Development of new treatments for rare CNS tumors

罕见中枢神经系统肿瘤新疗法的开发

• 批准号: 10926531
• 负责人: Marta Penas-Prado
• 金额: $ 8.73万
• 依托单位: DIVISION OF BASIC 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/10926531
• 关键词: 16 year old; 18 year old; Adolescent; Adrenal Cortex Hormones; Adult; Age; Area; Behavior; Biological Markers; Biology; Brain Neoplasms; Caring; Cell physiology; Cells; Central Nervous System Neoplasms; Chemotherapy and/or radiation; Child; Childhood; Classification; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; DNA Repair; DNA Sequence Alteration; Databases; Defect; Development; Diagnosis; Disease; Education; Ependymoma; Event; Face; Family; Future; Geographic Locations; Germany; Goals; Homologous Gene; Iatrogenesis; Immune; Immune response; Immunity; Immunologic Monitoring; Immunosuppression; Immunotherapy; In complete remission; Incidence; Information Technology; Institution; Institutional Review Boards; Knowledge; Laboratories; Lead; Leadership; Logistics; MYCN gene; Maintenance; Maintenance Therapy; Malignant Neoplasms; Malignant neoplasm of central nervous system; Measures; Molecular; Molecular Analysis; Molecular Profiling; Multicenter Studies; Mutation; Natural History; Nivolumab; Oncology Group; Outcome; Participant; Pathology; Pathway interactions; Patients; Phase; Phase I/II Clinical Trial; Phenotype; Placebo Control; Placebos; Plasma; Pre-Clinical Model; Predisposition; Protocols documentation; Radiation Oncologist; Radiation therapy; Randomized; Recurrence; Refractory; Relapse; Research; Research Design; Research Personnel; Resistance; Resolution; Risk; Role; SHH gene; Sampling; Site; Sonic Hedgehog Pathway; Spinal Neoplasms; Stable Disease; Structure; Subgroup; Superhelical DNA; Symptoms; TP53 gene; Teenagers; Therapeutic Trials; Time; Tissues; Topoisomerase; Toxic effect; Transforming Growth Factor beta; Treatment Protocols; Tumor Biology; Tumor Tissue; United States National Institutes of Health; Work; World Health Organization; checkpoint therapy; chemokine; chemotherapy; clinical care; clinically relevant; cohort; cooperative study; cytokine; disorder control; efficacy evaluation; efficacy testing; follow-up; high risk; immune checkpoint; inhibitor; medulloblastoma; molecular marker; molecular subtypes; multidisciplinary; neuro-oncology; novel; novel therapeutics; older patient; partial response; participant enrollment; patched protein; patient subsets; peripheral blood; phase 1 designs; precision medicine; predictive marker; prognostication; programs; prospective; rare cancer; repository; resistance mechanism; response; risk stratification; therapeutic target; treatment response; trial enrollment; tumor; tumor microenvironment; tumor progression; virtual; young adult

'OBJECTIVE 1. Examine the role of topoisomerase inhibition in targeting the alterations in DNA repair and hypercoiling in MYC and MYCN amplified CNS tumors. - PROGRESS: Recently, a new subtype of ependymoma characterized by MYCN amplification was discovered based on collaborative efforts between NOB investigators and the NCI Laboratory of Pathology, along with the work of other colleagues in Germany. This is a highly aggressive cancer, refractory to most established treatments, and driven by a molecular alteration that has been considered undruggable. Although medulloblastoma is a tumor considered rare in adults, 30% of all cases are diagnosed in late teenagers and young adults under the age of 40. Recurrent medulloblastoma is considered uncurable, and adults commonly do not have access to pediatric clinical trials. Combined MYC family amplifications and P53 pathway defects emerge in 32% of relapsed medulloblastomas. I have started a search for novel therapies for MYCN-amplified ependymoma, MYC or MYCN-amplified medulloblastoma, and other primary CNS tumors sharing the same molecular alteration, collaborating with other NIH investigators. We plan to exploit the DNA supercoiling that results from MYC and MYCN amplification. I lead an investigator-initiated, IND Phase I/II clinical trial using a Pegylated form of SN38 (PLX038) to test efficacy and predictive markers. This trial incorporates a novel Phase I design (time-to-event Bayesian optimal interval, TITE-BOIN) to shorten the trial duration and reduce the logistic difficulties caused by repeatedly suspending accrual. The Phase II component will incorporate correlatives at 3 timepoints: archival or baseline tissue before starting therapy, post cycle 2, and at the time of tumor progression. The protocol is currently undergoing IRB review. 