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

Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer

(2016) Qing-Bai She et al.   BMC CANCER

Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946)

(2016) William J. Scott et al.   ChemMedChem

A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma

(2016) Daniel W. Bowles et al.   Clinical Colorectal Cancer

Antimetastatic Properties of Low Molecular Weight Heparin

(2016) Heinz Läubli et al.   JOURNAL OF CLINICAL ONCOLOGY

PI3K p110β isoform synergizes with JNK in the regulation of glioblastoma cell proliferation and migration through Akt and FAK inhibition

(2016) Hua-Fu Zhao et al.   JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH

Treatment with the PI3K inhibitor buparlisib (NVP-BKM120) suppresses the growth of established patient-derived GBM xenografts and prolongs survival in nude rats

(2016) I. A. Netland et al.   JOURNAL OF NEURO-ONCOLOGY

Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR

(2016) Timothy P. Heffron et al.   ACS Medicinal Chemistry Letters

NVP-BEZ235, a novel dual PI3K–mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells

(2015) Zhiyun Yu et al.   CANCER LETTERS

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

(2015) J. R. Brown et al.   CLINICAL CANCER RESEARCH

Taselisib (GDC-0032), a Potent  -Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations

(2015) Z. S. Zumsteg et al.   CLINICAL CANCER RESEARCH

FDA Approval: Idelalisib Monotherapy for the Treatment of Patients with Follicular Lymphoma and Small Lymphocytic Lymphoma

(2015) B. W. Miller et al.   CLINICAL CANCER RESEARCH

Overcoming the blood–brain tumor barrier for effective glioblastoma treatment

(2015) O. van Tellingen et al.   DRUG RESISTANCE UPDATES

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma

(2015) Ursula Matulonis et al.   GYNECOLOGIC ONCOLOGY

A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors

(2015) Johanna C. Bendell et al.   INVESTIGATIONAL NEW DRUGS

The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL

(2015) K Balakrishnan et al.   LEUKEMIA

Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations

(2015) M. A. Bonelli et al.   MOLECULAR CANCER THERAPEUTICS

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

(2015) P. Foster et al.   MOLECULAR CANCER THERAPEUTICS

Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma

(2015) Patrick Y. Wen et al.   NEURO-ONCOLOGY

Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147), a Pan-Class I PI3K Inhibitor, in Combination With Erlotinib in Patients With Solid Tumors

(2015) J.-C. Soria et al.   ONCOLOGIST

PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer

(2015) Ana Bosch et al.   Science Translational Medicine

Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells

(2015) Genevieve L. Weber et al.   Oncotarget

A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

(2014) A. Jimeno et al.   ANNALS OF ONCOLOGY

Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer

(2014) Sara Tolaney et al.   BREAST CANCER RESEARCH AND TREATMENT

A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib

(2014) N. Elster et al.   BREAST CANCER RESEARCH AND TREATMENT

Multiple lesions in receptor tyrosine kinase pathway determine glioblastoma response to pan-ERBB inhibitor PF-00299804 and PI3K/mTOR dual inhibitor PF-05212384

(2014) Yanni Zhu et al.   CANCER BIOLOGY & THERAPY

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors

(2014) K. P. Papadopoulos et al.   CLINICAL CANCER RESEARCH

Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy

(2014) C. Saura et al.   CLINICAL CANCER RESEARCH

A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors

(2014) P. L. Bedard et al.   CLINICAL CANCER RESEARCH

A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors

(2014) R. El Meskini et al.   Disease Models & Mechanisms

Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo

(2014) Salvatore Lopez et al.   GYNECOLOGIC ONCOLOGY

RIST: A potent new combination therapy for glioblastoma

(2014) Lisa Nonnenmacher et al.   INTERNATIONAL JOURNAL OF CANCER

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

(2014) Timothy D. Cushing et al.   JOURNAL OF MEDICINAL CHEMISTRY

In vivo and ex vivo assessment of the blood brain barrier integrity in different glioblastoma animal models

(2014) Cindy Leten et al.   JOURNAL OF NEURO-ONCOLOGY

A Randomized, Phase 2 Trial of Docetaxel with or without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Relapsed or Metastatic Non–Small-Cell Lung Cancer

(2014) Benjamin Levy et al.   Journal of Thoracic Oncology

Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study

(2014) David Neal Franz et al.   LANCET ONCOLOGY

PI3K and Bcl-2 Inhibition Primes Glioblastoma Cells to Apoptosis through Downregulation of Mcl-1 and Phospho-BAD

(2014) Fresia Pareja et al.   MOLECULAR CANCER RESEARCH

Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K Pathway

(2014) P. Yu et al.   MOLECULAR CANCER THERAPEUTICS

Characterization of the Novel and Specific PI3K  Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

