Molecular Characterization of Circulating Tumor Cells to Elucidate Drug Resistance Mechanisms
Prostate cancer represents the most common malignancy in males. Two androgen receptor (AR)-targeted therapies, enzalutamide and abiraterone acetate, have been approved for treatment of metastatic castration resistant prostate cancer (CRPC). Many patients respond to these agents; however, they ultimately progress and acquire resistance to these therapies. To characterize resistant phenotypes that emerge following treatment with abiraterone or enzalutamide, we isolated and characterized circulating tumor cells (CTCs) from CRPC patients at varying timepoints on therapy. RNA sequencing was performed on pools of up to 10 CTCs, which enabled us to track changes of molecular characteristics of CRPC upon progression. By comparing drug-sensitive and drug-resistant patient samples, we identified dysregulated signaling pathways that could confer resistance to AR-targeted therapies. Experiments in cell culture models demonstrate that these pathways do indeed mediate resistance to enzalutamide. Importantly, we demonstrated that CTC sequencing offers a non-invasive method of identifying genomic and transcription alterations in drug resistant tumors that could facilitate the development of effective patient centric therapeutics.
With an introduction to RNA-seq and Q&A moderated by Natalie LaFranzo, PhD, Director of Scientific Projects and Market Development at Cofactor Genomics.
Vipul Bhargava, PhD
Vipul Bhargava is a computational biologist in Janssen Research and Development LLC. He leads computational analysis efforts geared towards understanding high-dimensional datasets generated from experimental medicine and clinical trials, while implementing various systems biology tools to identify novel targets, biomarkers and mechanisms of resistance through the translation of bioinformatics data. Vipul has expertise in implementing RNA sequencing methods, particularly low-input methods, to uncover the earliest, causative mechanisms of disease thereby facilitating early intervention in diseases.
Prior to joining Johnson & Johnson, Vipul obtained his PhD in Bioinformatics and Systems Biology from UC San Diego. In his graduate work, he developed a novel RNA sequencing methodology for generating gene expression profiles from as few as tens of cells. His method has applications in cases where obtaining a large number of cells is difficult such as with clinical biopsy samples, developmental biology and/or forensics.
Cofactor is a biotechnology and software company using RNA as the foundation for providing a better understanding of disease. We’re leading the charge on moving RNA out of discovery and into diagnostics. Working with the largest life-science and pharmaceutical companies in the world, we’ve developed streamlined and scalable protocols to interrogate RNA using pre-clinical RNA sequencing and analysis, clinical RNA assays, clinical database development, and custom assay design.
Cofactor’s team is built on solid scientific acumen, operating in an agile, dynamic environment to provide exceptional support for our partners. By standardizing RNA products, and developing validated, clinical assays, we’re enabling the evolution of precision medicine. Find out more about Cofactor Genomics at cofactorgenomics.com.
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