R01CA255792

Genomic Profiling of Single Circulating Tumor Cells in the Precision Medicine of Metastatic Prostate Cancer - 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.

Thomas Jefferson University

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Philadelphia, Pennsylvania 191075001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 358% from $693,113 to $3,177,343.