Researchers ID markers of resistance to two PCa therapies

October 4, 2016

Findings from a recent study indicate that CTCs detected in blood have the potential to reveal important genetic information that could guide treatment selection.

In an attempt to develop methods to genetically characterize circulating tumor cells (CTCs) in men with metastatic castration-resistant prostate cancer and enable precision medicine approaches to discover novel potential targets for therapy, researchers from Duke Cancer Institute have identified some blood markers associated with tumor resistance to two common hormone therapies.  

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“In this study, we demonstrated a method to isolate and characterize CTCs using copy number analysis of the whole genome and identified reproducible and recurrent copy gains and losses in CTCs from men with mCRPC who had developed resistance to enzalutamide [XTANDI] or abiraterone [ZYTIGA],” senior author Andrew Armstrong, MD, of Duke Cancer Institute, Durham, NC, told Urology Times. “These alterations were highly heterogeneous between patients, and we found evidence for clonal selection of CTCs over time during enzalutamide therapy.”

Additionally, recurrent alterations were found in androgen receptor and androgen signaling pathways, epigenetic and DNA repair pathways, cell cycle pathways, BRD4, ERG, and PTEN, each of which are linked to disease progression and may be targetable with novel or existing therapies.

For the study, Dr. Armstrong and colleagues from Duke Cancer Institute and the Duke Molecular Physiology Institute utilized a process called array-based comparative genomic hybridization to analyze the genome of the CTCs of 16 men with advanced, treatment-resistant prostate cancer. Dr. Armstrong noted that the technique enabled them to determine which genes had extra copies and which regions were deleted.

“After CTC isolation using white blood cell depletion and red cell lysis, CTC DNA and germline (leukocyte) DNA is isolated and amplified. Copy number analysis of gains or losses across the genome was [conducted] for CTCs versus leukocytes using pooled CTCs. Gains and losses were called based on pre-specified levels and consistent signals using multiple probes across the genomic loci. We ensured that this method was reproducible using the aCGH chip and CTC isolation method down to only a few CTCs per tube of whole blood,” Dr. Armstrong said.

Next: CTCs detected in blood have the potential to reveal important genetic information that could guide treatment selection in the future

 

The results, published online in Clinical Cancer Research (Sept. 6, 2016), revealed that CTCs detected in blood have the potential to reveal important genetic information that could guide treatment selection in the future.

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“For example, ERG overexpression has been linked to docetaxel [Taxotere] resistance,” Dr. Armstrong said. “We identified common gains in this oncogene which could be linked to taxane resistance. BRD4 is a bromodomain protein linked to oncogenic signaling and targetable with bromodomain inhibitors currently in clinical trials in prostate cancer. The number of alterations may be helpful for immune therapy response given recent links between genomic complexity and PD-1 inhibitor response. AR gain is targetable with novel AR pathway inhibitors.”

With the results in, further prospective validation studies are ongoing, looking at AR splice variants, DNA copy alterations and mutations in CTCs, and cell-free tumor DNA alterations.

“This sets the stage for larger prospective predictive medicine trials, some of which are ongoing, such as our Prostate Cancer Foundation Movember Challenge study investigating ARV7 in CTCs along with this broader genomic characterization,” Dr. Armstrong said. “This is being examined first for standard-of-care therapies like enzalutamide and abiraterone but should be examined for novel agents. This liquid biopsy approach has the potential to identify a range of potential predictive biomarkers linked to specific therapies.”

Dr. Armstrong receives unrelated research support for clinical trials (funded through Duke University) from Medivation/Astellas, Janssen, Sanofi, Bayer, Dendreon, and Gilead Sciences.

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