Development of PI3K inhibitors: lessons learned from early clinical trials

First-in-human phase I study exploring three schedules of OSI-027, a novel small molecule TORC1/TORC2 inhibitor, in patients with advanced solid tumors and lymphoma.

(2017) D. S. Tan et al.   JOURNAL OF CLINICAL ONCOLOGY

A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies.

(2017) I. Brana et al.   JOURNAL OF CLINICAL ONCOLOGY

Final results from a phase I, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase.

(2017) A. Jimeno et al.   JOURNAL OF CLINICAL ONCOLOGY

First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors.

(2017) H. Burris et al.   JOURNAL OF CLINICAL ONCOLOGY

A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies.

(2017) G. Edelman et al.   JOURNAL OF CLINICAL ONCOLOGY

Interim results from a phase I study of CAL-101, a selective oral inhibitor of phosphatidylinositol 3-kinase p110d isoform, in patients with relapsed or refractory hematologic malignancies.

(2017) R. R. Furman et al.   JOURNAL OF CLINICAL ONCOLOGY

First results from a phase I trial of AZD8055, a dual mTORC1 and mTORC2 inhibitor.

(2017) U. Banerji et al.   JOURNAL OF CLINICAL ONCOLOGY

First-in-human phase I study evaluating the safety, pharmacokinetics (PK), and intratumor pharmacodynamics (PD) of the novel, oral, ATP-competitive Akt inhibitor GDC-0068.

(2017) J. Tabernero et al.   JOURNAL OF CLINICAL ONCOLOGY

A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma.

(2017) V. Moreno Garcia et al.   JOURNAL OF CLINICAL ONCOLOGY

A first-in-human phase I study to evaluate GDC-0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced solid tumors.

(2017) A. J. Wagner et al.   JOURNAL OF CLINICAL ONCOLOGY

A phase I study of the AKT inhibitor (MK-2206) with concurrent trastuzumab and lapatinib in patients with HER2-positive solid tumors.

(2017) H. S. Han et al.   JOURNAL OF CLINICAL ONCOLOGY

A first-in-human phase I study of intravenous PI3K inhibitor BAY 80-6946 in patients with advanced solid tumors: Results of dose-escalation phase.

(2017) A. Patnaik et al.   JOURNAL OF CLINICAL ONCOLOGY

Pharmacokinetic (PK)/pharmacodynamic (PD) analysis of escalating repeat doses of the AKT inhibitor GSK2141795 (GSK795) in patients (pts) with ovarian cancer.

(2017) H. Gungor et al.   JOURNAL OF CLINICAL ONCOLOGY

CD133 status influences in prognosis of patients with metastatic colorectal cancer receiving cetuximab.

(2017) Dai Inoue et al.   JOURNAL OF CLINICAL ONCOLOGY

Association of peripheral blood guanylyl cyclase C (GCC) expressions with prognostic parameters and response to therapy in patients with colorectal cancer.

(2017) Celalettin Camci et al.   JOURNAL OF CLINICAL ONCOLOGY

A pilot study of pharmacokinetically guided dose management of capecitabine in CRC patients.

(2017) Katsuya Makihara et al.   JOURNAL OF CLINICAL ONCOLOGY

INPP4B: the New Kid on the PI3K Block

(2015) Irina U. Agoulnik et al.   Oncotarget

Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment

(2012) Irene Brana et al.   BMC Medicine

Abstract CT-02: A phase I, open label, dose escalation study of oral mammalian target of rapamycin inhibitor INK128 administered by intermittent dosing regimens in patients with advanced malignancies

(2012) Josep Tabernero et al.   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

GDC-0941, a Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death In Vitro and In Vivo

(2012) J. J. Wallin et al.   CLINICAL CANCER RESEARCH

Detection of Tumor PIK3CA Status in Metastatic Breast Cancer Using Peripheral Blood

(2012) M. J. Higgins et al.   CLINICAL CANCER RESEARCH

DNA Methylation As a Clinical Marker in Oncology

(2012) Jean-Pierre Issa   JOURNAL OF CLINICAL ONCOLOGY

Tumor Genetic Testing for Patient Selection in Phase I Clinical Trials: The Case of PI3K Inhibitors

