In search of synergistic drug interactions in cancer

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PROJECT SUMMARY Colorectal cancer (CRC) is the third most prevalent cancer worldwide, killing over 850,000 people every year, 50,000 of these in the US. Only a handful of small molecule drugs are approved for patient treatment. Small molecule drugs are often easy to formulate and more convenient for patients than antibody-based drugs, and combination therapies have proved quite effective – FOLFOX (folinic acid, 5FU and oxaliplatin) being the prime example in CRC. A recent study evaluated 2,025 clinically-relevant two-drug combinations on 125 tumor cell lines representing breast, colon and pancreas and noted that “synergy overall was rare…” We wondered whether this lack of drug-drug interaction might be a product of the simple and non-physiologic setting in which these tumor cells were grown – monolayer cultures on tissue culture plastic – and whether a more physiologic setting of 3-dimensional culture in the presence of a complex stroma might yield a different result. Our guiding hypothesis for this study, therefore, is that a more complex and physiological model of human tumors will reveal potentially clinically-relevant drug synergies. In this study we propose to use our well-characterized human cell-based Vascularized Micro-Tumor (VMT) model to test multiple drug combinations for potential synergies on colon cancer cells (both lines and patient-derived), exploring the idea that drugs may target pathways and combinations of pathways that are not necessarily active in 2D cultures, or may target tumor-stroma interactions that are just not present in monocultures. Indeed, we have already identified a drug that blocks tumor growth only in the VMT, and not in monolayer culture or in spheroids. The VMT platform comprises perfused living capillary beds in vitro that supply nutrients to the surrounding tissue in much the same way they do in vivo. Microtumors, comprised of tumor cells and stromal cells, embedded in extracellular matrix (ECM) are grown in the tissue chambers and these are surrounded and penetrated by the micro-vessels, which support their growth. This is a flexible and powerful platform, and one that is ideal for studying tumor biology, where remodeling of the vascular and stromal components is key to tumor progression. Our hypothesis is that: the VMT platform can reveal positive drug interactions not seen in simple 2D, monocultures. To test this hypothesis we will challenge five tumor lines, representing the 5 CRIS categories of colon cancer, against 25 drugs, representing most of the major signaling pathways, in all pairwise combinations. We will then repeat this study with 5 patient-derived tumor lines. Our Aims are: 1. Establish dose-response curves for each drug in the VMT. 2. Test all 2-way combinations of drugs in the VMT. 3. Compare drug responses in tumor lines versus patient-derived tumors in the VMT.