publication . Article . 2017

The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma

Hernández-García, Susana; San-Segundo, Laura; González-Méndez, Lorena; Corchete, Luis A; Misiewicz-Krzeminska, Irena; Martín-Sánchez, Montserrat; López-Iglesias, Ana-Alicia; Algarín, Esperanza Macarena; Mogollón, Pedro; Díaz-Tejedor, Andrea; ...
Open Access English
  • Published: 01 Dec 2017 Journal: Haematologica, volume 102, issue 12, pages 2,113-2,124 (issn: 0390-6078, eissn: 1592-8721, Copyright policy)
  • Publisher: Ferrata Storti Foundation
Abstract
[EN]Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several in vitro and in vivo models. Mechanisms of this synergistic combination were dissected by gene expression profiling, immunos...
Subjects
free text keywords: Dexamethasone, :MEDICINE [Research Subject Categories], Plasma Cell Disorders, Multiple myeloma, Kinesin spindle protein inhibitor, BAK activation, Filanesib, Pomalidomide, Monopolar spindles, Article
42 references, page 1 of 3

1.Kumar SK Lee JH Lahuerta JJ Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multi-center international myeloma working group stud y. Leukemia. 2012;26(1):149–157.21799510 [OpenAIRE] [PubMed]

2.Ocio EM Richardson PG Rajkumar SV New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG). Leukemia. 2014; 28(3):525–542.24253022 [OpenAIRE] [PubMed]

3.Bergsagel PL Kuehl WM Zhan F Sawyer J Barlogie B Shaughnessy J Jr Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005; 106(1):296–303.15755896 [OpenAIRE] [PubMed]

4.Niesvizky R Lentzsch S Badros AZ A phase I study of PD 0332991: complete CDK4/6 inhibition and tumor response in sequential combination with bortezomib and dexamethasone for relapsed and refractory multiple myeloma. ASH Annual Meeting Abstracts. 2010; 116(21):860. [OpenAIRE]

5.Rosenthal A Kumar S Hofmeister C A phase Ib study of the combination of the aurora kinase inhibitor alisertib (MLN8237) and bortezomib in relapsed multiple myeloma. Br J Haematol. 2016; 174(2):323–325.26403323 [OpenAIRE] [PubMed]

6.Kollareddy M Zheleva D Dzubak P Brahmkshatriya PS Lepsik M Hajduch M Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs. 2012; 30(6):2411–2432.22350019 [OpenAIRE] [PubMed]

7.Lonial S Shah JJ Zonder J Bensinger WI Cohen AD Kaufman JL Prolonged survival and improved response rates with ARRY-520 in relapsed/refractory multiple myeloma (RRMM) patients with low α-1 acid glycoprotein (AAG) levels: results from a phase 2 study. Blood. 2013; 122(21):285.

8.Ocio EM Mitsiades CS Orlowski RZ Anderson KC Future agents and treatment directions in multiple myeloma. Expert Rev Hematol. 2014;7(1):127–141.24350987 [OpenAIRE] [PubMed]

9.Jackson JR Patrick DR Dar MM Huang PS Targeted anti-mitotic therapies: can we improve on tubulin agents¿Nat Rev Cancer. 2007;7(2):107–117.17251917 [PubMed]

10.Blangy A Lane HA d’Herin P Harper M Kress M Nigg EA Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell. 1995;83(7):1159–1169.8548803 [PubMed]

11.Stern BM Murray AW Lack of tension at kinetochores activates the spindle checkpoint in budding yeast. Curr Biol. 2001; 11(18):1462–1467.11566107 [PubMed]

12.Tunquist BJ Woessner RD Walker DH Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol Cancer Ther. 2010;9(7):2046–2056.20571074 [PubMed]

13.Peperzak V Vikstrom I Walker J Mcl-1 is essential for the survival of plasma cells. Nat Immunol. 2013;14(3):290–297.23377201 [OpenAIRE] [PubMed]

14.Zhang B Gojo I Fenton RG Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood. 2002;99(6):1885–93.11877256 [PubMed]

