Presentation Abstract

Abstract Number: 3492
Presentation Title: Using CTCs to interrogate mechanisms of taxane resistance in the prospective TAXYNERGY clinical trial in prostate cancer
Presentation Time: Tuesday, Apr 09, 2013, 1:00 PM - 5:00 PM
Location: Hall A-E, Poster Section 2
Poster Board Number: 10
Author Block: Matthew S. Sung1, Ada Gjyrezi1, Guang Yu Lee1, Alexandre Matov1, Giuseppe Galletti1, Matthew Loftus2, Yusef Syed3, Timothy Lannin3, Atanas Hristov4, Christopher Mason1, Scott Tagawa1, Brian Kirby3, David Nanus1, Paraskevi Giannakakou1. 1Weill Cornell Medical College, New York City, NY; 2University of Virginia, Charlottesville, VA; 3Cornell University, Ithaca, NY; 4University for Information Science and Technology 'St Paul the Apostle', Ohrid, Macedonia, The Former Yugoslav Republic of
Abstract Body: Prostate cancer progression into castration-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR) signaling despite surgical and chemical androgen ablation. The taxanes represent the only class of chemotherapy that improves overall survival in CRPC patients. Despite their success, CRPC patients do progress on taxane treatment rendering taxane-resistant tumors. The molecular mechanisms underlying clinical taxane resistance in CRPC have not been well elucidated due to the lack of available tumor tissue to study. Circulating tumor cells (CTCs) represent a liquid biopsy of the original tumor and isolation of them can lead to their molecular characterization potentially revealing predictive biomarkers for taxane sensitivity or resistance. Here, we use a geometrically enhanced differential immunocapture (GEDI) microfluidic device that couples an anti-prostate specific membrane antigen (PSMA) antibody with optimized 3D geometry to capture and isolate live CTCs from whole blood of CRPC patients. The GEDI-microfluidic device was shown to have a 2-400 fold higher sensitivity for CTC capture than the FDA-approved CellSearch® system. We have previously shown that CRPC patient CTCs can be used to derive functional information that correlates to clinical response to taxane chemotherapy, namely AR subcellular localization status. We have developed a suite of other functional assays that can be performed on live GEDI-captured CTCs that enable their molecular characterization and allow us to test specific mechanistic hypotheses based on our extensive preclinical data. Included, and herein described, are the determination of AR subcellular localization, extent of effective drug-target engagement assessed by microtubule bundling, identification of RNA species relevant to the mechanism of taxane resistance and computer vision algorithms that will allow for enriched and automated analysis of high-volume image sets of GEDI-captured CTCs. In addition, we will be testing the hypothesis that distinct AR splice variants may affect patient sensitivity to taxane-based chemotherapy. This suite of assays are being rigorously applied in a phase II clinical trial in which chemotherapy-naïve CRPC patients will be initially treated with either docetaxel or cabazitaxel and clinically evaluated for an early switch to the other taxane following disease progression. This prospective, randomized, multi-site clinical trial will enroll 100 CRPC patients within one year. Patients will be followed until relapse and each patient will have 15 independent GEDI assays performed across five time points from baseline to chemotherapy crossover to relapse. The depth of coverage this suite of assays provides will offer unique insights for potential mechanisms of clinical taxane resistance and predictive biomarkers for taxane sensitivity in CRPC patient CTCs.