All-Human Microphysical Model of Metastasis Therapy

描述（由申请人提供）：转移治疗的全人类微物理模型成功根除转移性疾病仍然是降低实体瘤死亡率的巨大挑战。虽然消融方法很少可行，但全身化疗通常是抑制进展和增加生存时间的唯一可行选择，尽管它很少能治愈。我们对化疗药物为什么不能消除转移的理解，以及我们创造更有效治疗策略的能力，都受到我们在分子和细胞水平上解剖肿瘤-宿主相互作用的缺陷，以及缺乏筛选新疗法的相关模型系统的限制；并且缺乏所有人类系统以相关的方式做到这一点。有证据表明，肿瘤细胞受到转移性微环境的影响，对化疗变得更耐药，并且面对转移性疾病，化疗代谢发生改变。我们提出了一个系统，不仅将提供一个所有的人类上下文转移微环境，但一个密切相关的药物代谢和正常生理功能的肝脏，可能会阻碍或增强疗效或治疗的毒性。与其他常见的转移部位相比，肝脏在一天中会经历剧烈的代谢和激素状态波动。这些波动在多大程度上影响转移性肿瘤的恶性行为和化疗反应尚不清楚。在这个项目中，我们使用多孔板格式的3D微灌注器官型肝脏，以一种适合纳入药物开发管道的格式在体外捕捉这种情况的复杂性。我们的方法旨在促进功能宿主肝组织中相对较大的、临床相关的转移性结节（>0.5 mm）的发展。我们将(i)确定与标准培养物相比，宿主肝组织内传递给肿瘤细胞的激素、细胞因子和营养物质的周期/昼夜变化是否会改变肿瘤细胞的表型行为，如增殖、侵袭性和特定肿瘤标志物的表达；（ii）确定化疗药物对转移性肿瘤的疗效是否受到代谢和激素的昼夜控制的影响，使用肝脏转移性微环境中的一组人类肿瘤细胞，以及一般化疗药物（代谢和非代谢药物）和靶向生物疗法（激酶抑制剂类），如果是这样，（iii）评估肝脏的化疗毒性是否会因转移性累及或肝脏的周期性/日变化而改变（iv）验证肝脏轻度炎症状态刺激肿瘤生长并改变化疗疗效的假设。

DESCRIPTION (provided by applicant): All-Human Microphysical Model of Metastasis Therapy Successful eradication of metastatic disease remains the grand challenge in reducing mortality from solid tumors. Although ablative approaches are infrequently possible, systemic chemotherapy usually is the only feasible option for inhibiting progression and increasing survival time, though it is rarely curative. Our understanding of why chemotherapeutic agents fail to eliminate metastases, and our ability to create more effective therapeutic strategies, is limited by both our deficit in dissecting the tumor-host interactions at a molecular and cellular level, and a lack of relevant model systems to screen novel therapies; and a dearth of all human systems to do this in a relevant manner. There is evidence that the tumor cells are affected by the metastatic micro-environment to become more resistant to chemotherapy and that chemotherapeutic metabolism is altered in the face of metastatic disease. We propose a system that will not only provide an all human contextual metastatic micro-environment, but one that is intimately linked to drug metabolism and to normal physiological functions of liver that may hinder or augment the efficacy or toxicities of therapies. More than any other common site of metastasis, the liver experiences dramatic swings in metabolic and hormonal state throughout the day. The extent to which these fluctuations influence malignant behaviors and chemotherapy responses in metastatic tumors is unknown. In this project we capture the complexity of this situation in vitro in a format amenable to incorporation in the drug development pipeline, using a 3D micro- perfused organotypic liver in a multiwell plate format. Our approach is designed to foster development of relatively large, clinically relevant metastatic nodules (>0.5 mm) in functional host liver tissue. We will (i) determine whether cyclic/diurnal changes in hormones, cytokines and nutrients delivered to tumor cells within host liver tissue alters the phenotypic behavior of the tumor cells compared to standard culture, such as proliferation, invasive properties, and expression of specific tumor markers; (ii) Determine whether the efficacy of chemotherapy agents against metastatic tumors is influenced by diurnal control of metabolism and hormones, using a panel of human tumor cells within the liver metastatic microenvironment and both general chemotherapeutics (metabolized and non-metabolized agents) and a targeted bio-therapeutics (in the kinase inhibitor class) and if so, if these are related to properties of the tumor that can be measured in situ (iii) Assess whether the chemotherapeutic toxicities on the liver are altered by metastatic involvement or by cyclical/diurnal variations in the liver affluent (iv) Test the hypothesis that mild inflammatory states of liver stimulate tumor growth and alter efficacy of chemotherapeutics.