Abstract:
:Current treatment strategies for chronic lymphocytic leukemia (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. Mechanistic target of rapamycin (mTOR)-specific inhibitors have been previously assessed but their efficacy is limited due to a positive feedback loop via mTOR complex 2 (mTORC2), resulting in activation of prosurvival signaling. In this study, we show that the dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor PF-04691502 does not induce an mTORC2 positive feedback loop similar to other PI3K inhibitors but does induce substantial antitumor effects. PF-04691502 significantly reduced survival coincident with the induction of Noxa and Puma, independently of immunoglobulin heavy chain variable region mutational status, CD38, and ZAP-70 expression. PF-04691502 inhibited both anti-immunoglobulin M-induced signaling and overcame stroma-induced survival signals and migratory stimuli from CXCL12. Equivalent in vitro activity was seen in the Eμ-TCL1 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.
journal_name
Bloodjournal_title
Bloodauthors
Blunt MD,Carter MJ,Larrayoz M,Smith LD,Aguilar-Hernandez M,Cox KL,Tipton T,Reynolds M,Murphy S,Lemm E,Dias S,Duncombe A,Strefford JC,Johnson PW,Forconi F,Stevenson FK,Packham G,Cragg MS,Steele AJdoi
10.1182/blood-2014-11-610329subject
Has Abstractpub_date
2015-06-25 00:00:00pages
4032-41issue
26eissn
0006-4971issn
1528-0020pii
blood-2014-11-610329journal_volume
125pub_type
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