Figure 3: Targeting the PI3K inhibitor induced glucose/insulin feedback in vivo.

(A) Mean Blood glucose levels with standard deviation over time of wildtype c57/bl6 mice baring syngeneic K8484 KPC allografted tumors after treatment with a single dose of BKM120 in mice pretreated with metformin, SGLT2-inhibitor (SGLT2i), or a ketogenic diet (N = 5 mice). p-values calculated by Two-way repeated measures ANOVA for metformin, SGLT2i, and the ketogenic diet were 0.2136 (not significant), <0.0001, and 0.007 respectively. (B) Mean Blood levels of c-peptide with standard deviation of the same mice (N=5) taken 180 minutes after treatment with BKM120. p-values calculated by unpaired two sided t-test for metformin, SGLT2i, and ketogenic diet were 0.7566 (not significant), 0.0386, and 0.0117 respectively. (C) Immunohistochemical images for pS6 (ser-235) to observe the level of active PI3K signaling in these tumors. (D) Quantification of this staining is shown as mean number of positive cells per high power field with standard deviation (N = 5 mice/group). p-values comparing pS6 positive cells in BKM120 alone treated tumors as compared to those treated with BKM120 in combination with metformin, SGLT2i, or the ketogenic diet using two sided t-tests were 0.6186, <0.0001, and <0.0001 respectively. (E) IVIS images of luciferase reporter luminescence in mice with KPC K8484 tumors after 12 days of treatment with PI3Kα specific inhibitor BYL-719 alone or in combination with metformin, ketogenic diet, or SGLT2i (N=10 tumors/arm). (F) Mean values and standard deviation of quantification of luminescence from images in of these tumors. (G) Survival analysis of these animals, p-value = 0.0019 and 0.0001 respectively as determined by Log-rank (Mantel-Cox) test.