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.
Carcinoma morbidity and mortality result overwhelmingly from the dissemination of the tumor beyond the initial site of development, to not only avoid directed surgical and radiological removal but also appear as more resistant to systemic therapies than the primary tumor. Development of new approaches that are obviously needed for these disseminated carcinoma cells is stymied by our dearth of knowledge concerning the tumor biology and how chemotherapy is metabolized in the metastatic niche, particularly in response to cyclic and diurnal rhythms of hormones, nutrients and inflammatory signals. Current in vitro models fail to capture the complexity of the microenvironment, and whole animal models do not allow for real time and continuous monitoring of the events and cell behaviors during the critical first month of establishment. Bioreactors offer a unique window into this period;we propose to develop a next generation all human liver bioreactor that provides physiologic mimicry of the human situation to aid in drug development and therapeutic approaches to metastasized cancers.
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