCI POB 和我的部门在 2 个 NCI CCR 计划中发挥领导作用：NCI CCR 罕见肿瘤计划 (RTI) 促进 NCI 基础和临床研究人员（CCR 和 DCEG）以及校外研究人员之间的重点合作。罕见肿瘤患者参与网络 (RTPEN) 在癌症登月计划的支持下，旨在通过共享基础设施和网络将患者和研究人员联系起来，加速对罕见肿瘤的了解，并通过这些国内和国际患者合作开展罕见肿瘤的临床试验，倡导者、临床医生、临床和基础研究人员以及其他利益相关者。 RTPEN 的长期目标是有效研究罕见肿瘤的生物学和临床病程，将这些发现转化为改善护理和治疗，并确保所有患者都能参加可能有益于他们的临床试验。在与 NCI/DCEG 的合作中，我们开发了一种罕见肿瘤方案，为 CCR 和 DCEG 研究人员提供服务。该协议的主要目标是让患有一组罕见肿瘤的患者参与，全面研究他们的罕见肿瘤患者及其肿瘤和生物样本，以便开发更好的治疗方法。这项罕见的肿瘤研究将拥有校外合作者，并吸引倡导团体的参与。罕见肿瘤方案已开放招募，我们正在添加壁外站点。作为罕见肿瘤主方案的子方案，我们为脊索瘤患者制定了一项方案，该方案也开放招募。我们于 2019 年 4 月举办了首家儿科脊索瘤诊所，并于 2020 年 4 月因 COVID-19 举办了虚拟诊所，汇集了患者和家属、脊索瘤基金会成员以及脊索瘤患者护理专家。其他子协议正在开发中。最后，我们制定了一项全面研究儿童和年轻人 RASopathies 的提案。 RASopathies 是一种以 RAS 通路基因种系突变为特征的遗传性疾病。这些综合征，如 1 型神经纤维瘤病 (NF1)、努南综合征 (NS)、心面皮肤综合征和 Costello 综合征 (CS)，其发病率差异很大 (1:1000 NS -1:300,000 CS)，通常首先在儿童中诊断出来并表现出多种表现，包括危及生命的先天性心脏病、发育迟缓以及罹患肉瘤、白血病等儿科癌症的风险增加中枢神经系统肿瘤（与一般人群相比，风险增加高达 42 倍）。目前尚无针对 RASopathies 的批准药物疗法。这是 NCI CCR、NCI DCEG 以及校外研究人员和倡导团体的共同努力，将包括开发 RASopathies 自然史研究、开发针对 RASopathies 表现（包括与 RASopathies 相关的肿瘤）的治疗试验以及人群基因组学方法。 Marielle Yohe 博士的报告更详细地描述了该项目。