Technologies for Detecting Tumor-Derived Cell Clusters

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Technologies that can assess metastatic risk early and facilitate prompt interventions can significantly improve cancer outcomes because most cancer deaths are due to metastasis. Currently, very few markers are available for predicting metastatic risk. Disseminated tumor cells that enter circulation are pivotal in the metastatic cascade, and circulating tumor cells (CTCs) are being used as putative markers for monitoring tumor dynamics and treatment response. However, accumulating evidence suggests that tumor-derived cell clusters (TDCCs) may be a more important factor in metastasis and associated poor progression-free survival and overall survival. Clustering is an adaptive mechanism that enhances CTC survival and migration in the harsh conditions of the bloodstream, confers stemness, immune evasiveness, and increases their metastatic potential. TDCCs are reported to consist of either homotypic clusters composed of only cancer cells; or heterotypic clusters made of stromal cells or immune cells including fibroblasts (CAFs), macrophage-like cells (CAMLs), endothelial cells (TECs), tumor-macrophage hybrid cells (TMHCs), and neutrophils, along with tumor cells. Compared to single CTCs, TDCCs have been shown to have distinct molecular features, exhibit a higher proliferation rate, and 20 to 230-fold more metastatic potential than individual CTCs. Overall, these data suggest that composition and heterogeneity of TDCCs may be more informative for assessing metastatic risk or for predicting and following treatment response than assays based on single CTCs. The biology of formation, dissemination, and metastatic mechanisms associated with TDCCs are poorly understood because currently, very few technologies exist to study TDCCs. Studies that detect TDCCs or elucidate their biology merely adapt existing CTC-based technologies that are grossly inadequate for heterotypic clusters. There is an unmet need for technologies that combine cluster enrichment, enumeration, and downstream molecular analysis to better understand biology and the role of different cells in metastasis