Genomic profiling of single circulating tumor cells in the precision medicine of metastatic prostate cancer

点击翻译按钮获取中文摘要

PROJECT SUMMARY AND ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is the most lethal state of prostate cancer (PCa) and remains as the most challenging issue in PCa treatment. The development of more effective treatments for mCRPC is a significant unmet clinical need. There are substantial heterogeneities in treatment responses of mCRPC, necessitating the use of more personalized strategies in guiding treatment based on the specific genomic characteristics of individual patients. There are considerable limitations in using the traditional tissue- based genomic profiling to guide mCRPC treatment, partly because mCRPC is a bone-predominant metastatic disease, thus tissue samples are difficult to obtain and yields are generally low. Moreover, during treatments, the genomic profiles of tumors may change quickly to evade therapeutic or immune attacks, leading to drug resistance. In order to promptly and accurately capture these changes and adjust treatment plans, repeated tumor biopsies would be needed, which is difficult to perform in routine clinical practices given the invasive and bone-predominant nature of mCRPC. Therefore, in order to improve mCRPC prognosis, it is highly important to develop novel, non-invasive liquid biopsy approaches to real-time monitor treatment response and guide the use of different treatments. Circulating tumor cells (CTCs) are shed from tumors into blood and have extremely high malignant potential, and are arguably the most important subset of tumor cells to monitor and treat. CTCs can be non-invasively and repeatedly enumerated in real-time, and have exhibited promising prognostic potentials, as evidenced by the FDA-approval of the CellSearch platform for CTC enumerations as an independent prognostic factor of several metastatic cancers including mCRPC. However, national guidelines have not unanimously endorsed the use of CTC enumeration in routine clinical practices, mostly because it remains unclear what actions should be taken for high-risk patients with elevated CTCs. These facts highlight the importance of moving beyond CTC enumeration and towards in-depth genomic characterizations of CTCs. Large studies on single-cell CTC analysis have been rarely reported, partly due to the significant challenges on single-CTC detection, isolation, whole genome amplification (WGA), and sequencing bias identification and correction. We have established a comprehensive pipeline on the enrichment, enumeration, isolation, WGA, sequencing, and data analysis of single CTCs. Based on three PCa patient cohorts at the Sidney Kimmel Cancer Center, MD Anderson Cancer Center, and George Washington University Cancer Center, we will conduct genomic profiling of single CTCs to identify markers of treatment response and prognosis. To our best knowledge, this is the first large population-based study of single-CTC analysis in mCRPC. Findings from this study will significantly improve the potential of the clinical application of CTCs in mCRPC management, by precisely tailoring treatment to the genomic make-up of individual CTCs from individual patients.