Vaccinia virus expressing bone morphogenetic protein-4 in novel glioblastoma orthotopic models facilitates enhanced tumor regression and long-term survival

Journal of Translational Medicine

Aladar A Szalay³  Angelo L Vescovi¹  Elena Binda¹  Nanhai G Chen²  Jason Aguilar²  Qian Zhang²  Ulrike Geissinger²  Rohit Duggal² 

[1] Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, I-20126, Milano, Italy;Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, Suite 310, San Diego, CA 92109, USA;Department of Radiation Oncology, Moores Cancer Center, University of California, 3855 Health Sciences Drive, La Jolla, San Diego, CA 92093, USA

关键词: Cancer stem cells (CSCs) and differentiation;    Bone morphogenetic protein (BMP);    Glioblastoma multiforme (GBM);    Vaccinia virus (VACV);   

Others  :  827345
DOI  :  10.1186/1479-5876-11-155

 received in 2013-04-25, accepted in 2013-06-20,  发布年份 2013

【 摘 要 】

Background

Glioblastoma multiforme (GBM) is one of the most aggressive forms of cancer with a high rate of recurrence. We propose a novel oncolytic vaccinia virus (VACV)-based therapy using expression of the bone morphogenetic protein (BMP)-4 for treating GBM and preventing recurrence.

Methods

We have utilized clinically relevant, orthotopic xenograft models of GBM based on tumor-biopsy derived, primary cancer stem cell (CSC) lines. One of the cell lines, after being transduced with a cDNA encoding firefly luciferase, could be used for real time tumor imaging. A VACV that expresses BMP-4 was constructed and utilized for infecting several primary glioma cultures besides conventional serum-grown glioma cell lines. This virus was also delivered intracranially upon implantation of the GBM CSCs in mice to determine effects on tumor growth.

Results

We found that the VACV that overexpresses BMP-4 demonstrated heightened replication and cytotoxic activity in GBM CSC cultures with a broad spectrum of activity across several different patient-biopsy cultures. Intracranial inoculation of mice with this virus resulted in a tumor size equal to or below that at the time of injection. This resulted in survival of 100% of the treated mice up to 84 days post inoculation, significantly superior to that of a VACV lacking BMP-4 expression. When mice with a higher tumor burden were injected with the VACV lacking BMP-4, 80% of the mice showed tumor recurrence. In contrast, no recurrence was seen when mice were injected with the VACV expressing BMP-4, possibly due to induction of differentiation in the CSC population and subsequently serving as a better host for VACV infection and oncolysis. This lack of recurrence resulted in superior survival in the BMP-4 VACV treated group.

Conclusions

Based on these findings we propose a novel VACV therapy for treating GBM, which would allow tumor specific production of drugs in the future in combination with BMPs which would simultaneously control tumor maintenance and facilitate CSC differentiation, respectively, thereby causing sustained tumor regression without recurrence.

【 授权许可】

   
2013 Duggal et al.; licensee BioMed Central Ltd.

【 图 表 】

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