Ovarian cancer is the most common cause of gynecologic cancer death in the U.S. and is responsible for approximately 16,000 deaths each year in the US. Recurrent disease remains incurable and has a dismal prognosis. Novel therapeutic agents are urgently needed. We have demonstrated that engineered measles virus strains have significant antitumor activity against ovarian cancer lines and xenografts. Their tumor specificity is due to abundant expression of the measles virus receptor CD46 in ovarian cancer cells. The virus, upon entry into tumor cells, causes membrane fusion with neighboring cells, syncytia formation and death. Our group was the first to translate this approach into a phase I clinical trial of a measles virus derivative producing human carcinoembryonic antigen, MV-CEA (CEA added to facilitate monitoring of viral gene expression) in recurrent ovarian cancer patients. Despite low levels of viral replication, as evidenced by modest CEA elevation in a subgroup of patients, there was promising early evidence of antitumor activity, including CA-125 decreases and prolonged disease stabilization in heavily pretreated patients. We hypothesize that by increasing the efficiency and extent of tumor cell infection we can further augment the antitumor activity of measles virotherapy in ovarian cancer. 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 Iodide Symporter (NIS) therapeutic transgene, thus allowing imaging of viral distribution in vivo and use of 131I for radiovirotherapy;use of infected cell carriers for viral delivery;and, combining the measles virus with cyclophosphamide, an agent with immunosuppressive and antitumor properties. This grant proposal has, therefore, the following specific aims, 1) to perform a limited phase I trial of intraperitoneal (IP) administration of MV-NIS in patients with recurrent ovarian cancer;2) to optimize the efficacy of IP measles virotherapy for ovarian cancer in measles immune mice by employing virus infected cell carriers, and testing the added benefit of cyclophosphamide, an immunosuppressive drug with antitumor properties;3) to test the efficacy of intravenous (IV) measles virotherapy for ovarian cancer, and optimize it in measles immune mice by using virus infected cell carriers, with and without addition of cyclophosphamide; following optimization of IP or IV delivery the added value of 131I radiovirotherapy will also be tested.

Public Health Relevance

Ovarian cancer is the most common cause of gynecologic cancer death in the United States, and it is responsible for the deaths of 16,000 women each year. Our group is developing a novel approach to treat ovarian cancer by using measles virus strains that preferentially replicate in ovarian tumors. Based on promising data deriving from a phase I trial of the MV-CEA measles strain in recurrent ovarian cancer patients, in this application we seek to optimize delivery of the virus and weaken the immune response against the virus in order to increase the efficacy of the treatment. Furthermore, we test the potential of the viral strain MV-NIS, which allows imaging of the viral replication in the human body and use of radioactive iodine to augment the therapeutic effect.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136547-04
Application #
8249099
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Song, Min-Kyung H
Project Start
2009-06-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$507,051
Indirect Cost
$171,478
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Geekiyanage, Hirosha; Galanis, Evanthia (2016) MiR-31 and miR-128 regulates poliovirus receptor-related 4 mediated measles virus infectivity in tumors. Mol Oncol 10:1387-1403
Galanis, Evanthia; Atherton, Pamela J; Maurer, Matthew J et al. (2015) Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res 75:22-30
Iankov, I D; Kurokawa, C B; D'Assoro, A B et al. (2015) Inhibition of the Aurora A kinase augments the anti-tumor efficacy of oncolytic measles virotherapy. Cancer Gene Ther 22:438-44
Domingo-Musibay, E; Allen, C; Kurokawa, C et al. (2014) Measles Edmonston vaccine strain derivatives have potent oncolytic activity against osteosarcoma. Cancer Gene Ther 21:483-90
Liu, Yu-Ping; Steele, Michael B; Suksanpaisan, Lukkana et al. (2014) Oncolytic measles and vesicular stomatitis virotherapy for endometrial cancer. Gynecol Oncol 132:194-202
Liu, Yu-Ping; Wang, Jiahu; Avanzato, Victoria A et al. (2014) Oncolytic vaccinia virotherapy for endometrial cancer. Gynecol Oncol 132:722-9
Peng, K-W; Myers, R; Greenslade, A et al. (2013) Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses. Gene Ther 20:255-61
Msaouel, Pavlos; Opyrchal, Mateusz; Domingo Musibay, Evidio et al. (2013) Oncolytic measles virus strains as novel anticancer agents. Expert Opin Biol Ther 13:483-502
Liu, Chunsheng; Suksanpaisan, Lukkana; Chen, Yun-Wen et al. (2013) Enhancing cytokine-induced killer cell therapy of multiple myeloma. Exp Hematol 41:508-17
Iankov, Ianko D; Federspiel, Mark J; Galanis, Evanthia (2013) Measles virus expressed Helicobacter pylori neutrophil-activating protein significantly enhances the immunogenicity of poor immunogens. Vaccine 31:4795-801

Showing the most recent 10 out of 20 publications