(2012) Dejan Juric et al.   JOURNAL OF CLINICAL ONCOLOGY

Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study

(2012) Eric Van Cutsem et al.   JOURNAL OF CLINICAL ONCOLOGY

Management of Metabolic Effects Associated With Anticancer Agents Targeting the PI3K-Akt-mTOR Pathway

(2012) Naifa L. Busaidy et al.   JOURNAL OF CLINICAL ONCOLOGY

Abstract B154: A first-in-human trial of GDC-0068: A novel, oral, ATP-competitive Akt inhibitor, demonstrates robust suppression of the Akt pathway in surrogate and tumor tissues.

(2012) Y. Yan et al.   MOLECULAR CANCER THERAPEUTICS

Sequence analysis of mutations and translocations across breast cancer subtypes

(2012) Shantanu Banerji et al.   NATURE

Comprehensive molecular characterization of human colon and rectal cancer

(2012)   NATURE

β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer

(2012) Stephan P Tenbaum et al.   NATURE MEDICINE

Molecular prescreening to select patient population in early clinical trials

(2012) Jordi Rodón et al.   Nature Reviews Clinical Oncology

Dissecting “PI3Kness”: The Complexity of Personalized Therapy for Ovarian Cancer

(2012) Robert C. Bast et al.   Cancer Discovery

RAF/MEK Dependence of KRAS -Mutant Pancreatic Ductal Adenocarcinomas: Figure 1.

(2012) Aphrothiti J. Hanrahan et al.   Cancer Discovery

AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity

(2011) Sarat Chandarlapaty et al.   CANCER CELL

Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer

(2011) Brett S. Carver et al.   CANCER CELL

Abstract S1-6: TAMRAD: A GINECO Randomized Phase II Trial of Everolimus in Combination with Tamoxifen Versus Tamoxifen Alone in Patients (pts) with Hormone-Receptor Positive, HER2 Negative Metastatic Breast Cancer (MBC) with Prior Exposure to Aromatase Inhibitors (AI).

(2011) T Bachelot et al.   CANCER RESEARCH

18FDG-PET Predicts Pharmacodynamic Response to OSI-906, a Dual IGF-1R/IR Inhibitor, in Preclinical Mouse Models of Lung Cancer

(2011) E. T. McKinley et al.   CLINICAL CANCER RESEARCH

Antitumor Efficacy of PKI-587, a Highly Potent Dual PI3K/mTOR Kinase Inhibitor

(2011) R. Mallon et al.   CLINICAL CANCER RESEARCH

The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer

(2011) Niranjan Awasthi et al.   JOURNAL OF CELLULAR BIOCHEMISTRY

PI3K: A potential therapeutic target for cancer

(2011) Yingwei Chen et al.   JOURNAL OF CELLULAR PHYSIOLOGY

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

(2011) Seth A. Wander et al.   JOURNAL OF CLINICAL INVESTIGATION

Prognostic Validity of a Novel American Joint Committee on Cancer Staging Classification for Pancreatic Neuroendocrine Tumors

(2011) Jonathan R. Strosberg et al.   JOURNAL OF CLINICAL ONCOLOGY

First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors

(2011) Timothy A. Yap et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase II Trial of Cetuximab, Gemcitabine, and Oxaliplatin Followed by Chemoradiation With Cetuximab for Locally Advanced (T4) Pancreatic Adenocarcinoma: Correlation ofSmad4(Dpc4)Immunostaining With Pattern of Disease Progression

(2011) Christopher H. Crane et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase I, Dose-Escalation Study of BKM120, an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors

(2011) Johanna C. Bendell et al.   JOURNAL OF CLINICAL ONCOLOGY

PIK3CA Mutations in Patients with Advanced Cancers Treated with PI3K/AKT/mTOR Axis Inhibitors

