Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, accounting for most of 18,000 primary brain tumor cases each year in the US. Prognosis is dismal with a median survival of 12-15 mo, despite use of multimodality treatment. Novel therapeutic agents are urgently needed. During the current funding period of the Mayo Brain SPORE, our group was the first to demonstrate that engineered measles virus (MV) strains have significant antitumor activity against gliomas. Their tumor specificity is due to abundant expression of the MV receptor CD46 in glioma cells. The virus upon entry in the tumor cells, causes membrane fusion with neighboring cells, syncytia formation and death. In addition, we have translated this approach into the first human clinical trial of a measles virus derivative producing human carcinoembryonic antigen, MV-CEA (CEA added to facilitate viral monitoring) in recurrent GBM patients. We now hypothesize that by increasing the efficiency and extent of tumor cell destruction and by introducing a therapeutic transgene, we can further augment the antitumor activity of measles virotherapy in gliomas. We propose to accomplish this by testing the translational potential of three novel approaches;a different measles virus strain, MV-NIS, which encodes the sodium iodine symporter (NIS) gene, thus allowing Imaging of viral distribution in vivo;enhancing MV-NIS oncolysis, by exploiting NIS as therapeutic transgene with application of the beta and gamma emitter (radiovirotherapy);and combining measles virus derivatives with cyclophosphamide, an agent that has been shown to suppress anti-viral innate and adaptive immunity, and increase viral proliferation in tumors. This grant proposal has therefore the following specific aims: 1) to evaluate the therapeutic potential of MV-NIS based virotherapy and radiovirotherapy against GBM and compare its antitumor activity with MV-CEA;2) to test combinatorial strategies with cyclophosphamide, a suppressant of the innate immune response, in order to further increase the potency of measles virotherapy or radiovirotherapy;3) to perform toxicology and biodistribution studies in measles susceptible transgenic mice and Rhesus macaques in order to determine the safety of the optimal therapeutic strategy to be tested in a follow-up clinical trial;4) to employ the approach with the optimal safety/efficacy profile in a subsequent phase I clinical trial in patients with recurrent glioblastoma multiforme.

Public Health Relevance

Compared to other more common cancers malignant gliomas are responsible for a disproportionate amount of morbidity, in addition to significant decrease in life expectancy. In preclinical models, measles vaccine strains have potent antitumor activity against gliomas and demonstrate synergy with existing therapies. This application proposes to investigate strategies optimizing the use of measles vaccine strains as novel antitumor agents in the treatment of gliomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA108961-09
Application #
8729253
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
9
Fiscal Year
2014
Total Cost
$286,203
Indirect Cost
$99,262
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Oi, N; Yuan, J; Malakhova, M et al. (2015) Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1. Oncogene 34:2660-71
Choi, Jae Won; Schroeder, Mark A; Sarkaria, Jann N et al. (2014) Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells. Cancer Res 74:484-96
Bradley, Barrie S; Loftus, Joseph C; Mielke, Clinton J et al. (2014) Differential expression of microRNAs as predictors of glioblastoma phenotypes. BMC Bioinformatics 15:21
Walsh, Kyle M; Codd, Veryan; Smirnov, Ivan V et al. (2014) Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nat Genet 46:731-5
Bell, Michael P; Renner, Danielle N; Johnson, Aaron J et al. (2014) An elite controller of picornavirus infection targets an epitope that is resistant to immune escape. PLoS One 9:e94332
Catteau, Aurélie; Girardi, Hélène; Monville, Florence et al. (2014) A new sensitive PCR assay for one-step detection of 12 IDH1/2 mutations in glioma. Acta Neuropathol Commun 2:58
Johnson, Holly L; Jin, Fang; Pirko, Istvan et al. (2014) Theiler's murine encephalomyelitis virus as an experimental model system to study the mechanism of blood-brain barrier disruption. J Neurovirol 20:107-12
Gupta, Shiv K; Mladek, Ann C; Carlson, Brett L et al. (2014) Discordant in vitro and in vivo chemopotentiating effects of the PARP inhibitor veliparib in temozolomide-sensitive versus -resistant glioblastoma multiforme xenografts. Clin Cancer Res 20:3730-41
Assefnia, Shahin; Dakshanamurthy, Sivanesan; Guidry Auvil, Jaime M et al. (2014) Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies. Oncotarget 5:1458-74
Wang, Enfeng; Zhang, Chunyang; Polavaram, Navatha et al. (2014) The role of factor inhibiting HIF (FIH-1) in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme. PLoS One 9:e86102

Showing the most recent 10 out of 103 publications