Targeted therapy in ex vivo medulloblastoma/PNET

离体髓母细胞瘤/PNET 靶向治疗

• 批准号: 8297663
• 负责人: JAMES M OLSON
• 金额: $ 22.73万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-06 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297663
• 关键词: Age; Anaplasia; BMP2 gene; Biological; Biological Markers; Biology; Brain Neoplasms; Carboplatin; Categories; Cell Culture Techniques; Cell Line; Child; Childhood; Childhood Brain Neoplasm; Clinical; Clinical Data; Clinical Trials; Communities; Data; Development; Disease; Drug Combinations; Drug usage; European; FDA approved; Failure; Foundations; Future; Grant; Human; Isotretinoin; Laboratories; Learning; Malignant neoplasm of brain; Methods; MicroRNAs; Modeling; Molecular; Mus; Needles; Neoplasm Metastasis; Newly Diagnosed; Oncology Group; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Pre-Clinical Model; Primitive Neuroectodermal Tumor; Protocols documentation; Radiation; Radiosensitization; Recurrence; Regimen; Resistance; Retinoids; Risk; Sampling; Scheme; Specimen; Stratification; Supratentorial; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Treatment Protocols; Tumor Biology; Tumor Stem Cells; Variant; Vorinostat; Work; Xenograft Model; Xenograft procedure; base; clinical efficacy; clinically relevant; cohort; drug candidate; high risk; improved; in vivo; innovation; medulloblastoma; mouse model; neoplastic cell; neuro-oncology; notch protein; novel; oncology; outcome forecast; overexpression; pre-clinical; preclinical study; prevent; prognostic indicator; prospective; response; tumor

DESCRIPTION (provided by applicant): Children with medulloblastoma and primitive neuroectodermal (PNET) brain tumors are divided into average- and high-risk groups so that therapy intensity can be tailored. Unfortunately, the methods for stratifying patients are imperfect, so that > 25% of children categorized as "average risk" fail therapy and die of disease. We have identified P27 loss as a biomarker that identifies most of these children and could be used to appropriately place them in the high-risk category, where they would receive intensified therapy increasing survival chances. Another clinical problem is that PNET patients are grouped with medulloblastoma patients in clinical trials and treated identically. We have recently learned that PNET tumors are molecularly distinct from medulloblastomas and that PNET patients respond poorly to therapy that has been tailored for medulloblastoma patients. The critical barrier to tailoring sPNET therapy to the disease has been the lack of relevant sPNET pre-clinical models. We have generated patient-derived sPNET stem cell cultures and orthotopic mouse models and have used these to identify FDA-approved drugs that are more efficacious in pre-clinical studies than currently used drugs. In this renewal application, our Specific Aims are: 1) To identify prognostic indicators of therapy failure for medulloblastoma and sPNET patients. 2) To prioritize targeted therapies for future clinical trials. The expected outcomes are: 1) that we will further refine molecular biomarkers suitable for patient stratificatin in a prospective analysis of > 300 patients; 2) that we will generate clinically relevant sPNET and high risk medulloblastoma pre-clinical models and 3) consistent with our track record, we will promote a regimen for human sPNET and high risk medulloblastoma trials based on studies that exceed all current standards for advancement of pre-clinical results into clinical trials. The significance is that we will ultimately abandon an archaic patient stratification scheme in favor o a biologically-based strategy that appropriately directs patients into tailored therapy and that sPNET patients will be treated with therapeutic regimens that are based on relevant pre-clinical and clinical data. Ultimately both will yield higher cure rates and limit toxicity in pediatric bran tumor patients. PUBLIC HEALTH RELEVANCE: This proposal integrates newly identified biomarkers that identify children who are likely to fail standard medulloblastoma or supratentorial primitive neuroectodermal therapy with novel patient-derived pre-clinical brain tumor models that are used to identify and prioritize new therapies for pediatric brain tumor patients.

描述（由申请人提供）：患有髓母细胞瘤和原始神经外胚层（PNET）脑肿瘤的儿童被分为平均和高风险组，以便可以定制治疗强度。不幸的是，对患者进行分层的方法并不完善，因此，超过25%的儿童被归类为“平均风险”，治疗失败并死于疾病。我们已经确定P27丢失作为一种生物标志物，可以识别大多数这些儿童，并可用于将他们适当地置于高风险类别，在那里他们将接受强化治疗，增加生存机会。另一个临床问题是，PNET患者在临床试验中与髓母细胞瘤患者分组并接受相同的治疗。我们最近了解到PNET肿瘤在分子水平上与髓母细胞瘤不同，并且PNET患者对专为髓母细胞瘤患者设计的治疗反应较差。针对该疾病定制sPNET疗法的关键障碍是缺乏相关的sPNET临床前模型。我们已经产生了患者来源的sPNET干细胞培养物和原位小鼠模型，并使用这些来鉴定FDA批准的药物，这些药物在临床前研究中比目前使用的药物更有效。在本次更新申请中，我们的具体目标是：1）确定髓母细胞瘤和sPNET患者治疗失败的预后指标。2)为未来的临床试验优先考虑靶向治疗。预期成果是：1）我们将在一项超过300例患者前瞻性分析中进一步完善适合患者分层分子生物标志物; 2）我们将生成临床相关的sPNET和高风险髓母细胞瘤临床前模型，3）与我们的跟踪记录一致，我们将促进人类sPNET和高风险髓母细胞瘤试验的方案，这些试验的基础研究超过了目前所有的标准，临床结果转化为临床试验的 重要的是，我们将最终放弃陈旧的患者分层方案，而采用基于生物学的策略，适当指导患者进行定制治疗，并且sPNET患者将采用基于相关临床前和临床数据的治疗方案进行治疗。最终，这两种方法都将提高治愈率，并限制儿科麸质肿瘤患者的毒性。 公共卫生关系：该提案整合了新鉴定的生物标志物，这些生物标志物可识别可能无法通过标准髓母细胞瘤或幕上原始神经外胚层治疗的儿童，以及用于识别和优先考虑儿科脑肿瘤患者新疗法的新型患者来源的临床前脑肿瘤模型。