PROJECT SUMMARY Peritoneal carcinomatosis (PC) is the deadliest form of colorectal cancer (CRC) and gastric cancer (GC) metastasis, with a median survival of 10-18 months for CRC and less than this for GC. PC is a common form of metastasis in both CRC and GC, each with an incidence of between 10 and 50%. Unfortunately, there are few treatments available, and there exist large regional and ethnic disparities in each of these diseases, emphasizing the need for increased research on developing improved therapies. This development is slowed by the absence of appropriate in vitro models and the gaps in our knowledge of how metastasis occurs. Our application is focused on improving this situation. Here we propose to characterize and utilize a recently-developed in vitro PC model (the Vascularized Micro-Peritoneum, VMP) for use as a therapeutic development tool. The model is based on our vascularized micro-tumor (VMT) platform, a microphysiological system (MPS) that allows direct observation of living cells that are proliferating, metabolizing, migrating, and dying in a complex 3D environment. This application is in response to the Funding Opportunity Announcement PAR-22-099 titled “Cancer Tissue Engineering Collaborative: Enabling Biomimetic Tissue-Engineered Technologies for Cancer Research”, the stated goal of which is to “support the development and characterization of state-of-the-art biomimetic tissue- engineered technologies for cancer research.” In general, systemically-delivered drugs have not been especially effective against PC as much of the early growth occurs on the surface of the peritoneum, somewhat distant from the underlying blood vessels and so hard to target with high doses of drug. Most patients now receive neoadjuvant systemic therapy followed by cytoreductive surgery and hyperthermic intra-peritoneal chemoperfusion (HIPEC), which has resulted in a general increase in patient survival. Despite this improvement, most patients still develop recurrent disease in less than a year and the majority die due to disease by 5 years. Hence there is a huge unmet need for new and improved therapies for patients with PC, and repurposing drugs approved for other cancers might be a promising approach. Our hypothesis is that: A microphysiological system platform can be used to help identify improved therapies for peritoneal carcinomatosis. To test this hypothesis we will pursue the following aims: 1. Characterize a dual-tissue platform that models peritoneal carcinomatosis 2. Correlate platform performance to in vivo data in a prospective Clinical Study 3. Test drug sensitivities of PC tumors in the VMT/VMP

PROJECT NARRATIVE This proposal will seek to develop a novel microfluidic “tumor-on-a-chip” platform for studying peritoneal carcinomatosis – a diffuse spreading pattern of metastasis of the peritoneal cavity and the most lethal form of metastasis of colon and gastric cancer. Colon and gastric cancer are the third and fifth most prevalent cancers worldwide, respectively, and most people who die from the disease do so because of metastases, such as those to the peritoneal cavity. This platform will provide a new tool to help researchers understand this process, and ultimately identify drugs that will effectively treat and prevent this process from happening.