Oncolytic Herpes Simplex Virus and PI3K Inhibitor BKM120 Synergize to Promote Killing of Prostate Cancer Stem-like Cells

Overview

Journal Mol Ther Oncolytics

Publisher Cell Press

Date 2019 Apr 25

PMID 31016228

Citations 20

Authors

Lei Wang

Jianfang Ning

Hiroaki Wakimoto

Shulin Wu

Chin-Lee Wu

Melissa R Humphrey

Samuel D Rabkin

Robert L Martuza

Affiliations

Soon will be listed here.

Abstract

Novel therapies to override chemo-radiation resistance in prostate cancer (PCa) are needed. Prostate cancer sphere-forming cells (PCSCs) (also termed prostate cancer stem-like cells) likely participate in tumor progression and recurrence, and they are important therapeutic targets. We established PCSC-enriched spheres by culturing human (DU145) and murine (TRAMP-C2) PCa cells in growth factor-defined serum-free medium, and we characterized stem-like properties of clonogenicity and tumorigenicity. The efficacy of two different oncolytic herpes simplex viruses (oHSVs) (G47Δ and MG18L) in PCSCs was tested alone and in combination with radiation; chemotherapy; and inhibitors of phosphoinositide 3-kinase (PI3K), Wnt, and NOTCH ; and, G47Δ was tested with the PI3K inhibitor BKM120 in a PCSC-derived tumor model . PCSCs were more tumorigenic than serum-cultured parental cells. Human and murine PCSCs were sensitive to oHSV and BKM120 killing , while the combination was synergistic. oHSV combined with radiation, docetaxel, Wnt, or NOTCH inhibitors was not. In athymic mice bearing DU145 PCSC-derived tumors, the combination of intra-tumoral G47Δ and systemic BKM120 induced complete regression of tumors in 2 of 7 animals, and it exhibited superior anti-tumor activity compared to either monotherapy alone, with no detectable toxicity. oHSV synergizes with BKM120 in killing PCSCs , and the combination markedly inhibits tumor growth, even inducing regression .

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