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).

项目概要 肝母细胞瘤 (HB) 和肝细胞癌 (HCC) 是最常诊断的肝脏肿瘤 儿童中，HBs 最常见于 5 岁以下幼儿，而 HCCs 则更常见 常见于青少年。 HB 和 HCC 患者的结果和治疗选择差异很大， HB 患者的 5 年总体生存率超过 70%，HCC 患者的 5 年总体生存率低于 30%。虽然组合 化疗和手术对于低危HBs有效，高危HBs的3年总生存率为50%。高的- 大剂量化疗通常对高风险 HBs 无效，并且与显着的发病率相关。 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 针对无法从化疗中受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。 在之前的工作中，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 诊断时的高危 HBs。我们提出并回顾性评估了对患者进行分类的预测模型 基于风险——包括他们对积极治疗的需求。这些模型识别出不需要的患者 积极治疗、将从积极治疗中受益的患者以及患有更严重肿瘤的患者 可能发生转移并对化疗产生耐药性。我们开发并认证了分子检测 为这些模型使用的预测生物标志物分析患者和肿瘤。在此，我们建议前瞻性地 验证这些生物标志物、检测方法和模型，以生成第一个经过验证的分子诊断平台 HBs 和 HCC 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 AHEP1531（美国）、ChILTERN（欧盟）和 iPC（欧盟-美国合作）。