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Aurora A Inhibitor (MLN8237) plus Vincristine plus Rituximab Is Synthetic Lethal and a Potential Curative Therapy in Aggressive B-cell Non-Hodgkin Lymphoma

Aurora A Inhibitor (MLN8237) plus Vincristine plus Rituximab Is Synthetic Lethal and a Potential... Purpose: Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 (M), an Aurora A inhibitor with either vincristine (MV) or docetaxel (MD) in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab (R) to MV or MD was evaluated for synthetic lethality. Experimental Design: Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets, and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival, and mechanisms of response/relapse by gene expression profiling with protein validation. Results: MV is synergistic whereas MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of rituximab to MV is superior to MD, but both significantly induce apoptosis compared with doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single-agent activity for MLN8237, rituximab, docetaxel, and vincristine with tumor growth inhibition (TGI) of approximately 10% to 15%. Of the doublets, MV caused tumor regression, whereas TGI was observed with MD (approximately 55%–60%) and MR (approximately 25%–50%), respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, whereas MDR led to TGI of approximately 85%. Proliferation cell nuclear antigen, Aurora B, cyclin B1, cyclin D1, and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy. Conclusions: Addition of rituximab to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation. Clin Cancer Res; 18(8); 2210–9. ©2012 AACR . This article is featured in Highlights of This Issue, p. 2119 Received September 16, 2011. Revision received January 24, 2012. Accepted February 14, 2012. ©2012 American Association for Cancer Research. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Cancer Research American Association of Cancer Research

Aurora A Inhibitor (MLN8237) plus Vincristine plus Rituximab Is Synthetic Lethal and a Potential Curative Therapy in Aggressive B-cell Non-Hodgkin Lymphoma

Aurora A Inhibitor (MLN8237) plus Vincristine plus Rituximab Is Synthetic Lethal and a Potential Curative Therapy in Aggressive B-cell Non-Hodgkin Lymphoma

Clinical Cancer Research , Volume 18 (8): 2210 – Apr 15, 2012

Abstract

Purpose: Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 (M), an Aurora A inhibitor with either vincristine (MV) or docetaxel (MD) in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab (R) to MV or MD was evaluated for synthetic lethality. Experimental Design: Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets, and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival, and mechanisms of response/relapse by gene expression profiling with protein validation. Results: MV is synergistic whereas MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of rituximab to MV is superior to MD, but both significantly induce apoptosis compared with doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single-agent activity for MLN8237, rituximab, docetaxel, and vincristine with tumor growth inhibition (TGI) of approximately 10% to 15%. Of the doublets, MV caused tumor regression, whereas TGI was observed with MD (approximately 55%–60%) and MR (approximately 25%–50%), respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, whereas MDR led to TGI of approximately 85%. Proliferation cell nuclear antigen, Aurora B, cyclin B1, cyclin D1, and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy. Conclusions: Addition of rituximab to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation. Clin Cancer Res; 18(8); 2210–9. ©2012 AACR . This article is featured in Highlights of This Issue, p. 2119 Received September 16, 2011. Revision received January 24, 2012. Accepted February 14, 2012. ©2012 American Association for Cancer Research.

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Publisher
American Association of Cancer Research
Copyright
Copyright © 2012 American Association for Cancer Research
ISSN
1078-0432
eISSN
1557-3265
DOI
10.1158/1078-0432.CCR-11-2413
pmid
22374334
Publisher site
See Article on Publisher Site

Abstract

Purpose: Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 (M), an Aurora A inhibitor with either vincristine (MV) or docetaxel (MD) in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab (R) to MV or MD was evaluated for synthetic lethality. Experimental Design: Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets, and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival, and mechanisms of response/relapse by gene expression profiling with protein validation. Results: MV is synergistic whereas MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of rituximab to MV is superior to MD, but both significantly induce apoptosis compared with doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single-agent activity for MLN8237, rituximab, docetaxel, and vincristine with tumor growth inhibition (TGI) of approximately 10% to 15%. Of the doublets, MV caused tumor regression, whereas TGI was observed with MD (approximately 55%–60%) and MR (approximately 25%–50%), respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, whereas MDR led to TGI of approximately 85%. Proliferation cell nuclear antigen, Aurora B, cyclin B1, cyclin D1, and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy. Conclusions: Addition of rituximab to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation. Clin Cancer Res; 18(8); 2210–9. ©2012 AACR . This article is featured in Highlights of This Issue, p. 2119 Received September 16, 2011. Revision received January 24, 2012. Accepted February 14, 2012. ©2012 American Association for Cancer Research.

Journal

Clinical Cancer ResearchAmerican Association of Cancer Research

Published: Apr 15, 2012

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