Research and Development of Effective Therapies for Patients with Rare Tumors

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物，重点是基于目前对人类癌症分子发病机制的理解，开发更合理、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，正在进行成人癌症临床开发的新型分子靶向药物将应用于儿童癌症。此外，新的细胞毒性药物正在进行临床评估。临床试验分为单点试验和多点试验。此外，我们正在与儿童肿瘤小组（COG）、肉瘤合作小组SARC和NF临床试验联盟合作开展试验。临床试验的目标是顽固性实体瘤，如尤文氏肉瘤或横纹肌肉瘤，以及没有已知有效药物治疗的肿瘤，如肺泡软组织肉瘤、甲状腺髓样癌或恶性周围神经鞘肿瘤（MPNST）。这项工作通过NCI POB的药理学和实验治疗学（PET）部分进行。正在进行和正在开发的临床试验的例子包括：1)与儿童肿瘤组（COG）合作的例子：卡博赞替尼（XL184）治疗难治性实体瘤和选定实体瘤层的I期和II期试验。Cabozantinib是一种多受体酪氨酸激酶（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抑制为我们开发卡博赞替尼治疗小儿甲状腺髓样癌（MTC）提供了基本原理。然而，cabozantinib也靶向多种儿科癌症中过表达的rtk，包括儿童肉瘤中的VEGFR2，骨肉瘤、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，在针对MTC和包括脑肿瘤在内的难治性实体肿瘤的I期试验中开发cabozantinib。在该试验完成后，我们与COG合作开展了一项针对多个实体瘤层的cabozantinib II期试验。该试验已接近完成登记。2)与SARC肉瘤合作小组和国防部赞助的NF临床试验联盟合作的例子：mTOR途径参与人类癌症和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。我指导了一项SARC协调的多机构临床试验，针对难治性散发或NF1相关的恶性周围神经鞘肿瘤（MPNST）患者，使用mTOR抑制剂RAD001联合血管生成抑制剂贝伐单抗。该试验获得了国防部临床试验奖的资助。基于Karen Cichowski博士实验室的临床前工作，我们还开发了mTOR抑制剂西罗莫司与HSP90抑制剂ganetespib联合用于难治性肉瘤和MPNST成人的I/II期临床试验（PI: AeRang Kim, Co-PI: Brigitte Widemann）。两项试验都成功地完成了这种罕见的肿瘤并发表。基于有希望的临床前结果，我们开展了一项将mTOR抑制剂西罗莫司与MEK抑制剂联合使用的II期试验，该试验正在开放招募（PI: AeRang Kim, Co-PI: Brigitte Widemann）。SARC、国防部赞助的NF联盟和研究人员在开发MPNST有效疗法方面的密切合作表明，及时进行组织学特异性试验是可行的。3)与NCI CCR发育治疗诊所合作的例子：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，主要是由她指导的成人临床试验。同样，陈医生将在儿科肿瘤科的试验中评估成人患者。这确保患有罕见肿瘤的儿童和成人获得最佳的靶向治疗。我们制定了一项儿科-成人罕见肿瘤方案，目的是在选定的罕见肿瘤中进行深入的自然史研究。NCI POB和我的部门在两个NCI CCR计划中发挥领导作用：NCI CCR罕见肿瘤计划（RTI）促进NCI （CCR和DCEG）的基础和临床研究人员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）由癌症登月计划（Cancer Moonshot）支持，旨在通过共享的基础设施和网络连接患者和研究人员，加速对罕见肿瘤的了解，并通过患者、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的这些国家和国际合作，开发罕见肿瘤的临床试验。RTPEN的长期目标是有效地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获得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的研究人员提供服务。该方案的主要目标是参与一组罕见肿瘤患者，全面研究其罕见肿瘤患者及其肿瘤和生物样本，以开发更好的治疗方法。这种罕见肿瘤的努力将有校外合作者，也有倡导团体参与。罕见肿瘤方案正在开放登记，我们正在增加校外地点。作为主要罕见肿瘤协议的一个子协议，我们已经为脊索瘤患者制定了一项协议，该协议也开放注册。我们于2019年4月举办了首届小儿脊索瘤诊所，并于2020年4月举办了2019冠状病毒病的虚拟诊所，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，我们提出了全面研究儿童和青少年RASopathies的建议。RAS病是一种以RAS通路基因的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）、Noonan综合征（NS）、心-面部-皮肤综合征和Costello综合征（CS），发病率差异很大（1:1000 NS -1:30万CS），通常首先在儿童中被诊断出来，并表现出各种各样的表现，包括危及生命的先天性心脏病、发育不良和儿童癌症（如肉瘤、白血病、糖尿病和糖尿病）发展的风险增加。和中枢神经系统肿瘤（与一般人群相比，风险增加42倍）。目前还没有批准的药物治疗RASopathies。这是NCI CCR、NCI DCEG以及外部研究人员和倡导团体的共同努力，将包括RASopathy自然历史研究的发展，针对RASopathy表现（包括与RASopathy相关的肿瘤）的治疗试验的发展，以及人口基因组学方法。Marielle Yohe博士的报告对该项目进行了更详细的描述。

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.