2. Academic Validation
  3. Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses

Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses

  • Clin Cancer Res. 2014 Jun 15;20(12):3174-86. doi: 10.1158/1078-0432.CCR-13-2658.
Kathleen Coughlin 1,  Ravi Anchoori 2,  Yoshie Iizuka 1,  Joyce Meints 1,  Lauren MacNeill 1,  Rachel Isaksson Vogel 1,  Robert Z Orlowski 1,  Michael K Lee 1,  Richard B S Roden 3,  Martina Bazzaro 4
Affiliations

Affiliations

  • 1 Authors' Affiliations: Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Heath, Department of Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota; Departments of Pathology, Oncology, and Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland; and Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
  • 2 Authors' Affiliations: Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Heath, Department of Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota; Departments of Pathology, Oncology, and Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland; and Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Heath, Department of Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota; Departments of Pathology, Oncology, and Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland; and Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
  • 3 Authors' Affiliations: Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Heath, Department of Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota; Departments of Pathology, Oncology, and Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland; and Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Heath, Department of Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota; Departments of Pathology, Oncology, and Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland; and Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Heath, Department of Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota; Departments of Pathology, Oncology, and Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland; and Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
  • 4 Authors' Affiliations: Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Heath, Department of Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota; Departments of Pathology, Oncology, and Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland; and Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas mbazzaro@umn.edu.
PMID: 24727327 DOI: 10.1158/1078-0432.CCR-13-2658
Abstract

Purpose: Ovarian Cancer is the deadliest of the gynecologic malignancies. Carcinogenic progression is accompanied by upregulation of ubiquitin-dependent protein degradation machinery as a mechanism to compensate with elevated endogenous proteotoxic stress. Recent studies support the notion that deubiquitinating enzymes (DUB) are essential factors in proteolytic degradation and that their aberrant activity is linked to Cancer progression and chemoresistance. Thus, DUBs are an attractive therapeutic target for ovarian Cancer.

Experimental design: The potency and selectivity of RA-9 inhibitor for proteasome-associated DUBs was determined in ovarian Cancer cell lines and primary cells. The Anticancer activity of RA-9 and its mechanism of action were evaluated in multiple Cancer cell lines in vitro and in vivo in immunodeficient mice bearing an intraperitoneal ES-2 xenograft model of human ovarian Cancer.

Results: Here, we report the characterization of RA-9 as a small-molecule inhibitor of proteasome-associated DUBs. Treatment with RA-9 selectively induces onset of Apoptosis in ovarian Cancer cell lines and primary cultures derived from donors. Loss of cell viability following RA-9 exposure is associated with an unfolded protein response as mechanism to compensate for unsustainable levels of proteotoxic stress. In vivo treatment with RA-9 retards tumor growth, increases overall survival, and was well tolerated by the host.

Conclusions: Our preclinical studies support further evaluation of RA-9 as an ovarian Cancer therapeutic.

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