(2011) F. Janku et al.   MOLECULAR CANCER THERAPEUTICS

Integrated genomic analyses of ovarian carcinoma

(2011) D. Bell et al.   NATURE

A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer

(2011) Markus K Muellner et al.   Nature Chemical Biology

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

(2011) Pixu Liu et al.   NATURE MEDICINE

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

(2011) Paul B. Chapman et al.   NEW ENGLAND JOURNAL OF MEDICINE

Everolimus for Advanced Pancreatic Neuroendocrine Tumors

(2011) James C. Yao et al.   NEW ENGLAND JOURNAL OF MEDICINE

Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

(2011) José Baselga et al.   NEW ENGLAND JOURNAL OF MEDICINE

PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs

(2011) B Weigelt et al.   ONCOGENE

PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer

(2011) V Serra et al.   ONCOGENE

Toxicity as a Biomarker of Efficacy of Molecular Targeted Therapies: Focus on EGFR and VEGF Inhibiting Anticancer Drugs

(2011) R. Dienstmann et al.   ONCOLOGIST

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

PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis

(2011) N. Ilic et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Genomic Complexity and AKT Dependence in Serous Ovarian Cancer

(2011) Aphrothiti J. Hanrahan et al.   Cancer Discovery

mTOR Kinase Inhibition Causes Feedback-Dependent Biphasic Regulation of AKT Signaling

(2011) V. S. Rodrik-Outmezguine et al.   Cancer Discovery

Phase 3 trial of everolimus for metastatic renal cell carcinoma

(2010) Robert J. Motzer et al.   CANCER

Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors

(2010) K. A. Edgar et al.   CANCER RESEARCH

Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3' Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models

(2010) C. O'Brien et al.   CLINICAL CANCER RESEARCH

The PI3K Pathway As Drug Target in Human Cancer

(2010) Kevin D. Courtney et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive Breast Cancer After Prior HER2-Directed Therapy

(2010) Howard A. Burris et al.   JOURNAL OF CLINICAL ONCOLOGY

Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

(2010) Gideon Bollag et al.   NATURE

AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer

(2009) Krishna M. Vasudevan et al.   CANCER CELL

PIK3CA and PIK3CB Inhibition Produce Synthetic Lethality when Combined with Estrogen Deprivation in Estrogen Receptor-Positive Breast Cancer

(2009) R. J. Crowder et al.   CANCER RESEARCH

Should individual PI3 kinase isoforms be targeted in cancer?

(2009) Shidong Jia et al.   CURRENT OPINION IN CELL BIOLOGY

[18F]Fluorodeoxyglucose Positron Emission Tomography Correlates With Akt Pathway Activity but Is Not Predictive of Clinical Outcome During mTOR Inhibitor Therapy

(2009) Wen Wee Ma et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

(2009) Georg Hess et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor–Positive Breast Cancer

(2009) José Baselga et al.   JOURNAL OF CLINICAL ONCOLOGY

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

(2009) Tony S. Mok et al.   NEW ENGLAND JOURNAL OF MEDICINE

Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer

(2009) M. L. Sos et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells

(2009) Saskia M. Brachmann et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

(2009) M. G. Vander Heiden et al.   SCIENCE

A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition

(2008) Neil E. Torbett et al.   BIOCHEMICAL JOURNAL

89 POSTER Evaluation of peripheral blood cells and hair as surrogate tissues for clinical trial pharmacodynamic assessment of XL147 and XL765, inhibitors of the PI3K signaling pathway

(2008) A.D. Laird et al.   EJC SUPPLEMENTS

PKBα/Akt1 Acts Downstream of DNA-PK in the DNA Double-Strand Break Response and Promotes Survival

(2008) Lana Bozulic et al.   MOLECULAR CELL

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

(2008) Roger McLendon et al.   NATURE

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

Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation

(2008) A. Y. Choo et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity

(2008) J. Tsai et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

PTEN-deficient cancers depend on PIK3CB

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

Helical domain and kinase domain mutations in p110  of phosphatidylinositol 3-kinase induce gain of function by different mechanisms

(2008) L. Zhao et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA