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Transferrin Receptor Identifies a Comprehensive Pool of Circulating Tumor Cells with Unique Molecular Features from Metastatic Prostate Cancer Patients

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[Technical Report, Annual Report]

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Metastatic castration resistant prostate cancer CRPC is currently incurable, due to treatment resistance. Elucidation of resistance mechanisms requires frequent tumor sampling to monitor tumor evolution and tailor treatments to the individual. Circulating tumor cells CTCs represent a non-invasive, accessible liquid biopsy source of tumor cells, allowing for longitudinal molecular disease profiling. Due to limitations with existing EpCAM based CTC isolation assays we have identified and clinically tested Transferrin Receptor TfR as a novel cell-surface antigen that enables capture of all CTCs across the EMT gradient from metastatic patients. Mining large datasets TCGA, SU2C revealed TfR enrichment in metastatic patients, which significantly correlated with advanced state from localized PC to CRPC to the aggressive neuroendocrine NEPC. RNA-seq analysis indicates that TfR-CTCs possess unique expression profile and are enriched in EMT and tumor progression pathways, as compared to EpCAM- CTCs. Expression of androgen receptor AR splice variants AR-Vs is known to drive disease progression. We have developed a highly sensitive - down to single cell - digital droplet PCR assay for the quantitation of AR-Vs in patient CTCs. Isolation of TFR vs EpCAM CTCs from metastatic patients, revealed significant AR-V enrichment in TFR CTCs, while AR-FL expression was similar. When we analyzed single CTCs using the same ddPCR assay, we observed even more striking enrichment, with AR-Vs detected in 21 percent of single TFR-CTCs vs 0 percent in EpCAM-CTCs. These data support our hypothesis that TfR can identify a comprehensive pool of CTCs not limited to the epithelial-only phenotypes and provide an accurate representation of metastatic disease burden. To test this, we propose to prospectively collect peripheral blood from CRPC and NEPC patients to 1.

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  • Medicine and Medical Research

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[A, Approved For Public Release]