The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models

Foster, Paul; Yamaguchi, Kyoko; Hsu, Pin Pin; Qian, Fawn; Du, Xiangnan; Wu, Jianming; Won, Kwang‐Ai; Yu, Peiwen; Jaeger, Christopher T.; Zhang, Wentao; Marlowe, Charles K.; Keast, Paul; Abulafia, Wendy; Chen, Jason; Young, Jenny; Płonowski, Artur; Yakes, F. Michael; Chu, Felix; Engell, Kelly; Bentzien, Frauke; Lam, Sanh Tan; Dale, Stephanie; Yturralde, Olivia; Matthews, David J.; Lamb, Peter; Laird, A. Douglas

doi:10.1158/1535-7163.mct-14-0833

Cited by 46 publications

(36 citation statements)

References 27 publications

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“…Furthermore, 50 mg/kg WX-037 generated a tumour growth delay in HCT116 colorectal tumour xenograft models, which is consistent with previous unpublished studies using WX-037 and published studies using other pan class I PI3K inhibitors that reported tumour growth delay, or in some cases tumour stasis, with greater sensitivity in PIK3CA mutant or PTEN null cells and tumours [5, 14, 15, 46–51]. Pharmacokinetic studies indicated that concentrations of WX-037 in plasma and tumour tissue increased dose dependently and that WX-037 tumour and plasma levels generally exceeded the in vitro GI 50 concentration at an early time point (6 h), depending on the cell line and dose, whereas levels generally had decreased below the GI 50 value by the later time point (24 h).…”

Section: Discussionsupporting

confidence: 89%

Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Haagensen

Thomas

Schmalix

et al. 2016

Cancer Chemother Pharmacol

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PurposeTumours frequently have defects in multiple oncogenic pathways, e.g. MAPK and PI3K signalling pathways, and combinations of targeted therapies may be required for optimal activity. This study evaluated the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037, as single agents and in combination, in colorectal carcinoma cell lines and tumour xenograft-bearing mice.MethodsIn vitro growth inhibition, survival and signal transduction were measured using the Sulforhodamine B, clonogenic and Western blotting assays, respectively, in HCT116 and HT29 cell lines. In vivo anti-tumour efficacy and pharmacokinetic properties were assessed in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice.ResultsThe combination of WX-554 and WX-037 exhibited marked synergistic growth inhibition in vitro, which was associated with increased cytotoxicity and enhanced inhibition of ERK and S6 phosphorylation, compared to either agent alone. Pharmacokinetic analyses indicated that there was no PK interaction between the two drugs at low doses, but that at higher doses, WX-037 may delay the tumour uptake of WX-554. In vivo efficacy studies revealed that the combination of WX-037 and WX-554 was non-toxic and exhibited marked tumour growth inhibition greater than observed with either agent alone.ConclusionThese studies show for the first time that combination treatment with the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 can induce synergistic growth inhibition in vitro, which translates into enhanced anti-tumour efficacy in vivo.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3186-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Haagensen

Thomas

Schmalix

et al. 2016

Cancer Chemother Pharmacol

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“…Pilaralisib (XL147, SAR245408) is an orally bioavailable and reversible pan-class I A PI3K inhibitor against p110α/δ/γ with IC 50 of approximate 30 nM, but less potent upon p110β [43]. Apart from GBM, it exhibits dose-dependent anti-proliferative effects on breast cancer cells through inhibition on PI3K and Akt activation [44].…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

et al. 2017

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients’ prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

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“…36), which has shown activity in preclinical tumor models and in patients with solid tumors (36)(37)(38). In the phase I safety, pharmacokinetic (PK) and pharmacodynamic study in patients with solid tumors, the maximum tolerated dose (MTD) and recommended phase II dose of the pilaralisib capsule formation was 600 mg administered orally with continuous once-daily dosing (37).…”

Section: Introductionmentioning

confidence: 99%

Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma

Brown

Davids

Rodón

et al. 2015

Clinical Cancer Research

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Purpose: This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma. Patients and Methods: Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed. Results: Twenty-five patients were included in the study: 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%), and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%), and anemia (16.0%). Pilaralisib exposure on cycle 1 day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and 3 patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥50%. Overall, 14 patients (56.0%; 7 patients with CLL and 7 patients with lymphoma) had progression-free survival ≥6 months. Conclusions: Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development. Clin Cancer Res; 21(14); 3160–9. ©2015 AACR.

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The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models

Cited by 46 publications

References 27 publications

Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma

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