Mechanisms of microenvironment mediated resistance to cancer cell surface targeted therapeutics

项目摘要：FDA批准肿瘤药物进行临床试验的比率很低， 失败是由于在不能充分复制患者生理学的模型中预先筛选治疗所致。 肿瘤微环境（TME）是高度复杂的，由多种细胞类型组成，包括基质细胞， 免疫细胞和脉管系统。TME中肿瘤细胞和相邻细胞之间的相互作用导致 环境变化可以支持肿瘤生长、血管形成和转移，因此， 在预后和治疗功效中的重要作用（例如通过调节抗性）。这对临床非常重要。 预筛选模型，以包括TME，以评估这种多细胞肿瘤如何影响治疗效果。 串话对于进展至晚期去势抵抗性前列腺癌（CRPC）的男性， 当肿瘤转移时，该疾病总是致命的，因为目前的疗法是不治愈的。90%的患者 发展成骨转移，但骨微环境历来难以在动物中建模 模式或传统文化。因此，迫切需要骨髓TME的体外模型， 改进新疗法预筛选，改进临床试验设计、结果， 需要去诊所治疗在这里，我们建议建立一个骨髓的组织芯片模型， 用于测试转移性CRPC治疗剂的微环境。患者来源的前列腺肿瘤球体模型 包埋在胶原水凝胶中的实体瘤被多个驻留的骨髓基质细胞包围 来源于骨髓抽吸物、免疫细胞和iPSC内皮细胞脉管系统。细胞表面靶向 治疗，如IMMU-132具有治疗转移性癌症的巨大潜力。IMMU-132是一种 抗体药物偶联物，其具有抗Trop 2的抗体，Trop 2是在肿瘤细胞上表达的受体，其偶联至抗体药物偶联物。 SN-38药物SN-38是一种拓扑异构酶抑制剂，在快速增殖的细胞中诱导凋亡。我们有 访问IMMU-132在转移性CRPC中的II期试验的样品和数据，这将使我们能够 验证我们的骨髓组织芯片模型在UG 3阶段，我们将优化骨髓组织芯片， 模拟并证明正常和疾病芯片环境复制体内生理学。我们将 还验证芯片用于测量对细胞表面靶向治疗的反应。在UH 3中，我们将使用 临床试验数据，以建立代表对IMMU-132有反应和无反应的患者的组织芯片 并验证这些模型。这些芯片将用于确定TME诱导治疗的机制 耐药性和识别应答特征，用于对患者进行分层，以进行更有效的临床试验。的 芯片还可以用于筛选多种不同的细胞表面靶向疗法， 在未来的试验中。骨髓组织芯片可以很容易地适用于任何类型的癌症， 转移，并且可以测量一系列细胞表面靶向疗法。这些芯片有潜力成为 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.