Validation of Clinical Assays for Risk Stratification of Children With Pediatric Liver Neoplasms

小儿肝肿瘤儿童风险分层临床测定的验证

• 批准号: 10663695
• 负责人: Dolores Lopez-Terrada
• 金额: $ 33.3万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663695
• 关键词: 5 year old; 6 year old; Adolescent; Affect; Biological Assay; Biological Markers; Biology; CLIA certified; Cardiotoxicity; Categories; Certification; Cessation of life; Child; Childhood; Cisplatin; Classification; Clinical; Clinical Trials; Collaborations; Combination Drug Therapy; Combined Modality Therapy; Data; Development; Diagnosis; Drug resistance; Enrollment; Europe; European; Excision; Funding; Graft Rejection; Hepatic; Hepatoblastoma; High Dose Chemotherapy; Histology; Immunotherapy; Impairment; International; Intervention; Intervention Studies; Investigational Therapies; Lesion; Liver; Liver neoplasms; Malignant Neoplasms; Medical; Modeling; Molecular; Molecular Diagnosis; Molecular Profiling; Morbidity - disease rate; Neoplasm Metastasis; Neoplasms; Nonmetastatic; Operative Surgical Procedures; Outcome; Patient Recruitments; Patient-Focused Outcomes; Patients; Pediatric Neoplasm; Pediatric Oncology Group; Pediatric cohort; Play; Preparation; Primary carcinoma of the liver cells; Prognosis; Prognostic Marker; Quality of life; Resected; Resistance; Risk; Risk Estimate; Second Primary Cancers; Stratification; Survival Rate; Testing; Therapeutic Trials; Toxic effect; Treatment outcome; Treatment-related toxicity; Tumor Subtype; Unresectable; Validation; Work; aggressive therapy; biomarker validation; chemotherapeutic agent; chemotherapy; cohort; dosage; high risk; improved; improved outcome; liver cancer patient; liver transplantation; molecular marker; molecular modeling; nephrotoxicity; neurotoxicity; ototoxicity; participant enrollment; personalized medicine; predictive marker; predictive modeling; predictive test; profiles in patients; prospective; recruit; research clinical testing; response; risk prediction; risk prediction model; risk stratification; targeted treatment; transplantation therapy; treatment optimization; tumor

Project Summary Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most frequently diagnosed liver tumors in children, with HBs most commonly present in young children less than 5 years of age, and HCCs are more commonly seen in adolescents. HB- and HCC-patient outcomes and treatment options vary dramatically, with 5-year overall survival rates of over 70% for HB and under 30% for HCC patients. While a combination of chemotherapy and surgery is effective for lower-risk HBs, 3-year overall survival for high-risk HBs is 50%. High- dose chemotherapy, which is often ineffective for high-risk HBs, is associated with significant morbidity. Complete surgical resection is the only chance for a cure for HCC. Molecular biomarkers can help optimize treatments for patients that will not benefit from chemotherapy or that do not require high dosage chemotherapy and identify patients that require a combination of aggressive surgery and chemotherapy. In previous work, we, and our collaborators, identified prognostic biomarkers that distinguish between low- and high-risk HBs at diagnosis. We proposed and retrospectively evaluated predictive models to classify patients based on risk—including their need for aggressive therapies. These models identify patients that do not require aggressive therapies, patients that will benefit from aggressive therapies, and patients with tumors that are more likely to metastasize and become resistant to chemotherapy. We developed and certified molecular assays to profile patients and tumors for predictive biomarker used by these models. Here, we propose to prospectively validate these biomarkers, assays, and models to produce the first validated platform for the molecular diagnosis and therapy choice for HBs and HCC. We will benefit from a close collaboration with clinical-trial produced data in the USA and EU, including AHEP1531 (USA), ChILTERN (EU) and iPC (a EU-USA collaboration).

项目摘要 肝母细胞瘤（HB）和肝细胞癌（HCC）是最常见的肝脏肿瘤， 儿童，HB最常见于5岁以下的幼儿，HCC更多 常见于青少年。HB和HCC患者的结局和治疗选择差异很大， 5-HB患者的年总生存率超过70%，HCC患者的年总生存率低于30%。虽然一个组合的 化疗和手术对低风险的HB有效，高风险HB的3年总生存率为50%。高- 大剂量化疗通常对高危HB无效，但与显著的发病率相关。 完全手术切除是治愈HCC的唯一机会。分子生物标志物可以帮助优化 对不能从化疗中获益或不需要高剂量化疗的患者的治疗 并确定需要积极手术和化疗相结合的患者。 在以前的工作中，我们和我们的合作者，确定了区分低和低的预后生物标志物， 诊断时的高风险HB。我们提出并回顾性评估了预测模型来对患者进行分类， 包括他们对积极治疗的需求。这些模型识别出不需要 积极的治疗，患者将受益于积极的治疗，和患者的肿瘤， 可能转移并对化疗产生抗药性。我们开发并认证了分子检测， 对患者和肿瘤进行分析，以获得这些模型使用的预测性生物标志物。在此，我们建议前瞻性地 验证这些生物标志物、测定和模型，以产生第一个经验证的分子诊断平台 以及乙肝和肝细胞癌的治疗选择。我们将受益于与临床试验产生的数据的密切合作 在美国和欧盟，包括AHEP 1531（美国），奇尔滕（欧盟）和iPC（欧盟-美国合作）。