(2014) C. Fritsch et al.   MOLECULAR CANCER THERAPEUTICS

Targeting Class IA PI3K Isoforms Selectively Impairs Cell Growth, Survival, and Migration in Glioblastoma

(2014) Katrin Höland et al.   PLoS One

Radiosensitization of Glioblastoma Cell Lines by the Dual PI3K and mTOR Inhibitor NVP-BEZ235 Depends on Drug-Irradiation Schedule

(2014) Sebastian Kuger et al.   Translational Oncology

Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion

(2013) Yan Xie et al.   BIOCHEMICAL PHARMACOLOGY

Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation

(2013) Pascal Furet et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours

(2013) D W Bowles et al.   BRITISH JOURNAL OF CANCER

PTEN Loss Mitigates the Response of Medulloblastoma to Hedgehog Pathway Inhibition

(2013) C. Metcalfe et al.   CANCER RESEARCH

Conditional Loss of ErbB3 Delays Mammary Gland Hyperplasia Induced by Mutant PIK3CA without Affecting Mammary Tumor Latency, Gene Expression, or Signaling

(2013) Christian D. Young et al.   CANCER RESEARCH

The Somatic Genomic Landscape of Glioblastoma

(2013) Cameron W. Brennan et al.   CELL

Inhibition of DNA Double-Strand Break Repair by the Dual PI3K/mTOR Inhibitor NVP-BEZ235 as a Strategy for Radiosensitization of Glioblastoma

(2013) Carlos Rodrigo Gil del Alcazar et al.   CLINICAL CANCER RESEARCH

Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474)

(2013) Gordon W. Rewcastle et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

The novel phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor, BEZ235, circumvents erlotinib resistance ofepidermal growth factor receptormutant lung cancer cells triggered by hepatocyte growth factor

(2013) Takako Sano et al.   INTERNATIONAL JOURNAL OF CANCER

Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

(2013) Chudi O. Ndubaku et al.   JOURNAL OF MEDICINAL CHEMISTRY

BAY 80-6946 Is a Highly Selective Intravenous PI3K Inhibitor with Potent p110α and p110δ Activities in Tumor Cell Lines and Xenograft Models

(2013) Ningshu Liu et al.   MOLECULAR CANCER THERAPEUTICS

Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities

(2013) Mariella Gruber Filbin et al.   NATURE MEDICINE

Development of PI3K inhibitors: lessons learned from early clinical trials

(2013) Jordi Rodon et al.   Nature Reviews Clinical Oncology

Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors

(2012) B. Markman et al.   ANNALS OF ONCOLOGY

GDC-0941 enhances the lysosomal compartment via TFEB and primes glioblastoma cells to lysosomal membrane permeabilization and cell death

(2012) Stefanie Enzenmüller et al.   CANCER LETTERS

Trastuzumab-Resistant Cells Rely on a HER2-PI3K-FoxO-Survivin Axis and Are Sensitive to PI3K Inhibitors

(2012) A. Chakrabarty et al.   CANCER RESEARCH

Hedgehog Signaling Is a Novel Therapeutic Target in Tamoxifen-Resistant Breast Cancer Aberrantly Activated by PI3K/AKT Pathway

(2012) B. Ramaswamy et al.   CANCER RESEARCH

Molecular Pathways: Targeting Phosphoinositide 3-Kinase p110-Delta in Chronic Lymphocytic Leukemia

(2012) S. E. M. Herman et al.   CLINICAL CANCER RESEARCH

A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

(2012) D. S. Hong et al.   CLINICAL CANCER RESEARCH

The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer

(2012) T. Shimizu et al.   CLINICAL CANCER RESEARCH

High levels of p110δ PI3K expression in solid tumor cells suppress PTEN activity, generating cellular sensitivity to p110δ inhibitors through PTEN activation

(2012) Niki Tzenaki et al.   FASEB JOURNAL

The p110  and p110  isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

(2012) T. Utermark et al.   GENES & DEVELOPMENT

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function

(2012) Lomon So et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

(2012) Mark H. Norman et al.   JOURNAL OF MEDICINAL CHEMISTRY

Human target validation of phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor

(2012) S. NYLANDER et al.   JOURNAL OF THROMBOSIS AND HAEMOSTASIS

VS-5584, a Novel and Highly Selective PI3K/mTOR Kinase Inhibitor for the Treatment of Cancer

(2012) S. Hart et al.   MOLECULAR CANCER THERAPEUTICS

CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2005-2009

(2012) T. A. Dolecek et al.   NEURO-ONCOLOGY

A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types

(2011) Stephen Jamieson et al.   BIOCHEMICAL JOURNAL

Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799

(2011) Jun Ohwada et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Studies on the Expression Patterns of Class I PI3K Catalytic Subunits and Its Prognostic Significance in Colorectal Cancer

