posted on 2019-07-02, 00:00authored byBrenda
J. Green, Vivian Nguyen, Eshetu Atenafu, Phillip Weeber, Bill T. V. Duong, Punithan Thiagalingam, Mahmoud Labib, Reza M. Mohamadi, Aaron R. Hansen, Anthony M. Joshua, Shana O. Kelley
The
analysis of circulating tumor cells (CTCs) provides a means
to collect information about the evolving properties of a tumor during
cancer progression and treatment. For patients with metastatic prostate
cancer, noninvasive serial measurements of bloodborne cells may provide
a means to tailor therapeutic decisions based on an individual patient’s
response. Here, we used a high-sensitivity profiling approach to monitor
CTCs in patients with metastatic castrate-resistant prostate cancer
(mCRPC) undergoing treatment with abiraterone and enzalutamide, two
drugs used to treat advanced prostate cancer. The capture and profiling
approach uses antibody-functionalized magnetic nanoparticles to sort
cells according to protein expression levels. CTCs are tagged with
magnetic nanoparticles conjugated to an antibody specific for the
epithelial cell adhesion molecule (EpCAM) and sorted into four zones
of a microfluidic device based on EpCAM expression levels. Our approach
was compared to the FDA-cleared CellSearch method, and we demonstrate
significantly higher capture efficiency of low-EpCAM cells compared
to the commercial method. The nanoparticle-based approach detected
CTCs from 86% of patients at baseline, compared to CellSearch which
only detected CTCs from 60% of patients. Patients were stratified
as prostate specific antigen (PSA) progressive versus responsive based
on clinically acceptable definitions, and it was observed that patients
with a limited response to therapy had elevated levels of androgen
receptor variant 7 (ARV7) and the mesenchymal marker, N-cadherin,
expressed on their CTCs. In addition, these CTCs exhibited lower EpCAM
expression. The results highlight features of CTCs associated with
disease progression on abiraterone or enzalutamide, including mesenchymal
phenotypes and increased expression levels of ARV7. The use of a high-sensitivity
method to capture and profile CTCs provides more informative data
concerning the phenotypic properties of these cells as patients undergo
treatment relative to an FDA-cleared method.