1. ¹Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Department of Neuro–Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3. ³Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
4. ⁴Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5. ⁵Department of Molecular Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6. ⁶Oncolys BioPharma Inc., Tokyo, Japan
7. ⁷Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

Correspondence: Dr T Yokoyama, Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Unit BSRB 1004, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail: tyokoyama@mdanderson.org

⁸These authors contributed equally to this work.

Received 26 January 2008; Revised 1 April 2008; Accepted 1 April 2008; Published online 26 June 2008.

Abstract

Oncolytic adenoviruses are a promising tool in cancer therapy. In this study, we characterized the role of autophagy in oncolytic adenovirus-induced therapeutic effects. OBP-405, an oncolytic adenovirus regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad, OBP-301) with a tropism modification (RGD) exhibited a strong antitumor effect on glioblastoma cells. When autophagy was inhibited pharmacologically, the cytotoxicity of OBP-405 was attenuated. In addition, autophagy-deficient Atg5^-/- mouse embryonic fibroblasts (MEFs) were less sensitive than wild-type MEFs to OBP-405. These findings indicate that OBP-405-induced autophagy is a cell killing effect. Moreover, autophagy-inducing therapies (temozolomide and rapamycin) synergistically sensitized tumor cells to OBP-405 by stimulating the autophagic pathway without altering OBP-405 replication. Mice harboring intracranial tumors treated with OBP-405 and temozolomide survived significantly longer than those treated with temozolomide alone, and mice treated with OBP-405 and the rapamycin analog RAD001 survived significantly longer than those treated with RAD001 alone. The observation that autophagy inducers increase OBP-405 antitumor activity suggests a novel strategy for treating patients with glioblastoma.