BACKGROUND: Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. However, less is known regarding the relevance of this pathway in pediatric cancers. Here we have evaluated SAR245408, a novel small molecule PI3K inhibitor, against childhood cancer cell lines and xenografts. PROCEDURES: SAR245408 was tested against the PPTP in vitro cell line panel at concentrations from 10 to 100 µM and against the PPTP in vivo xenograft panels at a dose of 100 mg/kg administered orally daily × 14. RESULTS: In vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 µM (range 2.7-24.5 µM). SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for two of seven (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts. CONCLUSIONS: Under the conditions evaluated in this study, SAR245408 achieved modest single-agent activity against most PPTP preclinical models. Further exploration of SAR245408 in combination with standard agents or with other signaling inhibitors could be considered.
BACKGROUND: Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. However, less is known regarding the relevance of this pathway in pediatric cancers. Here we have evaluated SAR245408, a novel small molecule PI3K inhibitor, against childhood cancer cell lines and xenografts. PROCEDURES: SAR245408 was tested against the PPTP in vitro cell line panel at concentrations from 10 to 100 µM and against the PPTP in vivo xenograft panels at a dose of 100 mg/kg administered orally daily × 14. RESULTS: In vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 µM (range 2.7-24.5 µM). SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for two of seven (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts. CONCLUSIONS: Under the conditions evaluated in this study, SAR245408 achieved modest single-agent activity against most PPTP preclinical models. Further exploration of SAR245408 in combination with standard agents or with other signaling inhibitors could be considered.
Authors: Jinghui Zhang; Charles G Mullighan; Richard C Harvey; Gang Wu; Xiang Chen; Michael Edmonson; Kenneth H Buetow; William L Carroll; I-Ming Chen; Meenakshi Devidas; Daniela S Gerhard; Mignon L Loh; Gregory H Reaman; Mary V Relling; Bruce M Camitta; W Paul Bowman; Malcolm A Smith; Cheryl L Willman; James R Downing; Stephen P Hunger Journal: Blood Date: 2011-06-16 Impact factor: 22.113
Authors: Silvia Buonamici; Juliet Williams; Michael Morrissey; Anlai Wang; Ribo Guo; Anthony Vattay; Kathy Hsiao; Jing Yuan; John Green; Beatriz Ospina; Qunyan Yu; Lance Ostrom; Paul Fordjour; Dustin L Anderson; John E Monahan; Joseph F Kelleher; Stefan Peukert; Shifeng Pan; Xu Wu; Sauveur-Michel Maira; Carlos García-Echeverría; Kimberly J Briggs; D Neil Watkins; Yung-mae Yao; Christoph Lengauer; Markus Warmuth; William R Sellers; Marion Dorsch Journal: Sci Transl Med Date: 2010-09-29 Impact factor: 17.956
Authors: B Vanhaesebroeck; M J Welham; K Kotani; R Stein; P H Warne; M J Zvelebil; K Higashi; S Volinia; J Downward; M D Waterfield Journal: Proc Natl Acad Sci U S A Date: 1997-04-29 Impact factor: 11.205
Authors: Peter J Houghton; Christopher L Morton; Richard Gorlick; Richard B Lock; Hernan Carol; C Patrick Reynolds; Min H Kang; John M Maris; Stephen T Keir; E Anders Kolb; Jianrong Wu; Amy W Wozniak; Catherine A Billups; Larry Rubinstein; Malcolm A Smith Journal: Mol Cancer Ther Date: 2010-01-06 Impact factor: 6.261
Authors: Ana S Guerreiro; Sarah Fattet; Barbara Fischer; Tarek Shalaby; Shaun P Jackson; Simone M Schoenwaelder; Michael A Grotzer; Olivier Delattre; Alexandre Arcaro Journal: Clin Cancer Res Date: 2008-11-01 Impact factor: 12.531
Authors: Min H Kang; C Patrick Reynolds; John M Maris; Richard Gorlick; E Anders Kolb; Richard Lock; Hernan Carol; Stephen T Keir; Jianrong Wu; Dmitry Lyalin; Raushan T Kurmasheva; Peter J Houghton; Malcolm A Smith Journal: Pediatr Blood Cancer Date: 2014-02-20 Impact factor: 3.838
Authors: Jennifer L Anderson; Ann Park; Ryan Akiyama; William D Tap; Christopher T Denny; Noah Federman Journal: PLoS One Date: 2015-09-24 Impact factor: 3.240
Authors: Federica Saletta; Carol Wadham; David S Ziegler; Glenn M Marshall; Michelle Haber; Geoffrey McCowage; Murray D Norris; Jennifer A Byrne Journal: BBA Clin Date: 2014-06-28
Authors: Dominik Bogen; Jun S Wei; David O Azorsa; Pinar Ormanoglu; Eugen Buehler; Rajarshi Guha; Jonathan M Keller; Lesley A Mathews Griner; Marc Ferrer; Young K Song; Hongling Liao; Arnulfo Mendoza; Berkley E Gryder; Sivasish Sindri; Jianbin He; Xinyu Wen; Shile Zhang; John F Shern; Marielle E Yohe; Sabine Taschner-Mandl; Jason M Shohet; Craig J Thomas; Scott E Martin; Peter F Ambros; Javed Khan Journal: Oncotarget Date: 2015-11-03