Mechanisms of microenvironment mediated resistance to cancer cell surface targeted therapeutics

点击翻译按钮获取中文摘要

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.