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

项目摘要/摘要 自从现代化疗出现以来，骨肉瘤患者的生存结果没有改变 四十年前，开发治疗这种疾病的新的有效疗法一直是一个挑战。我们的实验室很长- 长期的任务是通过全面的基因组和蛋白质组学来确定骨肉瘤的新分子靶点。 对患者来源的细胞系、异种移植和人类肿瘤进行分析，最终目的是识别 和/或针对这些靶点开发和测试治疗方法。为了实现这一目标，我们已经建立了一个强大的 用于识别新靶点的简档平台；b)扩展了我们的骨肉瘤患者来源的异种移植的曲目 (PDX)模型以反映疾病异质性；以及c)对8-10个新的 每年作为儿科临床前试验联盟(PPTC)的一部分以及独立于该联盟的药物。 所有这些努力构成了我们目前研究计划的基础，并为我们成功奠定了坚实的基础。 实现我们的目标。 我们的总体目标是有效地评估具有高活性潜力的新药物的疗效。 骨肉瘤基于我们的基因组和蛋白质组学研究中的靶点数据 合理组合，将有效药物转移到儿童的临床试验中 肿瘤学小组。我们有三个具体的目标：1)选择和测试体内针对表面靶标的药物 通过对骨肉瘤移植瘤和患者肿瘤进行全面的蛋白质组学鉴定；2)选择和 体内抗骨肉瘤移植瘤综合基因组图谱确定的靶点的测试试剂 和患者肿瘤；以及3)根据靶点、毒性和疗效对合理组合的药物进行测试 单个代理的数据。 来自PPTC管道的药物将根据蛋白质组目标或基因组改变进行选择 存在于至少一部分可用的骨肉瘤PDX模型中。该试剂将在选定的队列中进行测试 低/高表达蛋白靶标或存在/不存在基因组改变。在具有多个型号的情况下 目标表达，每个模型使用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 将用于控制组和试验组，每个试验组每个手臂的总n约为30 老鼠。标准的PPTC程序将用于肿瘤植入和治疗。肿瘤的尺寸将是 每周测量两次，并根据完全反应的标准PPTC定义对反应进行量化， 保持完全应答、部分应答、病情稳定、病情进展。对于组合 研究，将根据疗效和毒性数据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-药物结合物；2)两种分子靶向剂和 3)表面蛋白靶向剂和分子靶向剂。我们的研究结果将指导 骨肉瘤的下一代临床试验。

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.