Figure 4: Impact of circumventing the on target glucose/insulin feedback of PI3K inhibitors upon tumor growth.

(A) Graph of mean tumor volumes with standard deviation of K8484 KPC with doxycycline inducible hairpins targeting Renilla (ShRenilla) or Insulin Receptor (ShIR), treated with doxycycline and as indicated with the PI3K inhibitor BYL-719 and/or co-administration of a ketogenic diet (N=8, 9, 8, 10, for shRenilla tumors treated with vehicle, BYL719, Ketogenic diet, and BYL + Ketogenic diet respectively, and N= 8,8,10,8 for shIR tumors treated with vehicle, BYL719, Ketogenic diet, and BYL + Ketogenic diet respectively. (B) Graph of mean ES272 Pik3ca mutant breast cancer allograft tumor volumes with standard deviation treated with BYL-719 and/or insulin along with the ketogenic (keto) as indicated. N=3,3,5,5,5,3,4,4 for Vehicle, Insuln, BYL, BYL+Insulin, Ketogeinic Diet, Ketogenic+Insulin, Ketogenic+BYL, and Ketogenic+BYL+Insulin respectively. (C) Graph of mean tumor volume with standard deviation of patient derived endometrial xenografts (PDX) treated with BKM120 and/or a ketogenic diet (N=5/arm, (p-value = 0.0028 by ANOVA comparison between the BKM120 alone and BKM120 plus ketogenic diet treated mice). (D-E) Histology and quantification of phospho-Insulin Receptor (pINSR), phospho-AKT (pAKT), phospho-S6 (pS6), cleaved caspase 3 (Cl. Casp 3), and ki67 of the tumors from D taken 4 hours after the last treatment with Vehicle, ketogenic diet, BKM120, or the combination of the ketogenic diet with BKM120 (BKM120/Keto). Quantification is depicted as score per high powered field, 4 images were taken for each of the five mice N=5. p-values from two sided t-tests comparing the blinded scoring in BKM120 treated tumors as compared to those treated with BKM120 with the ketogenic diet were 0.005, 0.005, 0.017 and 0.028 and for pINSR, pAKT, pS6 and Cl. Casp 3 respectively.