Abstract 4249: The Pi3Kβ/δ inhibitor AZD8186 has potential to treat tumours in combination with key signalling pathway inhibitors

Abstract

AZD8186 inhibits Pi3K isoforms Pi3Kβ and δ, with selectivity over Pi3Kα and γ. In solid tumours Pi3Kβ drives tumour growth when the tumour suppressor PTEN is deleted, mutated or downregulated. It also mediates signals from specific GPCR receptors. Pi3Kδ signals downstream of the B-cell receptor, creating potential for targeted treatment of haematological malignancies such as CLL, MCL & indolent NHL and possibly DLBCL. AZD8186 is differentiated from many other agents that target Pi3K family members as it isn't likely to impact glucose control. AZD8186 has single agent activity in a range of models, although maximal benefit is anticipated when used in combination. Loss of PTEN mediated control, and hence dependency on PI3Kβ occurs in many solid tumour types, and is altered in up to 40-50% of tumours in some individual disease states. Commonly PTEN dysregulation is associated with other activation of other signaling pathways. To explore this we have combined AZD8186 with a number of different agents. In HCC70 (triple negative breast cancer) and PC3 (prostate cancer) xenografts combination of AZD8186 (25mg/kg bid) with single dose docetaxel (15mg/kg) gives >90% tumour growth inhibition (TGI), compared to 40-50% with docetaxel alone. AZD8186 also combines with other targeted agents. In HCC70, AZD8186 (25mg/kg bid) combined with selumetinib (10mg/kg) gave 94% TGI compared to 66%, and 47% with each single agent. In combination with AZD2014 (mTORC1/2 inhibitor) (15mg/kg qd) in HCC70 xenografts AZD8186 (25mg/kg bid) gave regressions (-23%) compared to TGI of 87% and 77% for each agent alone. In 786-0 (renal cancer) xenografts AZD8186 (12.5mg/kg bid) and AZD2014 (15mg/kg qd) gave regression of -82% compared to TGI of 33% and regression of -39% with each agent alone. This data establishes the potential for AZD8186 to be used in combination with a number of different agents including the ability to customise dose and schedule to optimise both tolerability as well as anti-tumour effects. Further exploration of the combination opportunities for AZD8186 with other molecular targeted agents would inform on the potential for inhibitors of Pi3Kβ and δ to give benefit in different tumour types. Citation Format: Simon T. Barry, Kathryn Cronin, Marie Cumberbatch, Rebecca Ellston, Emily Foster, Urs Hancox, Lyndsey Hanson, Liz Harrington, Carol Lenaghan, Stefan Symeonides, Cath Trigwell, Lara Ward. The Pi3Kβ/δ inhibitor AZD8186 has potential to treat tumours in combination with key signalling pathway inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4249. doi:10.1158/1538-7445.AM2014-4249

Concomitant Inhibition of PI3Kβ and BRAF or MEK in PTEN-Deficient/BRAF-Mutant Melanoma Treatment: Preclinical Assessment of SAR260301 Oral PI3Kβ-Selective Inhibitor

“…In addition to SAR260301, other selective PI3Kb inhibitors in clinical development include GSK2636771, which is being examined in phase I/IIa trials as monotherapy for PTEN-deficient solid tumors (NCT01458067) and combined with enzalutamide for castration-resistant prostate cancer (CRPC; NCT02215096; ref. 49), and AZD8186 PI3Kb/d inhibitor in phase I (NCT01884285), which has shown inhibitory activity against PTEN-deficient tumor cells and preclinical antitumor potential in combination with signaling pathway inhibitors (49,50). Interestingly, phase I data showed that GSK2636771 is well tolerated with manageable DLTs (hypophosphatemia and hypomagnesemia), and has preliminary single-agent activity in a PTEN-deficient tumor (PR observed in a patient with PTEN-deficient CRPC).…”

“…S1). In these studies, SAR260301 inhibited PI3Kb with a potency 26-fold higher than PI3Kd (IC 50 32 vs. 823 nmol/L), showed lower potency against PI3Ka (IC 50 2,825 nmol/L) and no inhibitory activity against PI3Kg or VPS34 ( 30% inhibition at 3 or 10 mmol/L). In conclusion, SAR260301 is a PI3Kb-selective inhibitor in cellular setting, inhibiting PI3Kb 26-fold, 88-fold, >94-fold, and >313-fold more potently than PI3Kd, PI3Ka, PI3Kg, and VPS34, respectively.…”

“…The combination rays correspond to SAR26030:vemurafenib or SAR260301:selumetinib ratio of 1:3, 1:1, 3:1 and 9:1, estimated based on effective fractions. These fractions were based on IC 40 calculations because SAR260301 single agent being poorly active, IC 40 values were better estimated than IC 50 . The combination index (Ki), based on the Loewe additivity equation, was determined for each ray.…”