(2011) Binbin Cui et al.   CELL BIOCHEMISTRY AND BIOPHYSICS

Antitumor Activity of NVP-BKM120--A Selective Pan Class I PI3 Kinase Inhibitor Showed Differential Forms of Cell Death Based on p53 Status of Glioma Cells

(2011) D. Koul et al.   CLINICAL CANCER RESEARCH

The catalytic phosphoinositol 3-kinase isoform p110δ is required for glioma cell migration and invasion

(2011) Sze Ki Luk et al.   EUROPEAN JOURNAL OF CANCER

Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor (GDC-0980) for the Treatment of Cancer

(2011) Daniel P. Sutherlin et al.   JOURNAL OF MEDICINAL CHEMISTRY

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110  Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

(2011) A. S. Guerreiro et al.   MOLECULAR CANCER RESEARCH

PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity

(2011) J. Yuan et al.   MOLECULAR CANCER THERAPEUTICS

Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway–dependent and PI3K pathway–independent mechanisms

(2011) Pixu Liu et al.   NATURE MEDICINE

Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide

(2011) G. Prasad et al.   NEURO-ONCOLOGY

PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma

(2011) J R Molina et al.   ONCOGENE

The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Induces Tumor Regression in a Genetically Engineered Mouse Model of PIK3CA Wild-Type Colorectal Cancer

(2011) Jatin Roper et al.   PLoS One

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

(2011) A. Chakrabarty et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer

(2011) Matthew T. Burger et al.   ACS Medicinal Chemistry Letters

CAL-101, a p110  selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability

(2010) B. J. Lannutti et al.   BLOOD

Cross-signaling among phosphinositide-3 kinase, mitogen-activated protein kinase and sonic hedgehog pathways exists in esophageal cancer

(2010) Lingyun Wei et al.   INTERNATIONAL JOURNAL OF CANCER

Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma

(2010) Ho-Shin Gwak et al.   INTERNATIONAL JOURNAL OF CANCER

Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound26(PKI-587), a Highly Efficacious Dual Inhibitor

(2010) Aranapakam M. Venkatesan et al.   JOURNAL OF MEDICINAL CHEMISTRY

PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts

(2010) Hongbo Chen et al.   JOURNAL OF NEURO-ONCOLOGY

Antitumor Efficacy Profile of PKI-402, a Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor

(2010) Robert Mallon et al.   MOLECULAR CANCER THERAPEUTICS

Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma

(2010) D. Koul et al.   NEURO-ONCOLOGY

Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells

(2010) Jun Sunayama et al.   NEURO-ONCOLOGY

FDA Approval Summary: Temsirolimus as Treatment for Advanced Renal Cell Carcinoma

(2010) V. E. Kwitkowski et al.   ONCOLOGIST

Crosstalk Between the PI3K/mTOR and MEK/ERK Pathways Involved in the Maintenance of Self-Renewal and Tumorigenicity of Glioblastoma Stem-Like Cells

(2010) Jun Sunayama et al.   STEM CELLS

PIKing the right isoform: the emergent role of the p110β subunit in breast cancer

(2010) Silvia Carvalho et al.   VIRCHOWS ARCHIV

Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin

(2010) Steven D. Knight et al.   ACS Medicinal Chemistry Letters

PI3Kγ activation by CXCL12 regulates tumor cell adhesion and invasion

(2009) María Monterrubio et al.   BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Peroxisome proliferator-activated receptor   agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity

(2009) N. T. Ihle et al.   MOLECULAR CANCER THERAPEUTICS

Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941

(2009) F. I. Raynaud et al.   MOLECULAR CANCER THERAPEUTICS

Mutations in the Phosphatidylinositol-3-Kinase Pathway Predict for Antitumor Activity of the Inhibitor PX-866 whereas Oncogenic Ras Is a Dominant Predictor for Resistance

(2008) N. T. Ihle et al.   CANCER RESEARCH

Targeting the Phosphoinositide 3-Kinase Isoform p110  Impairs Growth and Survival in Neuroblastoma Cells

(2008) D. Boller et al.   CLINICAL CANCER RESEARCH

Targeting the PI3K p110  Isoform Inhibits Medulloblastoma Proliferation, Chemoresistance, and Migration

(2008) A. S. Guerreiro et al.   CLINICAL CANCER RESEARCH

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

(2008) Michael G. Kharas et al.   JOURNAL OF CLINICAL INVESTIGATION

The Identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer†

(2008) Adrian J. Folkes et al.   JOURNAL OF MEDICINAL CHEMISTRY

Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

(2008) S.-M. Maira et al.   MOLECULAR CANCER THERAPEUTICS

Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

(2008) Jeffrey A Engelman et al.   NATURE MEDICINE

PTEN-deficient cancers depend on PIK3CB

(2008) S. Wee et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA