DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Ubiquitin-Mediated Protein Degradation Pathways for Ovarian Cancer Treatment

Posted September 21, 2016

Martina Bazzaro, Ph.D., University of Minnesota

Dr. Martina Bazzaro with images from her molecular biology research (University of Minnesota)

The risk of developing ovarian cancer in the United States is about 1 in 75 women with more than 22,000 new cases diagnosed each year.  Approximately two-thirds of all new diagnoses are late stage disease with only a 20% survival rate over five years.  By identifying proteins that are aberrantly regulated in cancer cells, and using small molecules to selectively interfere with the expression of those proteins, new detection methods and treatment options may become available for ovarian cancer patients.

In 2009, Dr. Martina Bazzaro, of the University of Minnesota, received an Ovarian Cancer Academy - Early-Career Investigator Award from the Ovarian Cancer Research Program (OCRP) to study the use of proteasomes and Pan-HDAC inhibitors in combination or alone as a method of treating ovarian cancer.  Dr. Bazarro found that deubiquitinating enzymes (DUBs) are capable of protein degradation upstream of proteasomes and tested probes to specifically target those DUBs and cells that overexpress them.  Because the FDA had recently approved a proteasome-associated deubiquitinating inhibitor for the treatment of cancer, Dr. Bazzaro directed efforts towards understanding the mechanisms through which targeting ubiquitin-mediated protein degradation causes death in ovarian cancer cells.  RA-9, the lead compound identified, was found to have the capability to selectively kill ovarian cancer cells.  Selectively targeting DUBs using small molecules such as RA-9 induced the onset of cell death. Importantly, in vivo experiments using a xenograft mouse model of human ovarian cancer showed that treatment with RA-9 slowed tumor growth and increased overall survival [6].  Other significant findings of her research include the overexpression of the USP14 subunit in ovarian cancer clinical samples as compared with normal cells. Recent data published in Oncotarget by Dr. Bazzaro’s lab showed that USP14 is a promising biomarker for stratifying endometrial cancer patients and can be targeted with the FDA-approved small molecule inhibitor VLX1570 [1].  This targeted approach was shown to decrease cell viability in chemotherapy-resistant endometrial cancer cells.  Furthermore, Dr. Bazzaro found that combination therapies of Bortezomib (26S proteasome inhibitor), chloroquine and Vorinostat (HDAC inhibitor) showed synergistic antitumor effects in ovarian cancer cell lines and provided evidence that the mechanism may function through ER stress and autophagy. 

In addition to this outstanding research conducted by Dr. Bazzaro, her laboratory has produced numerous peer-reviewed publications [1-10] as well as several presentations made to universities and government entities across the country. The research from this award has also resulted in the filing of a provisional patent with the Office for Technology and Commercialization for the use of USP14 as a predictive biomarker for recurrence in endometrial cancer.  Dr. Bazzaro hopes that the findings and efforts from this OCRP award may soon lead to clinical trials to test DUB inhibitors, alone or in combination with autophagy inhibitors, for the treatment of chemoresistant ovarian cancer.

Publications:

[1] Vogel R, Pulver T, Heilmann W, et al.  2016.  USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment.  Oncotarget 7(21):30962-30976.

[2] Iizuka Y, Cichocki F, Sieben A, et al.  2015.  UNC-45A is a nonmuscle myosin IIA chaperone required for NK cell cytotoxicity via control of lytic granule secretion. J Immunol 195(10):4760-4770.

[3] Griffin P, Sexton A, Macneill L, et al.  2015.  Method for measuring the activity of deubiquitinating enzymes in cell lines and tissue samples.  J Vis Exp 10(99):e52784.

[4] Vogel RI, Coughlin K, Scotti A, et al.  2015.  Simultaneous inhibition of deubiquitnating enzymes (DUBs) and autophagy synergistically kills breast cancer cells. Oncotarget 6(66):4159-70.

[5] Rivard C and Bazzaro M. 2015.  Measurement of deubiquitinating enzyme activity via a suicidal HA-Ub-VS probe.  Methods Mol Biol 1249:193-200.

[6] Coughlin K, Anchoori R, Iizuka I, et al.  2014.  Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses.  Clin Cancer Res 20(12):3174-3186.

[7] Pribyl L, Couglin K, Iizuka Y, et al. 2014.  Method for obtaining primary ovarian cancer cells from solid specimens. J Vis Exp (84):e51581.

[8] Sueblinvong T, Ghebre R, Iizuka Y, et al. 2012.  Establishment, characterization and downstream application of primary ovarian cancer cells derived from solid tumors.  PLoS One 7(11):e50519.

[9] Bazzaro M, Anchoori RK, Mudiam MK, et al.  2010.  α,β-unsaturated carbonyl system of chalcone-based derivatives is responsible for broad inhibition of proteasomal activity and preferential killing of human papilloma virus (HPV) positive cervical cancer cells. J Med Chem 54(2):449-456.

[10] Anchoori RK, Khan SR, Sueblinvong T, et al. 2011.  Stressing the ubiquitin-proteasome system without 20S proteolytic inhibition selectively kills cervical cancer cells. PLoS One 6(8):e23888.

Links:

Public and Technical Abstracts:  Combination of Proteasome and Pan-HDAC Inhibitors for Treatment of Ovarian Cancer

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Last updated Wednesday, September 21, 2016