'OBJECTIVE 2. Examine the role of maintenance smoothened inhibition in adult patients with medulloblastoma (MB) and activation of the Sonic Hedgehog pathway (SHH-MB subgroup). - PROGRESS: Unlike MB in children, robust prospective trials have not taken place for older patients. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the SHH pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. The Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo-Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial) (PI: Anita Mahajan, Radiation Oncologist Mayo Clinic). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high-risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year. As the Neuro-Oncology Co-Chair for this cooperative study, which is currently undergoing regulatory approval, I have participated in all aspects of study design. 'OBJECTIVE 3. Examine the role of immunotherapy in treating patients with Rare CNS Tumors. - PROGRESS: To date, there is little evidence that immune checkpoint treatment is effective in most patients with primary CNS tumors. Various factors have been postulated including an immune-suppressive tumor microenvironment and systemic immunosuppression that is either iatrogenic (corticosteroids, chemotherapy) or produced by the cancer (ie TGF-B). My actively accruing multicenter basket clinical trial (NCT 03173950) is enrolling patients with selected recurrent rare CNS cancers who have completed prior standard therapies across 10 participating centers in the US, with NOB being the leading site. Participants receive nivolumab for up to 16 cycles. The primary efficacy endpoint is disease control rate (DCR; partial responses, complete responses, or stable disease for at least 6 months). Extensive monitoring of immune response in peripheral blood is done longitudinally. Immune cell phenotyping, cell function, and plasma chemokines and cytokines will be measured on these samples. Additional future studies will include the correlation of changes in immunity with survival and the development and resolution of immune-related toxicities and changes in participants' symptoms and function. Future plans also include determining if certain tumor types or molecular subgroups are more susceptible to checkpoint inhibitor therapy, as well as elucidating potential mechanisms of resistance to set the rationale for subsequent clinical trials for patients with specific diagnoses or baseline biomarkers. The trial enrolls patients in two different cohorts (Cohort 1: heaviliy pretreated and Cohort 2: non-heavily pretreated), exploring the hypothesis of differential effect based on extent of prior treatment and asking the question of whether heavy pretreatment limits the immune response or increases the tumor mutational burden thus favoring a response. Cohort 1 has completed full accrual in July 2023 (n=75) and Cohort 2 has reached the preplanned accrual for interim efficacy analysis. 