Abstract
BackgroundSerial analysis of biomarkers in the circulation of patients undergoing treatment (“liquid biopsies”) can provide new insights into drug effects. In particular the analysis of cell-free, circulating nucleic acids such as microRNAs (miRs) can reveal altered expression patterns indicative of mechanism of drug action, cancer growth, and tumor–stroma interactions.ResultsHere we analyzed plasma miRs in patients with hormone receptor positive, metastatic breast cancer with prior disease progression during aromatase inhibitor therapy (n = 8) in a phase I/II trial with the multiple tyrosine kinase inhibitor dovitinib (TKI258). Plasma miR levels were measured by quantitative RT-qPCR before and after treatment with dovitinib. A candidate miR signature of drug response was established from a 379 miR screen for detectable plasma miRs as well as from the published literature. Changes in miR expression patterns and tumor sizes were compared. In this analysis we identified miR-21-5p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-375 and miR-424-5p as potential indicators of a response to dovitinib. The altered expression patterns observed for the six circulating miRs separated patients with resistant disease from those with drug responsive disease. There was no relationship between adverse effects of dovitinib treatment and identifiable changes in miR patterns.ConclusionWe conclude that changes in the expression patterns of circulating miRs can be indicators of drug responses that merit prospective studies for validation.
Highlights
Serial analysis of biomarkers in the circulation of patients undergoing treatment (“liquid biopsies”) can provide new insights into drug effects
In patients with metastatic renal cell carcinoma that were previously treated with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor and an mechanistic target of rapamycin (mTOR) inhibitor, dovitinib
The comparative miR analysis was done with the pre-treatment and the earliest available plasma sample after initiation of dovitinib treatment
Summary
Serial analysis of biomarkers in the circulation of patients undergoing treatment (“liquid biopsies”) can provide new insights into drug effects. In particular the analysis of cell-free, circulating nucleic acids such as microRNAs (miRs) can reveal altered expression patterns indicative of mechanism of drug action, cancer growth, and tumor– stroma interactions. One of the hallmarks of cancer is the oncogenic activation of receptor tyrosine kinases (RTKs) that control cell growth and survival [1,2,3]. Integrated analysis of clinical and preclinical studies indicates that inhibition of FGFR signaling by dovitinib disrupts the paracrine interaction between prostate cancer and stromal cells and mediates the antitumor effect [10]. In pretreated patients with metastatic renal cell carcinoma, dovitinib showed significant antitumor activity in a phase-I study [11]. In patients with metastatic renal cell carcinoma that were previously treated with a VEGFR tyrosine kinase inhibitor and an mTOR inhibitor, dovitinib
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
