Targeting cancer stem cell self-renewal and proliferation mechanisms using in vitro microscale models

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Project SummaryAlmost half a million new cases of colorectal cancer (CRC) worldwide are diagnosed each year. Unfortunately, the great majority of patients are not cured by current chemotherapy. Recent clinical data has led to the hierarchical tumor model, which proposes that a minority of tumor cells (cancer initiating cells) are responsible for the majority of the metastatic potential. Colorectal cancer initiating cells (CCIC) are highly resistant to current CRC chemotherapy, but they share many features with normal colon stem cells. Identifying drugs with anti-CCIC activity that are not toxic to normal colon stem cells is an important, high-impact goal that can improve CRC chemotherapy and patient survival.There are primarily two kinds of assays for screening drugs that specifically target CCIC, but both have their limitations. In vitro assays are fast but most "hits" fail when tested in human, mainly due to dose-limiting toxicities against normal intestine and other organs. In vivo animal assays are expensive and time consuming for screening a large number of compounds. They are better for uncovering side effects, but still do not place human cells in the appropriate microenvironment to study intercellular interactions important for chemoresistance.Intellectual MeritIn this proposal, the team will combine cancer biology and physical science to develop a novel drug-screening platform to identify drugs that specifically target CCIC. In Aim 1, the team will characterize drug effectiveness and toxicity using an in vitro gastrointestinal tract (GI) microscale cell culture analog (ìCCÁ), coupled with a multi-chamber silicon PK-PD model representing the systemic circulation. This device provides a much more physiological environment for drug testing than current in vitro technologies. In Aim 2, the team will examine the drug effects on intestinal homeostasis using a microscale 3D hydrogel GI structure that mimics the geometry of human intestinal crypts. In Aim 3, the promising drug candidates will be tested in a state-of-the-art in vivo CCIC mouse model. We will use these three assays sequentially to identify safe CCIC drugs from a library of compound. Broader ImpactThe proposed study attempts to develop several fundamental technologies that can potentially revolutionize the process of CRC drug discovery. If proven successful, the team will disseminate this method to the colon cancer research community and make an impact on millions of lives.The educational part of this career proposal is devoted to providing future researchers with exposure to Biomedical Engineering. The undergraduate Cornell iGEM team will combine genetic engineering with microfluidic devices for their annual project competition. An annual workshops will be organized for the Institute for Biology Teachers to introduce Biomedical Devices to the middle school and high school teachers. The team will also develop a week-long research workshop for the CURIE Academy, a summer immersion program for engaging high school girls interested in engineering.