Therapies for patients with rare tumors and genetic tumor predisposition

罕见肿瘤和遗传肿瘤易感性患者的治疗

• 批准号: 10487193
• 负责人: Brigitte Widemann
• 金额: $ 238.43万
• 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/10487193
• 关键词: Adolescent; Adult; Advanced Development; Advocate; Age; Alveolar Soft Part Sarcoma; Benign; Biological Markers; Biology; Boston; Brazil; Bromodomain; CCR; CDK4 gene; CDKN2A gene; Child; Childhood; Chordoma; Clinic; Clinical; Clinical Trials; Clinical Trials Network; Collaborations; Combined Modality Therapy; Cutaneous; Data; Development; Developmental Therapeutics Program; Disease remission; Division of Cancer Epidemiology and Genetics; Dose; Enrollment; Ensure; Europe; Evaluation; Ewings sarcoma; Excision; Extramural Activities; Fostering; Genetic; Genetic Predisposition to Disease; Goals; Growth; Histologic; Hospitals; Infrastructure; Inherited; Interferon-alpha; International; Investigational Therapies; KDR gene; Knowledge; Leadership; Lesion; MEKs; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical; Mendelian disorder; Molecular Genetics; Monitor; Morbidity - disease rate; Mus; NF1 gene; National Institute of Neurological Disorders and Stroke; Natural History; Neurofibromatoses; Neurofibromatosis 1; Neurofibrosarcoma; Neurosurgeon; New Agents; Operative Surgical Procedures; Outcome Measure; PDL1 inhibitors; Paclitaxel; Pain; Pathogenesis; Patients; Pediatric Hospitals; Pediatric Oncology; Pediatric Oncology Group; Peripheral Nerve Sheath Neoplasm; Peripheral Nervous System; Phase I Clinical Trials; Phase I/II Clinical Trial; Phase I/II Trial; Phase II Clinical Trials; Philadelphia; Plexiform Neurofibroma; Population; Positioning Attribute; Positron-Emission Tomography; Predisposition; Primary Neoplasm; Progression-Free Survivals; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Reporting; Research Personnel; Resected; Resources; Rhabdomyosarcoma; Risk; Role; S phase; Series; Solid Neoplasm; Standardization; Syndrome; TEK gene; Time; Toxic effect; Transgenic Organisms; United States National Institutes of Health; Washington; Woman; base; cancer genetics; cancer therapy; cell free DNA; clinical center; drug development; drug discovery; early phase clinical trial; effective therapy; functional outcomes; hyperactive Ras; inhibitor/antagonist; irinotecan; medullary thyroid carcinoma; motor disorder; mouse model; nervous system development; nervous system disorder; neurofibroma; novel; novel therapeutics; osteosarcoma; overexpression; partial response; participant enrollment; patient engagement; patient oriented; phase I trial; phase II trial; preclinical trial; prevent; programs; rare cancer; refractory cancer; response; sarcoma; single cell sequencing; small molecule inhibitor; success; targeted agent; targeted treatment; therapy development; trial design; tumor; tumorigenesis; young adult

Aim 1: Natural history and clinical trials for NF1 related peripheral nerve sheath tumors NF1 is the most frequent inherited single gene disorder of the nervous system (1:3000) and is characterized by benign and malignant tumors of the central and peripheral nervous system, and by the development of a variety of non-tumor manifestations. The protein product of the NF1 gene, neurofibromin, regulates Ras activity and lack of functional neurofibromin leads to hyperactive Ras and tumorigenesis. People with NF1 develop multiple tumors including cutaneous neurofibromas (cNF), which never transform to malignancy; plexiform neurofibromas (PN), which are histologically benign but can cause substantial morbidity and transform to highly aggressive cancers called malignant peripheral nerve sheath tumors (MPNST); atypical neurofibromas (AN), which are histologically borderline lesions and at risk for transformation to MPNST. The natural history of these tumors was incompletely understood and there were no effective medical therapies for NF1 related peripheral nerve sheath tumors. Our NIH NF1 natural history study allowed us to comprehensively characterize the growth rate of PN in NF1 and the development of associated morbidities. In our study the majority of PN were associated with morbidities (for example, pain, disfigurement, airway or motor dysfunction), which manifest at an early age. Using volumetric MRI analysis of PN to longitudinally monitor PN growth we identified that PN grow most rapidly in young children compared to adults who typically have minimal or no growth of their PN. My team directed a series of clinical trials targeting NF1 PN with the goal of the progression free survival (PFS) or achieving PN volume reduction. With the exception of pegylated interferon alpha-2b, none of the trials resulted in a partial response (PR), defined as PN volume reduction greater or equal to 20% compared to baseline, or clinically meaningful improvement in PFS. We then identified the MEK inhibitor selumetinib as the first active agent against NF1 PN. In a phase I clinical trial for children with inoperable PN we reported PN shrinkage in 71% of patients. Subsequently we developed a phase II clinical trial which incorporated standardized patient reported and functional outcome measures in addition to assessment of response by volumetric MRI analysis. This larger phase II trial confirmed the previously reported response rate. In addition, we observed clinically meaningful improvement in pain and function and lesser disfigurement. Based on the results of this trial selumetinib received FDA approval for children with NF1 and inoperable, symptomatic PN in April 2020, and approval in Europe and Brazil in 2021. Dr. Andrea Gross in the POB has developed a trial, which will assess if selumetinib can prevent the development of morbidity in young children with asymptomatic but growing PN. In collaboration with the NCI Adult Developmental Therapeutics Clinic we are currently also conducting a phase II trial of selumetinib for adults with NF1 and inoperable PN, which is actively enrolling patients. We are collaborating with Drs. Drs. Jack Shern and Taylor Sundby in the POB to identify biomarkers of malignant transformation such as cell free DNA and single cell sequencing of resected tumors. We have made substantial progress in the understanding AN. Through comprehensive evaluations we have identified that AN are precursor lesions for MPNST. Our collaborator, Dr. Prashant Chittiboina, neurosurgeon at NINDS, subsequently demonstrated that many AN can be safely removed surgically with marginal margins. Resection of these lesions may thus be a way to prevent malignant transformation. AN are characterized by heterozygous CDKN2A/B loss. We therefore developed a clinical trial of the CDK4/6 inhibitor abemaciclib specifically for patients with NF1and unrespectable AN. Aim 2: Natural history and clinical trials for children and adults with rare tumors The primary goal is to develop new agents for the treatment of cancers and other rare tumors or genetic tumor predisposition. Clinical trials target refractory solid tumors such as Ewing sarcoma or rhabdomyosarcoma, medullary thyroid carcinoma (MTC), and very rare tumors with no known effective medical therapy such as alveolar soft part sarcoma, or chordoma. We also aim to understand the biology and natural history of these rare tumors through the Cancer Moonshot MyPART network, described in a separate report. Examples of clinical trials ongoing and in development include a 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 MET, VEGFR2, RET, KIT and TIE-2, that are overexpressed in a variety of pediatric cancers. We collaborated with the COG PEP-CTN in the development of a cabozantinib in a phase I and II trial. The phase II trial completed enrollment and recently reported activity in patients with refractory osteosarcoma. In collaboration with SARC and Dr. Patrick Grohar (Children's Hospital of Philadelphia, PA) we are conducting a phase I/II clinical trial of trabectedin and irinotecan for patients with Ewing sarcoma. The correlative FLT-PET imaging is performed at the NIH Clinical Center for these patients. We have a substantial effort in the development of effective therapies for MPNST, a highly aggressive sarcoma. Approximately 50% of MPNST occur in people with NF1. In collaboration with Dr. Karen Cichowski (Brigham and Women Hospital Boston, MA), who conducts preclinical trials with targeted therapies in her NF1 transgenic MPNST mouse model, Dr. AeRang Kim (Children's National Hospital, Washington, DC) and the sarcoma cooperative group SARC we have conducted several clinical trials specifically for MPNST, unfortunately not achieving the desired response rates. A new phase I/II clinical trial combining a MEK inhibitor, a bromodomain inhibitor and a PD-L1 inhibitor is in development for patients with refractory sarcomas and MPNST based on data from the Cichowski and DeRaedt lab demonstrating substantial tumor shrinkage in mice and will commence enrollment soon. An example for our collaboration with the NCI DTC to provide access to promising investigational therapies to children and young adults with refractory solid tumors is Dr. Chen's phase II trial of nilotinib and paclitaxel for patients with many rare tumors, which is open for enrollment for patients 12 years and older. We are also collaborating with Dr. Chen by enrolling children with refractory cancers such as alveolar soft part sarcoma, on primarily adult clinical trials directed by her. Similarly, Dr. Chen evaluates adult patients on clinical trials coordinated by the Pediatric Oncology Branch trials. This ensures that children and adults with rare tumors get optimal access to targeted therapies. The NCI POB and my Section have a leadership role in several NCI 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. Given the success of selumetinib in the treatment of the rasopathy NF1, we collaborated with CCR, DCEG and extramural investigators in the development of the Advancing RAS/Rasopathies Therapies (ART) program, which takes a comprehensive approach to study RASopathies.

NF1是最常见的遗传性神经系统单基因疾病（1:3000），以中枢和周围神经系统的良恶性肿瘤为特征，并发展为多种非肿瘤表现。NF1基因的蛋白产物神经纤维蛋白调节Ras活性，缺乏功能性神经纤维蛋白会导致Ras过度活跃和肿瘤发生。患有NF1的患者会出现多种肿瘤，包括皮肤神经纤维瘤（cNF），但不会转化为恶性肿瘤；丛状神经纤维瘤（PN），组织学上是良性的，但可引起大量发病率并转化为高度侵袭性的癌症，称为恶性周围神经鞘瘤（MPNST）；非典型神经纤维瘤（AN），这是组织学上边缘性病变，有转化为MPNST的风险。这些肿瘤的自然历史尚不完全清楚，并且没有有效的药物治疗NF1相关的周围神经鞘肿瘤。我们的NIH NF1自然历史研究使我们能够全面表征NF1中PN的生长速度和相关发病率的发展。在我们的研究中，大多数PN与发病有关（例如，疼痛，毁容，气道或运动功能障碍），这些症状在早期就表现出来。使用体积核磁共振分析的PN纵向监测PN生长，我们发现，与成人相比，儿童的PN生长最快，而成人的PN通常很少或没有生长。我的团队指导了一系列针对NF1 PN的临床试验，目标是无进展生存（PFS）或实现PN体积减少。除聚乙二醇干扰素α -2b外，没有一项试验导致部分缓解（PR），定义为与基线相比PN体积减少大于或等于20%，或临床上有意义的PFS改善。然后，我们确定了MEK抑制剂selumetinib作为抗NF1 PN的第一种活性剂。在一项针对无法手术的儿童PN的I期临床试验中，我们报告了71%的患者PN萎缩。随后，我们开发了一项II期临床试验，该试验结合了标准化的患者报告和功能结果测量，以及通过体积MRI分析评估反应。这项规模更大的II期试验证实了先前报道的缓解率。此外，我们观察到疼痛和功能的临床有意义的改善和较少的毁容。根据该试验的结果，selumetinib于2020年4月获得FDA批准用于NF1和无法手术的症状性PN患儿，并于2021年在欧洲和巴西获得批准。POB的Andrea Gross博士已经开展了一项试验，该试验将评估selumetinib是否可以预防无症状但正在生长的PN的幼儿发病率的发展。与NCI成人发育治疗诊所合作，我们目前也在进行一项用于NF1和不可手术性PN成人的selumetinib II期试验，该试验正在积极招募患者。我们正在与博士合作。Drs。Jack Shern和Taylor Sundby在POB中鉴定恶性转化的生物标志物，如游离细胞DNA和切除肿瘤的单细胞测序。我们在谅解AN方面取得了实质性进展。通过综合评估，我们确定AN是MPNST的前兆病变。我们的合作者，nind的神经外科医生Prashant Chittiboina博士，随后证明了许多AN可以安全地通过手术切除。因此，切除这些病变可能是防止恶性转化的一种方法。AN以杂合子CDKN2A/B缺失为特征。因此，我们开发了CDK4/6抑制剂abemaciclib的临床试验，专门用于nf1和不受重视的AN患者。目标2：患有罕见肿瘤的儿童和成人的自然病史和临床试验主要目标是开发治疗癌症和其他罕见肿瘤或遗传肿瘤易感性的新药。临床试验的目标是难治性实体肿瘤，如尤文氏肉瘤或横纹肌肉瘤、甲状腺髓样癌（MTC），以及非常罕见的肿瘤，如肺泡软组织肉瘤或脊索瘤，目前尚无有效的药物治疗方法。我们还旨在通过癌症Moonshot MyPART网络了解这些罕见肿瘤的生物学和自然历史，这在另一份报告中有描述。正在进行和正在开发的临床试验的例子包括cabozantinib （XL184）治疗难治性实体瘤和特定实体瘤层的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，包括MET、VEGFR2、RET、KIT和TIE-2，这些受体酪氨酸激酶在多种儿科癌症中过表达。我们与COG PEP-CTN合作，在I期和II期试验中开发cabozantinib。II期试验完成了入组，最近报道了在难治性骨肉瘤患者中的疗效。我们与SARC和Patrick Grohar博士（费城儿童医院，PA）合作，正在开展trabectedin和伊立替康治疗尤文氏肉瘤的I/II期临床试验。相关的FLT-PET成像在NIH临床中心对这些患者进行。我们在开发MPNST（一种高度侵袭性肉瘤）的有效疗法方面付出了巨大的努力。大约50%的MPNST发生在NF1患者中。Karen Cichowski博士（马萨诸塞州波士顿布里格姆妇女医院）在她的NF1转基因MPNST小鼠模型中进行了靶向治疗的临床前试验，AeRang Kim博士（华盛顿特区国家儿童医院）和SARC肉瘤合作小组合作，我们专门针对MPNST进行了几次临床试验，不幸的是没有达到预期的反应率。基于Cichowski和DeRaedt实验室的数据，一项针对难治性肉瘤和MPNST患者的新的I/II期临床试验正在开发中，该试验显示小鼠肿瘤显著缩小，并将很快开始招募。我们与NCI DTC合作，为患有难治性实体瘤的儿童和年轻人提供有前景的研究性治疗的一个例子是，陈博士为患有许多罕见肿瘤的患者进行了尼罗替尼和紫杉醇的II期试验，该试验对12岁及以上的患者开放。我们还与Dr. Chen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，陈医生评估由儿科肿瘤科临床试验协调的成年患者的临床试验。这确保患有罕见肿瘤的儿童和成人获得最佳的靶向治疗。NCI POB和我的部门在几个NCI倡议中发挥领导作用：NCI CCR罕见肿瘤倡议（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。鉴于selumetinib在治疗rasopathy NF1方面的成功，我们与CCR， DCEG和外部研究人员合作开发了先进的RAS/Rasopathies疗法（ART）项目，该项目采用综合方法研究Rasopathies。