Mechanisms of microenvironment mediated resistance to cancer cell surface targeted therapeutics

项目摘要：FDA对临床试验中肿瘤药物的批准率较低，通常为临床试验 失败的原因是在不能充分复制患者生理学的模型中对治疗进行预筛选。 肿瘤微环境(TME)是高度复杂的，由包括基质细胞在内的多种细胞类型组成， 免疫细胞和血管系统。TME中肿瘤细胞和邻近细胞之间的相互作用导致 能够支持肿瘤生长、血管形成和转移的环境变化，从而发挥 在预后和治疗效果中的重要作用(例如，通过调节耐药性)。对临床具有重要意义。 包括TME的预筛选模型，以评估这种多细胞疗法如何影响治疗效果 相声。对于患有晚期去势抵抗前列腺癌(CRPC)的男性，这些患者已经进展到 转移，这种疾病总是致命的，因为目前的治疗方法不能治愈。其中90%的患者有 发生了骨转移，但骨微环境历来难以在动物身上建立模型 模特或传统的共同文化。因此，迫切需要建立骨髓TME的体外模型。 改进新疗法的预筛选，改进临床试验设计、结果并加快速度 需要去诊所接受治疗。在这里，我们建议创建一个骨髓的组织芯片模型 测试转移性CRPC疗法的微环境。患者来源的前列腺肿瘤球体模型 多个骨髓基质细胞包围的胶原水凝胶包埋的实体瘤 来源于骨髓抽提物、免疫细胞和IPSC血管内皮细胞。细胞表面靶向 IMMU-132等疗法在治疗转移性癌症方面具有巨大的潜力。IMMU-132是一种 抗体药物结合物，与抗trp-2的抗体偶联，trp-2是一种表达在肿瘤细胞上的受体 药物SN-38。SN-38是一种拓扑异构酶抑制剂，可诱导快速增殖的细胞凋亡。我们有 获得IMMU-132在转移性CRPC的II期试验的样本和数据，这将使我们能够 验证我们的骨髓组织芯片模型。在UG3阶段，我们将优化我们的骨髓组织芯片 模拟和演示正常和疾病芯片环境复制体内的生理学。我们会 还验证了该芯片用于测量对细胞表面靶向治疗的反应。在UH3中，我们将使用 构建组织芯片的临床试验数据，这些芯片代表对IMMU-132有反应和没有反应的患者 并对这些模型进行验证。这些芯片将用于确定TME诱导治疗的机制 耐药和识别应答的特征，用于对患者进行分层，以便进行更有效的临床试验。这个 芯片还可以用来筛选多种不同的细胞表面靶向治疗，帮助直接进行治疗选择 在未来的试验中。骨髓组织芯片可以很容易地适用于任何含有骨骼的癌症类型。 转移，并可以测量一系列的细胞表面靶向治疗。这些芯片有可能成为 提高转移性癌症治疗临床试验成功率的有力工具。

Project Summary: Rates of FDA approval for oncology drugs in clinical trials are low and often clinical trial failures are driven by pre-screening of therapies in models that cannot adequately replicate patient physiology. The tumor microenvironment (TME) is highly complex consisting of multiple cell types including stromal cells, immune cells and vasculature. The interplay between tumor cells and neighboring cells in the TME results in environmental changes that can support tumor growth, vascularization and metastasis and, thus, plays an important role in prognosis and treatment efficacy (e.g. by modulating resistance). It is important for clinical prescreening models to include the TME to assess how treatment efficacy can be impacted by this multicellular crosstalk. For men with advanced castrate resistant prostate cancer (CRPC) that have progressed to metastasis, the disease is invariably lethal as current therapies are not curative. 90% of these patients have developed bone metastases but the bone microenvironment has been historically difficult to model in animal models or traditional co-culture. Therefore, in vitro models of the bone marrow TME are urgently needed to improve pre-screening of novel therapeutics, improve clinical trial design, outcomes and expedite much needed treatments to the clinic. Here we propose to create a tissue chip model of the bone marrow microenvironment for testing metastatic CRPC therapeutics. Patient-derived prostate tumor spheroids model the solid tumor embedded in a collagen hydrogel surrounded by multiple resident bone marrow stromal cells derived from bone marrow aspirates, immune cells and iPSC endothelial cell vasculature. Cell-surface targeted therapies, such as IMMU-132 have great potential for treatment of metastatic cancers. IMMU-132 is an antibody drug conjugate, with an antibody against Trop 2, a receptor expressed on tumor cells, coupled to the drug SN-38. SN-38 is a topoisomerase inhibitor that induced apoptosis in rapidly proliferating cells. We have access to samples and data from a Phase II trial of IMMU-132 in metastatic CRPC which will allow us to validate our bone marrow tissue chip model. In the UG3 phase, we will optimize our bone marrow tissue chip model and demonstrate that normal and disease chip environments replicate the in vivo physiology. We will also validate the chip for measuring responses to cell surface targeted therapies. In the UH3, we will use clinical trial data to build tissue chips that represent patients who respond and do not respond to IMMU-132 and validate these models. These chips will be used to determine mechanisms of TME-induced treatment resistance and identify signatures of response for use in stratifying patients for more efficient clinical trials. The chips can also be used to screen multiple different cell-surface targeted therapies helping direct therapy choice in future trials. The bone marrow tissue chips can be easily adapted for any cancer type that has bone metastases and can measure a range of cell surface targeted therapies. These chips have the potential to be a powerful tool for improving clinical trial success rates in therapies for metastatic cancer.