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The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the E?-TCL1 mouse model

The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the E?-TCL1 mouse model
The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the E?-TCL1 mouse model
Current treatment strategies for CLL involve a combination of conventional chemotherapeutics, monoclonal antibodies and targeted signaling inhibitors. However, CLL remains largely incurable with drug resistance and treatment relapse a common occurrence; leading to the search for novel treatments. mTOR specific inhibitors have been previously assessed but their efficacy is limited due to a positive feedback loop via mTORC2, resulting in activation of pro-survival signaling. Here we show that the dual PI3K/mTOR inhibitor PF-04691502 does not induce an mTORC2 positive feedback loop similar to other PI3K inhibitors but does induce substantial anti-tumor effects. PF-04691502 significantly reduced survival coincident with the induction of Noxa and Puma, independently of IGHV mutational status, CD38 and ZAP-70 expression. PF-04691502 inhibited both anti-IgM induced signaling and overcame stroma-induced survival signals as well as migratory stimuli from CXCL12. Equivalent in vitro activity was seen in the E?-TCL-1 murine model of CLL. In vivo, PF-04691502 treatment of tumor-bearing animals resulted in a transient lymphocytosis, followed by a clear reduction in tumor in the blood, bone marrow, spleen and lymph nodes. These data indicate that PF-04691502 or other dual PI3K/mTOR inhibitors in development may prove efficacious for the treatment of CLL, increasing our armamentarium to successfully manage this disease.
0006-4971
4032-4041
Blunt, Matthew D.
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Carter, Matthew J.
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Larrayoz, Marta
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Smith, Lindsay D.
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Aguilar-Hernandez, Maria
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Cox, Kerry L.
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Tipton, Thomas R.W.
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Reynolds, Mark
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Murphy, Sarah
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Lemm, Elizabeth
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Dias, Samantha
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Duncombe, Andrew S.
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Strefford, Jonathan C.
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Johnson, Peter W.M.
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Forconi, Francesco
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Stevenson, Freda K.
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Packham, Graham
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Cragg, Mark S.
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Steele, Andrew J.
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Blunt, Matthew D.
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Carter, Matthew J.
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Larrayoz, Marta
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Smith, Lindsay D.
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Aguilar-Hernandez, Maria
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Cox, Kerry L.
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Tipton, Thomas R.W.
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Reynolds, Mark
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Murphy, Sarah
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Lemm, Elizabeth
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Dias, Samantha
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Duncombe, Andrew S.
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Strefford, Jonathan C.
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Johnson, Peter W.M.
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Forconi, Francesco
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Stevenson, Freda K.
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Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Cragg, Mark S.
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Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089

Blunt, Matthew D., Carter, Matthew J., Larrayoz, Marta, Smith, Lindsay D., Aguilar-Hernandez, Maria, Cox, Kerry L., Tipton, Thomas R.W., Reynolds, Mark, Murphy, Sarah, Lemm, Elizabeth, Dias, Samantha, Duncombe, Andrew S., Strefford, Jonathan C., Johnson, Peter W.M., Forconi, Francesco, Stevenson, Freda K., Packham, Graham, Cragg, Mark S. and Steele, Andrew J. (2015) The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the E?-TCL1 mouse model. Blood, 125 (26), 4032-4041. (doi:10.1182/blood-2014-11-610329). (PMID:25957390)

Record type: Article

Abstract

Current treatment strategies for CLL involve a combination of conventional chemotherapeutics, monoclonal antibodies and targeted signaling inhibitors. However, CLL remains largely incurable with drug resistance and treatment relapse a common occurrence; leading to the search for novel treatments. mTOR specific inhibitors have been previously assessed but their efficacy is limited due to a positive feedback loop via mTORC2, resulting in activation of pro-survival signaling. Here we show that the dual PI3K/mTOR inhibitor PF-04691502 does not induce an mTORC2 positive feedback loop similar to other PI3K inhibitors but does induce substantial anti-tumor effects. PF-04691502 significantly reduced survival coincident with the induction of Noxa and Puma, independently of IGHV mutational status, CD38 and ZAP-70 expression. PF-04691502 inhibited both anti-IgM induced signaling and overcame stroma-induced survival signals as well as migratory stimuli from CXCL12. Equivalent in vitro activity was seen in the E?-TCL-1 murine model of CLL. In vivo, PF-04691502 treatment of tumor-bearing animals resulted in a transient lymphocytosis, followed by a clear reduction in tumor in the blood, bone marrow, spleen and lymph nodes. These data indicate that PF-04691502 or other dual PI3K/mTOR inhibitors in development may prove efficacious for the treatment of CLL, increasing our armamentarium to successfully manage this disease.

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Submitted date: 6 November 2014
Accepted/In Press date: 2 May 2015
e-pub ahead of print date: 8 May 2015
Published date: June 2015
Organisations: Cancer Sciences

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Local EPrints ID: 377380
URI: https://eprints.soton.ac.uk/id/eprint/377380
ISSN: 0006-4971
PURE UUID: bbab1440-4d37-4818-9b22-6b71289b0c5f
ORCID for Jonathan C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596

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Date deposited: 03 Jun 2015 11:43
Last modified: 31 Jan 2019 01:37

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Contributors

Author: Matthew J. Carter
Author: Marta Larrayoz
Author: Maria Aguilar-Hernandez
Author: Kerry L. Cox
Author: Thomas R.W. Tipton
Author: Mark Reynolds
Author: Sarah Murphy
Author: Elizabeth Lemm
Author: Samantha Dias
Author: Andrew S. Duncombe
Author: Graham Packham ORCID iD
Author: Mark S. Cragg ORCID iD

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