'OBJECTIVE 4. Discover gaps in knowledge in the care and treatment of patients with Rare CNS Tumors. - PROGRESS: The World Health Organization (WHO) classification of primary CNS tumors includes more than 130 tumor types with varying clinical behavior and outcome. Most brain and spine neoplasms have an annual incidence of less than 1,000 cases per year in the US. Given the rarity of these tumors, there is limited understanding of their natural history and molecular makeup and a paucity of proven therapies. In collaboration with the pathology team, I launched a multicenter study across the BTTC/CONNECT consortium to collect tumor tissue and structured clinical information in deceased and lost to follow-up adults with rare CNS tumors. The study's objectives are: 1) to study the clinical course of adult patients with select rare CNS tumors included under the NCI-CONNECT program. This will include analyzing the impact of patient, tumor, and therapy-related factors and correlate with outcome (progression-free interval and overall survival), and 2) identifying clinically relevant molecular markers in previously collected tumor tissue that define molecular subtypes, response to therapy and high-risk molecular signatures for aggressive clinical behavior of rare CNS tumors in adults. Molecular analysis and clinical data abstraction of around 100 cases from 6 different collaborating institutions is currently underway. Starting in 2020, the weekly multidisciplinary NIH Neuro-Oncology Tumor Board was transitioned to a virtual format and expanded to include NCI-CONNECT consortium sites and neighbor institutions in the area NIH geographic area under my leadership. In collaboration with the information technology team, I am leading the development of a database to assist with the logistics of the tumor board, serve as an educational repository of cases and allow interrogation of the database for research purposes

'目标1。检查拓扑异构酶抑制在靶向MYC和MYCN扩增的CNS肿瘤中DNA修复和高涂层的改变中的作用。 - 进展：最近，根据NOB研究人员与NCI病理学实验室的合作努力以及德国其他同事的工作，发现了一种以MYCN扩增为特征的新型子类型。这是一种高度侵略性的癌症，对大多数已建立的治疗方法难治性，并由被认为不可能的分子改变驱动。尽管髓母细胞瘤在成年人中被认为很少见，但在所有病例中，有30％均在40岁以下的青少年和年轻人中被诊断出来。复发性髓母细胞瘤被认为是不可育的，而成年人通常无法接受儿科临床试验。在32％的复发性髓母细胞瘤中出现了MYC家族放大和p53途径缺陷。我已经开始寻找用于MYCN扩增的室内室室瘤，MYC或MYCN放大的髓母细胞瘤，以及其他同一分子改变的其他主要CNS肿瘤，与其他NIH研究者合作。我们计划利用MYC和MYCN扩增产生的DNA超螺旋。我领导研究人员发起的IND I/II期临床试验，采用SN38（PLX038）的类化形式来测试功效和预测标记。该试验结合了新的I期设计（事件时间贝叶斯最佳间隔，Tite-Boin），以缩短试验持续时间并减少由于反复暂停应计引起的逻辑困难。 II期分量将在3个时间点上合并相关性：开始治疗前的档案或基线组织，第二周期和肿瘤进展时。该协议目前正在进行IRB审查。 '目标2。检查成年髓母细胞瘤（MB）患者维持平稳抑制作用的作用以及Sonic刺猬途径（SHH-MB亚组）的激活。 - 进度：与儿童的MB不同，对老年患者的强大前瞻性试验没有进行。 MB的临床和分子分类现在提供了更好的预后，并且正在小儿治疗试验中纳入。已经确定，在16岁以上的患者中，大约60％的MB发生了导致SHH途径激活的基因组改变。在该队列中，通常会发现蛋白质修补的同源物（PTCH）和平滑（SMO）突变。在肿瘤带有SHH分子特征的患者中，据估计，超过80％的患者可以对SHH途径抑制剂有反应。 The Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo-Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial) (PI: Anita Mahajan, Radiation Oncologist Mayo诊所）。这项试验将以MB（任何分子亚组和风险分层）或松果体胚胎肿瘤年龄以上的患者注册患者。患者将被分配到三个队列之一：（1）平均风险非SHH-MB，（2）平均风险SHH-MB和（3）高危MB或松果体胚胎肿瘤。所有患者将接受放射治疗和化学疗法的方案指导的综合治疗。在1中，SHH-MB患者将随机分为平滑的抑制剂或安慰剂作为维持治疗一年。作为当前正在接受监管部门的合作研究的神经肿瘤学共同主席，我参与了研究设计的各个方面。 '目标3。检查免疫疗法在治疗稀有中枢神经系统肿瘤患者中的作用。 - 进展：迄今为止，几乎没有证据表明免疫检查点治疗在大多数原发性中枢神经系统肿瘤患者中都是有效的。已经假定各种因素，包括免疫抑制肿瘤微环境和全身免疫抑制，该环境是医源性的（皮质类固醇，化学疗法）或由癌症（IE TGF-B）产生的。我积极进行多中心篮子临床试验（NCT 03173950）正在招募患有选定的经常性稀有中枢神经系统癌症患者，这些患者已在美国10个参与中心完成了先前的标准疗法，而NOB是领先地点。参与者将获得多达16个周期的Nivolumab。主要疗效终点是疾病控制率（DCR；部分反应，完全反应或稳定疾病至少6个月）。对外周血中免疫反应的广泛监测进行纵向进行。免疫细胞表型，细胞功能以及血浆趋化因子和细胞因子将在这些样品上测量。未来的其他研究将包括免疫变化与生存以及免疫相关毒性的发展和解决，以及参与者症状和功能的变化。未来的计划还包括确定某些肿瘤类型或分子亚组是否更容易受到检查点抑制剂治疗的影响，以及阐明抗药性的潜在机制，以为具有特定诊断或基线生物标志物患者的后续临床试验设定基本原理。该试验将患者参与了两个不同的队列（队列1：经过预处理和队列2：未经预处理预处理），探讨了基于先前治疗程度的差异效应的假设，并询问了重度预处理的问题，即严重预处理是否会限制免疫反应或增加肿瘤突变负担，从而增加了反应。队列1已于2023年7月完成全额应计（n = 75），同类群体2已达到预先计划的应计进行临时疗效分析。 '目标4。发现稀有中枢神经系统肿瘤患者护理和治疗知识的差距。 - 进展：世界卫生组织（WHO）原发性中枢神经系统肿瘤的分类包括130多种肿瘤类型，具有不同的临床行为和结果。在美国，大多数大脑和脊柱肿瘤的年发病率每年少于1,000例。鉴于这些肿瘤的稀有性，对它们的自然史和分子构成以及贫困疗法的缺乏的了解有限。与病理团队合作，我在BTTC/Connect Consortium上启动了一项多中心研究，以收集死者的肿瘤组织和结构化临床信息，并因患有罕见CNS肿瘤的后续成年人而丢失。该研究的目标是：1）研究NCI连接计划中的成年患者的临床病程。这将包括分析患者，肿瘤和与治疗相关的因素的影响，并与结果（无进展间隔和整体存活）相关，以及2）在先前收集的肿瘤组织中鉴定临床相关的分子标记，这些分子标记定义了分子亚型，对治疗的反应，对稀有cns tamors contressive Clanical Clanical Charmors themors tymors tymors themors themors tymors tymors themors tymors tymors tymors themors tymors tymors tymors。目前正在进行来自6个不同协作机构的大约100例病例的分子分析和临床数据抽象。从2020年开始，将每周的多学科NIH NIH神经肿瘤委员会过渡到虚拟格式，并扩展到包括NIH NIH地理区域的NCI联合财团和邻居机构。在与信息技术团队的合作中，我正在领导数据库的开发，以协助肿瘤委员会的后勤工作，作为案例的教育存储库，并允许询问数据库以进行研究目的