YB‐1 dependent virotherapy in combination with temozolomide as a multimodal therapy approach to eradicate malignant glioma

• Published in: International journal of cancer Vol. 129; no. 5; pp. 1265 - 1276
• Main Authors: Holzmüller, Regina, Mantwill, Klaus, Haczek, Cornelia, Rognoni, Emanuel, Anton, Martina, Kasajima, Atsuko, Weichert, Wilko, Treue, Denise, Lage, Hermann, Schuster, Tibor, Schlegel, Jürgen, Gänsbacher, Bernd, Holm, Per S.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2011; Wiley-Blackwell
• Subjects: Adenoviridae - genetics; Animal tumors. Experimental tumors; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Blotting, Southern; Blotting, Western; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Cisplatin - administration & dosage; Combined Modality Therapy; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Daunorubicin - administration & dosage; Experimental tumors, general aspects; Genetic Therapy; Genetic Vectors - therapeutic use; glioma; Glioma - genetics; Glioma - secondary; Glioma - therapy; Humans; Immunoenzyme Techniques; Medical sciences; Mice; Mice, Nude; oncolytic adenovirus; Oncolytic Virotherapy; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; temozolomide; Tumor Cells, Cultured; Tumors; virotherapy; Virus Replication; Y-Box-Binding Protein 1 - genetics; YB‐1; Antineoplastic agent; oncolytic adenovirus; Adenoviridae; YB-1; Virotherapy; Malignant glioma; Cancerology; Nervous system diseases; Transcription factor YB1; Rodentia; Malignant tumor; Oncolytic virus; Virus; Alkylating agent; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Central nervous system disease; glioma; Combined treatment; Temozolomide; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.25783

The human Y‐box binding protein 1 (YB‐1) is known to be a promising target for cancer therapy. We have demonstrated that YB‐1 plays an important role in the adenoviral life cycle by regulating the adenoviral E2‐gene expression. Thus, we studied the oncolytic effect of the recombinant adenovirus Ad‐Delo3‐RGD, in which the transactivation domain CR3 of the E1A protein is ablated to enable viral replication only in YB‐1 positive cancer cells. In vitro Southern Blot analysis and cytopathic effect assays demonstrate high anti‐glioma potency, which was significantly increased in combination with temozolomide (TMZ), daunorubicin and cisplatin. Since vascular endothelial growth factor (VEGF) is thought to promote the hypervascular phenotype of primary, malignant brain tumors, we also tested Ad‐Delo3‐RGD in regard to the inhibition of VEGF expression. Indeed, we found that Ad‐Delo3‐RGD induced VEGF down regulation, which was even amplified under hypoxic conditions. Tumor‐bearing nudemice treated with the YB‐1 dependent oncolytic adenovirus showed significantly smaller tumors than untreated controls. Furthermore, combination therapy with TMZ led to a regression in all treated animals with complete tumor regression in 33 % of analyzed mice, which was verified by bioluminescence imaging and histological studies. In addition, histopathological evaluation revealed enhanced apoptosis and a reduction in tumor vessel formation, indicating that Ad‐Delo3‐RGD has an anti‐angiogenic effect in addition to its oncolytic capacity in vivo. Hence, our results demonstrate that the combination therapy of YB‐1 dependent virotherapy and TMZ is effective in a xenograft glioma mouse model and might be useful in a YB‐1 based clinical setting.