Genomically informed agent selection and testing in osteosarcoma patient-derived xenograft models

项目总结/摘要 自现代化疗出现以来，骨肉瘤患者的生存结局没有改变 四十年前，在这种疾病中开发新的有效疗法一直是一项挑战。我们的实验室很长- 长期使命是通过全面的基因组学和蛋白质组学方法， 对患者来源的细胞系和异种移植物以及人类肿瘤进行分析，最终目标是识别 和/或开发和测试针对这些靶标的治疗剂。为了实现这一目标，我们（a）建立了一个强大的 分析平台，以确定新的目标; B）扩大了我们的骨肉瘤患者来源的异种移植物的库 (PDX)反映疾病异质性的模型;和c）对8-10种新的 代理商每年都作为儿科临床前测试联盟（PPTC）的一部分，以及独立于它。 所有这些努力构成了我们目前研究计划的基础，并使我们能够成功地 实现我们的目标。 我们的总体目标是有效地评估具有高潜力的新药物在以下方面的疗效： 基于我们的基因组和蛋白质组分析的靶数据，骨肉瘤作为单一药物和 合理组合，通过儿童基金会将有效药物投入临床试验， 肿瘤组。我们有三个具体的目标：1）选择和测试药物在体内针对表面靶点 通过骨肉瘤异种移植物和患者肿瘤的全面蛋白质组学分析鉴定; 2）选择和 针对通过骨肉瘤异种移植物的综合基因组谱鉴定的靶点的体内测试试剂 和患者肿瘤;和3）基于靶向、毒性和功效进行合理组合的药剂的测试 单个代理的数据。 来自PPTC管道的试剂将基于蛋白质组学靶点或基因组改变进行选择。 存在于可获得的骨肉瘤PDX模型的至少一个子集中。将在选定的队列中检测该药物 低/高表达蛋白靶或存在/不存在基因组改变。如果有多个模型， 靶向表达，每个模型将使用3-5只小鼠，在可用模型较少的情况下，每个模型使用8-10只小鼠 将用于对照组和实验组，每组实验的总n数约为30 小鼠标准PPTC程序将用于肿瘤植入和治疗。肿瘤尺寸将是 每周测量两次，并根据完全缓解的标准PPTC定义对缓解进行量化， 维持完全缓解、部分缓解、疾病稳定和疾病进展。用于组合 根据疗效和毒性数据，将考虑三种潜在的组合类型- a）两种 表面蛋白靶向剂，如两种抗体-药物缀合物; 2）两种分子靶向剂， 3)表面蛋白靶向剂和分子靶向剂。我们的研究结果将指导 下一代骨肉瘤临床试验

Project Summary/ Abstract Survival outcomes for patients with osteosarcoma have not changed since the advent of modern chemotherapy four decades ago and it has been challenging to develop new effective therapies in this disease. Our lab’s long- term mission is to identify novel molecular targets in osteosarcoma via comprehensive genomic and proteomic profiling of patient-derived cell lines and xenografts as well as human tumors with the ultimate goal of identifying and/or developing and testing therapeutics against these targets. To achieve this goal, we have a) built a robust profiling platform to identify novel targets; b) expanded our repertoire of osteosarcoma patient derived xenograft (PDX) models to reflect disease heterogeneity; and c) conducted high-throughput in vivo testing of 8-10 new agents each year both as part of Pediatric Preclinical Testing Consortium (PPTC) as well as independent of it. All of these efforts form the basis of our current research proposal and place us strongly poised to successfully achieve our goals. Our overall objective is to efficiently evaluate the efficacy of new agents with high potential to have activity in osteosarcoma based on target data from our genomic and proteomic profiling both as single agents and in rational combinations, with the vision of moving effective agents into clinical trials through the Children’s Oncology Group. We have three specific aims- 1) to select and test agents in vivo against surface targets identified by comprehensive proteomic profiling of osteosarcoma xenografts and patient tumors; 2) to select and test agents in vivo against targets identified by comprehensive genomic profiling of osteosarcoma xenografts and patient tumors; and 3) to perform testing of rationally combined agents based on target, toxicity and efficacy data of single agents. Agents from the PPTC pipeline will be selected based on either the proteomic target or genomic alteration being present in at least a subset of available osteosarcoma PDX models. The agent will be tested in selected cohorts of low/ high expressing protein target or present/ absent genomic alteration. In cases with multiple models with target expression, 3-5 mice per model will be used and in cases with few models available, 8-10 mice per model will be used for control and experiment groups with an overall n per arm per experiment of approximately 30 mice. Standard PPTC procedures will be used for tumor implantation and treatment. Tumor dimensions will be measured twice a week and response quantified as per standard PPTC definitions of complete response, maintained complete response, partial response, stable disease and progressive disease. For combination studies, three potential types of combinations will be considered based on efficacy and toxicity data- a) two surface protein targeted agents such as two antibody-drug conjugates; 2) two molecularly targeted agents and 3) a surface protein targeted agent and a molecularly targeted agent. Our results will guide the development of the next generation of clinical trials in osteosarcoma.