Technologies for analysis of circulating tumor cells (CTCs) continue to evolve rapidly, and the latest high content scanning platforms have underscored the phenotypic heterogeneity of CTC populations. Among liquid biopsies, CTC enumeration remains the most extensively validated prognostic marker to date, but other clinically relevant phenotypes like androgen receptor (AR) localization or presence of AR-V7 splice variant are important new predictors of therapy response. Serial genomic profiling of CTCs or circulating tumor DNA (ctDNA) is helping to define primary and acquired resistance mechanisms and helping to guide patient selection for targeted therapies such as poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibition. The era of liquid biopsy-based biomarkers has arrived, driven by powerful new enrichment and analysis techniques. As new blood-based markers are identified, their biological significance as disease drivers must be elucidated to advance new therapeutic strategies, and their clinical impact must be translated through assay standardization, followed by analytical and clinical validation. These efforts, already ongoing on multiple fronts, constitute the critical steps toward more effective precision management of advanced prostate cancer.
PWD and PCP are employees of Cynvenio Biosystems Inc. FB is employed by Menarini Silicon Biosystems. SK, MT, PDC, MWM, and SG are employees of ResearchDx. JU and KD are employees of Liquid Genomics. SR is an employee of NantHealth. PD is affiliated with Liquid Genomics. These companies all developed platforms used in this work.
Highly tumorigenic, drug‐resistant cancer stem‐like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem‐like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem‐like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem‐like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug‐resistant phenotype.
Human beta-defensin 2 (HBD2) has been shown to interact with pathogenic bacteria and components of the mammalian innate and adaptive immune response. We describe a quick and reliable method for the production of HBD2 in Escherichia coli. HBD2 was expressed as an insoluble fusion, chemically cleaved and oxidised to give a single, folded HBD2 beta-isoform. The purified peptide was analysed by high resolution mass spectrometry, displayed a well-dispersed (1)H NMR spectrum, was a chemoattractant to HEK293 cells expressing CCR6 and acted as an antimicrobial agent against E. coli, P. aeruginosa, C. albicans and S. aureus.
PURPOSE:In metastatic castrate sensitive prostate cancer (mCSPC), combined androgen axis inhibition is a standard of care. Noninvasive biomarkers that guide initial therapy decisions are needed. We hypothesized that CellSearch CTC count, an FDA-cleared assay in metastatic castrate resistant PC (mCRPC), is a relevant biomarker in mCSPC.METHODS: SWOG S1216 is a phase 3 prospective randomized trial of androgen deprivation therapy (ADT) combined with orteronel or bicalutamide for mCSPC. CellSearch CTC count was measured at registration (baseline). Prespecified CTC cutpoints of 0, 1-4 and ≥5 were correlated with baseline patient characteristics and, in a stratified subsample, were also correlated with two prespecified trial secondary endpoints: 7-month PSA ≤0.2 ng/ml vs. 0.2-4.0 vs. >4.0 (intermediate endpoint for overall survival); and progression-free survival (PFS) ≤ vs. >2 years.RESULTS: 523 patients submitted baseline samples, and CTCs were detected (median 3) in 33%. Adjusting for two trial stratification factors (disease burden and timing of ADT initiation), men with undetectable CTCs had nearly 9-times the odds of attaining 7-month PSA ≤ 0.2 vs. > 4.0 (odds ratio [OR] 8.8, 95%CI 2.7-28.6, p < 0.001, N=264) and 4-times the odds of achieving > 2 years PFS (OR 4.0, 95%CI 1.9-8.5, p < 0.001, N=336) compared to men with baseline CTCs ≥5.
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