15.San Miguel J Weisel K Moreau P Pomalidomide plus low-dose dex-amethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055–1066.24007748 [OpenAIRE] [PubMed]

42 references, page 1 of 3
Abstract
[EN]Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several in vitro and in vivo models. Mechanisms of this synergistic combination were dissected by gene expression profiling, immunos...
Subjects
free text keywords: Dexamethasone, :MEDICINE [Research Subject Categories], Plasma Cell Disorders, Multiple myeloma, Kinesin spindle protein inhibitor, BAK activation, Filanesib, Pomalidomide, Monopolar spindles, Article
42 references, page 1 of 3

1.Kumar SK Lee JH Lahuerta JJ Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multi-center international myeloma working group stud y. Leukemia. 2012;26(1):149–157.21799510 [OpenAIRE] [PubMed]

2.Ocio EM Richardson PG Rajkumar SV New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG). Leukemia. 2014; 28(3):525–542.24253022 [OpenAIRE] [PubMed]

3.Bergsagel PL Kuehl WM Zhan F Sawyer J Barlogie B Shaughnessy J Jr Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005; 106(1):296–303.15755896 [OpenAIRE] [PubMed]

4.Niesvizky R Lentzsch S Badros AZ A phase I study of PD 0332991: complete CDK4/6 inhibition and tumor response in sequential combination with bortezomib and dexamethasone for relapsed and refractory multiple myeloma. ASH Annual Meeting Abstracts. 2010; 116(21):860. [OpenAIRE]

5.Rosenthal A Kumar S Hofmeister C A phase Ib study of the combination of the aurora kinase inhibitor alisertib (MLN8237) and bortezomib in relapsed multiple myeloma. Br J Haematol. 2016; 174(2):323–325.26403323 [OpenAIRE] [PubMed]

6.Kollareddy M Zheleva D Dzubak P Brahmkshatriya PS Lepsik M Hajduch M Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs. 2012; 30(6):2411–2432.22350019 [OpenAIRE] [PubMed]

7.Lonial S Shah JJ Zonder J Bensinger WI Cohen AD Kaufman JL Prolonged survival and improved response rates with ARRY-520 in relapsed/refractory multiple myeloma (RRMM) patients with low α-1 acid glycoprotein (AAG) levels: results from a phase 2 study. Blood. 2013; 122(21):285.

8.Ocio EM Mitsiades CS Orlowski RZ Anderson KC Future agents and treatment directions in multiple myeloma. Expert Rev Hematol. 2014;7(1):127–141.24350987 [OpenAIRE] [PubMed]

9.Jackson JR Patrick DR Dar MM Huang PS Targeted anti-mitotic therapies: can we improve on tubulin agents¿Nat Rev Cancer. 2007;7(2):107–117.17251917 [PubMed]

10.Blangy A Lane HA d’Herin P Harper M Kress M Nigg EA Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell. 1995;83(7):1159–1169.8548803 [PubMed]

11.Stern BM Murray AW Lack of tension at kinetochores activates the spindle checkpoint in budding yeast. Curr Biol. 2001; 11(18):1462–1467.11566107 [PubMed]

12.Tunquist BJ Woessner RD Walker DH Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol Cancer Ther. 2010;9(7):2046–2056.20571074 [PubMed]

13.Peperzak V Vikstrom I Walker J Mcl-1 is essential for the survival of plasma cells. Nat Immunol. 2013;14(3):290–297.23377201 [OpenAIRE] [PubMed]

14.Zhang B Gojo I Fenton RG Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood. 2002;99(6):1885–93.11877256 [PubMed]

15.San Miguel J Weisel K Moreau P Pomalidomide plus low-dose dex-amethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055–1066.24007748 [OpenAIRE] [PubMed]

42 references, page 1 of 3
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publication . Article . 2017

The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma

Hernández-García, Susana; San-Segundo, Laura; González-Méndez, Lorena; Corchete, Luis A; Misiewicz-Krzeminska, Irena; Martín-Sánchez, Montserrat; López-Iglesias, Ana-Alicia; Algarín, Esperanza Macarena; Mogollón, Pedro; Díaz-Tejedor, Andrea; ...