Indiana University Center for Pediatric Pharmacology and Precision Medicine

许多儿童癌症的治疗进展是一个令人惊叹的成功故事。许多人的生存 在过去的三十年里，儿童恶性肿瘤呈对数增长。然而，尽管如此， 显著的进步，30%的癌症儿童患上复发的疾病，其中大多数死于 疾病。此外，许多化疗药物都与显著的副作用有关--这可能 在某些情况下会使人虚弱，甚至危及生命。生物标记物发现的进展，包括基因组学， 药物基因组学、转录组学和蛋白质组学在改善这些患者方面为他们带来了巨大的希望 治疗的精确度、安全性和有效性。我们建议将知情候选基因组学与靶向基因组学相结合 蛋白质组学在我们专注的多因素方法中与全基因组测序并行翻译和 优化儿童的治疗方法。我们的总体假设是，精心挑选的生物标志物的组合 与儿童癌症化疗的毒性和总体反应有关；使用高度 指导个别儿童治疗的预测性生物标记物将导致改善结果。的目标是 这项中心拨款申请是为了确定预测反应和毒性的生物标记物的最佳组合。 并评估治疗患有危及生命的癌症的儿童的治疗益处，这些癌症是 严重的药物不良反应。我们提出了两个跨学科和紧密联系的项目，由我们的 管理核心。项目I将测试使用精确医学方法(结合 基于NGS的肿瘤分子特征和靶向种系药物基因组学)选择 复发和难治性儿童肉瘤的个体化治疗策略优于使用 传统的方法。项目I还将评估治疗复发性儿科疾病的联合治疗方案。 肉瘤是通过使用我们自己的患者来源的细胞系和 并将致力于发现新的靶点，以完善我们的精准医学方法，以改进 这组致命的儿科疾病的结果。项目二将利用一种新的血浆蛋白面板 造血细胞移植(HCT)治疗相关的窦性梗阻综合征的生物标志物预后 作为评估去纤肽(一种在欧洲被批准用于治疗糖尿病的药物)的随机试验的基础 SOS)用于预防这种与治疗相关的潜在致命肝毒性。这项建议将使 通过为医生提供关键信息来做出更安全的明智决定，从而产生显著的积极影响 以及在儿童中更有效地使用药物。此外，我们的应用程序将确保培训和 儿科和发育药理学方面的研究仍然处于开发和使用的前沿 在所有儿童用药中。这些多学科研究的直接结果将是发现新的 生物标志物和预测性签名将提高危及生命的儿童的治疗精度 并最大限度地减少与治疗相关的严重副作用。

The progress in the treatment of many childhood cancers is a story of amazing successes. Survival for many childhood malignancies has improved logarithmically over the past three decades. However, despite these remarkable advances, 30% of children with cancer develop relapsed disease, the majority of whom die of their diseases. Furthermore, many chemotherapeutic agents are associated with significant side effects—which can be debilitating and even life threatening in some cases. Advances in biomarker discovery, including genomics, pharmacogenomics, transcriptomics, and proteomics, offer great hope to these patients in terms of improved therapeutic precision, safety, and efficacy. We propose to combine informed candidate genomics with targeted proteomics in our focused multifactorial approach in parallel with whole genome sequencing to translate and optimize therapeutics in children. Our overall hypothesis is that combinations of carefully selected biomarkers are associated with toxicity and overall response to pediatric cancer chemotherapy; and that using highly predictive biomarkers to guide therapy for individual children will result in improved outcomes. The objective of this center grant application is to identify the best combinations of biomarkers to predict response and toxicities and to evaluate the therapeutic benefit of treating children with life-threatening cancers who are at high risk for severe adverse drug effects. We propose two interdisciplinary and closely interlinked projects supported by our Administrative Core. Project I will test the hypothesis that using a precision medicine approach (incorporating focused NGS based tumor molecular characterization and targeted germline pharmacogenomics) in selecting individualized therapeutic strategies to relapsed and refractory pediatric sarcomas is superior to using a traditional approach. Project I will also evaluate therapeutic combinations for treatment of relapsed pediatric sarcomas informed by focused tumor molecular analysis using our own patient-derived cell lines and xenografts and will aim to discover novel targets to refine our precision medicine approach to improve outcomes in this deadly group of pediatric diseases. Project II will utilize a novel panel of plasma protein biomarkers prognostic of hematopoietic cell transplant (HCT) therapy-related sinusoidal obstruction syndrome in children as the basis of a randomized trial evaluating defibrotide (a drug approved in Europe for treatment of SOS) for prevention of this potentially fatal treatment-associated liver toxicity. This proposal will make a significant positive impact by providing critical information for physicians to make informed decisions for safer and more effective use of drugs in children. Furthermore, our application will ensure that both training and research, in pediatric and developmental pharmacology, remains at the forefront of the development and use of all medications in children. The direct outcome of these multidisciplinary studies will be discovery of new biomarkers and predictive signatures that will increase the precision of treatment for life-threatening childhood cancers and minimize severe treatment-associated side effects.