Combination therapy of prostate cancer with HPMA copolymer conjugates containing PI3K/mTOR inhibitor and docetaxel.

Abstract

Combination therapies have been investigated to address the current challenges of anti-cancer therapeutics. In particular, a novel paradigm of combination therapy targeting both cancer stem/progenitor cells and bulk tumor cells is promising to improve the long-term therapeutic benefit against prostate cancer. Among the therapeutic agents with anti-CSC activities, the PI3K/mTOR inhibitors exhibit preferential inhibitory effect on prostate cancer stem/progenitor cells and potent cytotoxicity against bulk tumor cells. The combination of PI3K/mTOR inhibitor and traditional chemotherapy docetaxel may show superior therapeutic effect over single drug treatment. Aiming to further improve the combinational anti-tumor and anti-CSC effect, we developed the combination therapy containing two HPMA copolymer-drug conjugates, incorporated with PI3K/mTOR inhibitor GDC-0980 (P-(GDC-0980)) and docetaxel (P-DTX), respectively. The anti-tumor and anti-CSC effects of the single and combination therapy were investigated in vitro and on PC-3 prostate cancer xenografts in nude mice. Our evaluations showed that P-(GDC-0980) suppressed CD133+ prostate stem/progenitor cell growth even at the low dose which does not cause significant growth inhibition in bulk tumor cells. The combination therapy exhibited effective anti-CSC effect as well as enhanced anti-bulk tumor effect in vitro. Among all the single and combination dosing regimens of free drugs and conjugates, the macromolecular combination therapy showed significantly prolonged mice survival in vivo.

• Authors: Yan Zhou, Jiyuan Yang, Rui Zhang, Jindřich Kopeček
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 89 Pg. 107-15 (Jan 2015) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 25481033 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
• Bridged Bicyclo Compounds, Heterocyclic
• Methacrylates
• Phosphoinositide-3 Kinase Inhibitors
• Polymers
• Protein Kinase Inhibitors
• Pyrimidines
• Taxoids
• Docetaxel
• TOR Serine-Threonine Kinases
• hydroxypropyl methacrylate

Topics

• Animals
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Docetaxel
• Drug Therapy, Combination (methods)
• Humans
• Male
• Methacrylates (chemistry, pharmacology)
• Mice
• Mice, Nude
• Phosphoinositide-3 Kinase Inhibitors
• Polymers (chemistry, pharmacology)
• Prostatic Neoplasms (drug therapy, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Stem Cells (drug effects, metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Taxoids (pharmacology)