Our efforts to treat malignant gliomas are focused on methods to transfer the caspase genes to tumors. Because the apoptotic pathway may be disrupted in tumors and caspases are the mainstay of apoptosis programs, this approach is one of the most promising strategies for cancer gene therapy. However, if caspases were transduced to normal brain cells, they will undergo apoptosis. To restrict induction of apoptosis to tumor cells, we need to establish a tumor specific expression system of caspases. Telomerase is a particularly attractive target for the tumor-targeting system. It is because a vast majority of malignant gliomas have telomerase activity, while most normal brain cells do not. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit (hTERT). Therefore, we hypothesize that by using the hTERT promoter-driven vector system, the expression of caspases can be restricted to telomerase-positive malignant gliomas. In preliminary studies, we constructed the caspase-8 (initiator caspase) or rev-caspase-6 (executioner caspase) expression vector with the hTERT promoter (hTERT/caspase-8 or rev-caspase-6) and demonstrated that each construct induced apoptosis in telomerase-positive malignant glioma cells, but not in cultured astrocytes lacking telomerase. Furthermore, the growth of subcutaneous tumors in nude mice was significantly suppressed by the treatment with the hTERT/rev-caspase-6. Additionally, the antitumor effect of hTERT/caspase-8 or rev-caspase-6 was enhanced by the combination with anticancer drug, cisplatin. The goal of this proposal is to investigate whether treatment with the hTERT/caspase-8 or rev-caspase-6 construct is an effective approach for telomerase-positive malignant gliomas using an experimental model of human malignant gliomas.
The specific aims are: 1) to select tumor model systems for the in vivo treatment with hTERT/caspase-8 or rev-caspase-6 construct, 2) to investigate the antitumor effect of the hTERT/caspase-8 or rev-caspase-6 construct on intracranial tumors, 3) to investigate their in vitro and in vivo antitumor efficacy combined with conventional therapy (cisplatin, temozolomide, or gamma-irradiation), and 4) to investigate the molecular mechanisms underlying the effect of the hTERT/caspase-8 or rev-caspase-6. A unique focus of this work is the emphasis on the telomerase-specific gene transfer of caspases. We anticipate that the studies described in the current proposal will lead to a novel and promising targeting approach for malignant gliomas expressing telomerase activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088936-05
Application #
6758007
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wolpert, Mary K
Project Start
2001-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2004
Total Cost
$237,825
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurosurgery
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Yokoyama, T; Iwado, E; Kondo, Y et al. (2008) Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells. Gene Ther 15:1233-9
Aoki, Hiroshi; Kondo, Yasuko; Aldape, Kenneth et al. (2008) Monitoring autophagy in glioblastoma with antibody against isoform B of human microtubule-associated protein 1 light chain 3. Autophagy 4:467-75
Aoki, Hiroshi; Iwado, Eiji; Eller, Mark S et al. (2007) Telomere 3'overhang-specific DNA oligonucleotides induce autophagy in malignant glioma cells. FASEB J 21:2918-30
Yokoyama, Tomohisa; Kondo, Yasuko; Kondo, Seiji (2007) Roles of mTOR and STAT3 in autophagy induced by telomere 3'overhang-specific DNA oligonucleotides. Autophagy 3:496-8
Kondo, Yasuko; Kondo, Seiji (2007) Telomerase RNA inhibition using antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate. Methods Mol Biol 405:97-112
Shinojima, Naoki; Yokoyama, Tomohisa; Kondo, Yasuko et al. (2007) Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 3:635-7
Aoki, Hiroshi; Takada, Yasunari; Kondo, Seiji et al. (2007) Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 72:29-39
Iwado, Eiji; Daido, Shigeru; Kondo, Yasuko et al. (2007) Combined effect of 2-5A-linked antisense against telomerase RNA and conventional therapies on human malignant glioma cells in vitro and in vivo. Int J Oncol 31:1087-95
Fujiwara, Keishi; Iwado, Eiji; Mills, Gordon B et al. (2007) Akt inhibitor shows anticancer and radiosensitizing effects in malignant glioma cells by inducing autophagy. Int J Oncol 31:753-60
Iwamaru, A; Kondo, Y; Iwado, E et al. (2007) Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells. Oncogene 26:1840-51

Showing the most recent 10 out of 27 publications