Targeting Class I PI3Ks in the Treatment of T-cell Acute Lymphoblastic Leukemia
Final rept. 1 Aug 2010-31 Jul 2013
COLUMBIA UNIV NEW YORK
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This research project aims to evaluate the antileukemic activity of inhibiting the PI3K pathway in T-cell acute lymphoblastic leukemia T-ALL using genetic models and pharmacologic approaches. In this project we have established a broad panel of primary T-ALL cultures and primary xenograft models of human T-ALL as experimental therapeutic platform Aim 3 Task1. In in vitro evaluation of the activity of the CAL130 inhibitor in primary T-ALL cells demonstrated significant antileukemic effects of this drug Aim 3, Task 2. We have performed an initial evaluation of the efficacy of CAL130 treatment in T-ALL cells xenografted in immunodeficient mice Aim 3, task 3 and analysis of the impact of PTEN and NOTCH mutations in CAL130 response Aim 3 Task 6. Finally we have established a synergistic effect between the inhibition of the PI3K-AKT pathway and glucocorticoid therapy in vitro Aim 3 Task 4and in vivo Aim 3 Task 5. Overall these results highlight the role of the PI3K pathway as therapeutic target for the treatment of T-ALL and warrant the clinical testing of PI3K inhibitors alone and in combination with glucocorticoids in the clinic.
- Medicine and Medical Research