Combinatorial drug therapy for cancer in the post-genomic era.

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Published in Nat Biotechnol on July 10, 2012

Authors

Bissan Al-Lazikani1, Udai Banerji, Paul Workman

Author Affiliations

1: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, UK. bissan.al-lazikani@icr.ac.uk

Associated clinical trials:

A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer (CLEOPATRA) (CLEOPATRA) | NCT00567190

Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212 | NCT01072175

I-SPY 2 TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2) | NCT01042379

Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With Locally Advanced or Metastatic Breast Cancer (BOLERO-3) | NCT01007942

A Combination Therapy Study of MK-2206 and AZD6244 in Participants With Advanced Solid Tumors (MK-2206-010) | NCT01021748

A Study of Ridaforolimus (MK-8669) in Combination With Dalotuzumab (MK-0646) Compared to Standard of Care Treatment in Estrogen Receptor Positive Breast Cancer Patients (MK-8669-041 AM3) | NCT01234857

A Study Evaluating the Safety, Tolerability and Pharmacokinetics of GDC-0973 in Combination With GDC-0941 When Administered in Patients With Locally Advanced or Metastatic Solid Tumors | NCT00996892

Combination of AUY922 With Trastuzumab in HER2+ Advanced Breast Cancer Patients Previously Treated With Trastuzumab | NCT01271920

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HSP90 inhibition: two-pronged exploitation of cancer dependencies. Drug Discov Today (2011) 1.40

Targeting the molecular chaperone heat shock protein 90 (HSP90): lessons learned and future directions. Cancer Treat Rev (2012) 1.40

First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res (2012) 1.39

Objective assessment of cancer genes for drug discovery. Nat Rev Drug Discov (2013) 1.34

Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells. Cancer Res (2009) 1.34

First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res (2013) 1.33

Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT. Mol Cancer Ther (2006) 1.33

Synthesis and biological evaluation of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem Lett (2007) 1.33

A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest New Drugs (2010) 1.30

Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models. Cancer Res (2006) 1.29

Magnetic resonance spectroscopic pharmacodynamic markers of the heat shock protein 90 inhibitor 17-allylamino,17-demethoxygeldanamycin (17AAG) in human colon cancer models. J Natl Cancer Inst (2003) 1.29

Inhibitors of the HSP90 molecular chaperone: attacking the master regulator in cancer. Curr Top Med Chem (2006) 1.29

Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. PLoS One (2012) 1.27

EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines. Clin Cancer Res (2009) 1.24

Can molecular biomarker-based patient selection in Phase I trials accelerate anticancer drug development? Drug Discov Today (2009) 1.24

Role for amplification and expression of glypican-5 in rhabdomyosarcoma. Cancer Res (2007) 1.24

Death by chaperone: HSP90, HSP70 or both? Cell Cycle (2009) 1.22

Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells. Mol Cancer Ther (2006) 1.21

A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. J Mol Biol (2007) 1.20

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues. Mol Cancer Ther (2007) 1.19

Exploiting the cancer genome: strategies for the discovery and clinical development of targeted molecular therapeutics. Annu Rev Pharmacol Toxicol (2012) 1.19

The Cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res (2004) 1.19

In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography. Cancer Res (2006) 1.19

The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors. Bioorg Med Chem Lett (2005) 1.17

Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem (2009) 1.17

BRAF and NRAS mutations in melanoma: potential relationships to clinical response to HSP90 inhibitors. Mol Cancer Ther (2008) 1.16

Expression of kinase-defective mutants of c-Src in human metastatic colon cancer cells decreases Bcl-xL and increases oxaliplatin- and Fas-induced apoptosis. J Biol Chem (2004) 1.16

The clinical applications of heat shock protein inhibitors in cancer - present and future. Curr Cancer Drug Targets (2003) 1.16

Structure-based design of molecular cancer therapeutics. Trends Biotechnol (2009) 1.16

Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem (2006) 1.15

Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity. Mol Cancer Ther (2005) 1.15

Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors. Clin Cancer Res (2008) 1.14

Drugging the PI3 kinome. Nat Biotechnol (2006) 1.14

Targeting CDC37: an alternative, kinase-directed strategy for disruption of oncogenic chaperoning. Cell Cycle (2009) 1.13

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery. Mol Cancer Ther (2007) 1.12

In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res (2005) 1.11

Magnetic resonance spectroscopy monitoring of mitogen-activated protein kinase signaling inhibition. Cancer Res (2005) 1.11

Structural basis of the radicicol resistance displayed by a fungal hsp90. ACS Chem Biol (2009) 1.10

Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem (2007) 1.10

Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis. Mol Cancer Ther (2006) 1.10

Discovery and development of pyrazole-scaffold Hsp90 inhibitors. Curr Top Med Chem (2006) 1.10

Targeted therapeutics for cancer treatment: major progress towards personalised molecular medicine. Curr Opin Pharmacol (2008) 1.09

Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways. Biochem Pharmacol (2006) 1.08

Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity. Mol Cancer Ther (2007) 1.08

Application of meso scale technology for the measurement of phosphoproteins in human tumor xenografts. Assay Drug Dev Technol (2007) 1.08

Genes and proteins governing the cellular sensitivity to HSP90 inhibitors: a mechanistic perspective. Curr Cancer Drug Targets (2003) 1.07

In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors. Cancer Res (2007) 1.07

The phosphoinositide 3-kinase inhibitor PI-103 downregulates choline kinase alpha leading to phosphocholine and total choline decrease detected by magnetic resonance spectroscopy. Cancer Res (2010) 1.07

3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone. Bioorg Med Chem Lett (2005) 1.06

Combining trail with PI3 kinase or HSP90 inhibitors enhances apoptosis in colorectal cancer cells via suppression of survival signaling. Oncotarget (2013) 1.05