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.

目标1：NF1相关周围神经鞘瘤的自然史和临床试验NF1是最常见的神经系统遗传性单基因疾病（1:3000），其特征是中枢和周围神经系统的良性和恶性肿瘤，以及各种非肿瘤表现的发展。 NF1 基因的蛋白质产物神经纤维蛋白调节 Ras 活性，功能性神经纤维蛋白的缺乏会导致 Ras 过度活跃和肿瘤发生。患有 NF1 的人会出现多种肿瘤，包括皮肤神经纤维瘤 (cNF)，但这种肿瘤永远不会转变为恶性肿瘤；丛状神经纤维瘤 (PN)，组织学上是良性的，但可导致大量发病并转化为高度侵袭性癌症，称为恶性周围神经鞘瘤 (MPNST)；非典型神经纤维瘤 (AN)，其组织学上属于边界病变，有转化为 MPNST 的风险。这些肿瘤的自然史尚不完全清楚，并且对于 NF1 相关的周围神经鞘瘤没有有效的药物治疗。我们的 NIH NF1 自然史研究使我们能够全面描述 NF1 中 PN 的增长率以及相关疾病的发展。在我们的研究中，大多数 PN 与疾病（例如疼痛、毁容、气道或运动功能障碍）相关，这些疾病在很小的时候就表现出来。使用 PN 的体积 MRI 分析来纵向监测 PN 的生长，我们发现，与通常 PN 生长很少或没有生长的成年人相比，幼儿的 PN 生长最快。我的团队指导了一系列针对 NF1 PN 的临床试验，目标是无进展生存期 (PFS) 或实现 PN 体积减少。除聚乙二醇化干扰素 α-2b 外，所有试验均未产生部分缓解 (PR)，部分缓解定义为与基线相比 PN 体积减少大于或等于 20%，或 PFS 具有临床意义的改善。然后我们确定 MEK 抑制剂 selumetinib 是第一个针对 NF1 PN 的活性药物。在一项针对无法手术的 PN 儿童的 I 期临床试验中，我们报告 71% 的患者 PN 缩小。随后，我们开展了一项 II 期临床试验，除了通过体积 MRI 分析评估反应之外，还纳入了标准化患者报告和功能结果测量。这项更大规模的二期试验证实了之前报道的缓解率。此外，我们观察到疼痛和功能的临床有意义的改善以及更少的毁容。根据该试验的结果，selumetinib 于 2020 年 4 月获得 FDA 批准用于治疗患有 NF1 和无法手术的有症状 PN 的儿童，并于 2021 年在欧洲和巴西获得批准。 POB 的 Andrea Gross 博士开发了一项试验，该试验将评估 selumetinib 是否有效可以预防无症状但 PN 不断增长的幼儿发病。我们目前还与 NCI 成人发育治疗诊所合作，针对患有 NF1 和无法手术的 PN 的成人进行 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。博士。 Jack Shern 和 Taylor Sundby 在 POB 中鉴定恶性转化的生物标志物，例如无细胞 DNA 和切除肿瘤的单细胞测序。我们在理解 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、NINDS 的神经外科医生 Prashant Chittiboina 博士随后证明，许多 AN 可以安全地通过手术切除，并保留边缘。因此，切除这些病变可能是预防恶变的一种方法。 AN 的特点是杂合 CDKN2A/B 缺失。因此，我们专门针对 NF1 和不值得尊敬的 AN 患者开发了 CDK4/6 抑制剂 abemaciclib 的临床试验。目标 2：患有罕见肿瘤的儿童和成人的自然史和临床试验主要目标是开发用于治疗癌症和其他罕见肿瘤或遗传肿瘤倾向的新药物。临床试验针对难治性实体瘤，如尤文肉瘤或横纹肌肉瘤、甲状腺髓样癌 (MTC)，以及非常罕见且尚无有效药物治疗的肿瘤，如腺泡软组织肉瘤或脊索瘤。我们还旨在通过 Cancer Moonshot MyPART 网络了解这些罕见肿瘤的生物学和自然史，这在另一份报告中进行了描述。正在进行和正在开发的临床试验的例子包括卡博替尼 (XL184) 用于难治性实体瘤和选定实体瘤层的 I 期和 II 期试验。卡博替尼是多种受体酪氨酸激酶 (RTK) 的小分子抑制剂，包括 MET、VEGFR2、RET、KIT 和 TIE-2，这些受体在多种儿科癌症中过度表达。我们与 COG PEP-CTN 合作开发了卡博替尼的 I 期和 II 期试验。 II 期试验完成了入组，并最近报告了在难治性骨肉瘤患者中的活动。我们与 SARC 和 Patrick Grohar 博士（宾夕法尼亚州费城儿童医院）合作，正在针对尤文肉瘤患者进行曲贝替定和伊立替康的 I/II 期临床试验。相关 FLT-PET 成像是在 NIH 临床中心为这些患者进行的。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莱根妇女医院）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（华盛顿特区儿童国家医院）和肉瘤合作小组与之合作SARC 我们专门针对 MPNST 进行了多项临床试验，遗憾的是没有达到预期的缓解率。一项针对难治性肉瘤和 MPNST 患者的新 I/II 期临床试验正在开发中，该试验结合了 MEK 抑制剂、溴结构域抑制剂和 PD-L1 抑制剂，该试验基于 Cichowski 和 DeRaedt 实验室的数据，显示小鼠肿瘤明显缩小，并将开始即将报名。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希望的研究疗法的一个例子是陈博士针对许多罕见肿瘤患者进行的尼罗替尼和紫杉醇 II 期试验，该试验现已开放供患者入组12 岁及以上。我们还与陈博士合作，招募患有难治性癌症（例如肺泡软组织肉瘤）的儿童，进行由她指导的主要成人临床试验。同样，陈博士在儿科肿瘤科试验协调的临床试验中对成年患者进行评估。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。 NCI POB 和我的部门在 NCI 的多项计划中发挥着领导作用：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。鉴于司美替尼在治疗 RASopathies NF1 方面取得的成功，我们与 CCR、DCEG 和校外研究人员合作开发了 Advancing RAS/Rasopathies Therapies (ART) 项目，该项目采用综合方法来研究 RASopathies。