canSAR: updated cancer research and drug discovery knowledgebase

Bulusu, Krishna C.; Tym, Joseph E; Coker, Elizabeth A.; Schierz, Amanda C.; Al‐Lazikani, Bissan

doi:10.1093/nar/gkt1182

Cited by 76 publications

(77 citation statements)

References 16 publications

(22 reference statements)

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“…Primer pairs with comparable efficiency of amplification were identified and efficiency was assessed using serial dilutions of cDNA (20) prepared from OAW28 ovarian carcinoma cells that contain wild type FGFR3 and TACC3 (21). Primers used are: N-terminal region of FGFR3, FGFR3-N: Forward 5′-AAGACGATGCCACTGACAAG-3′, Reverse 5′-CCCAGCAGGTTGATGATGTTTTTG-3′; C-terminal region of TACC3, TACC3-C: Forward 5′-TCCTTCTCCGACCTCTTCAAGC-3′, Reverse 5′-TAATCCTCCACGCACTTCTTCAG-3′.…”

Section: Methodsmentioning

confidence: 99%

Detection, Characterization, and Inhibition of FGFR–TACC Fusions in IDH Wild-type Glioma

Stefano

Fucci

Frattini

et al. 2015

Clinical Cancer Research

236

200

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Purpose Oncogenic fusions consisting of FGFR and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets. We analyzed frequency, molecular features of FGFR-TACC fusions, and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade-II–III glioma. Experimental Design Overall, 795 gliomas (584 GBM, 85 grade-II–III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR-TACC breakpoints and associated molecular profile. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response. Results Three of 85 IDH1/2 wild type (3.5%) but none of 126 IDH1/2 mutant grade-II–III glioma harbored FGFR3-TACC3 fusions. FGFR-TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3-TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification whereas co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo. The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively. Conclusions RT-PCR-sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intra-tumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with a FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients.

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Section: Methodsmentioning

confidence: 99%

Detection, Characterization, and Inhibition of FGFR–TACC Fusions in IDH Wild-type Glioma

Stefano

Fucci

Frattini

et al. 2015

Clinical Cancer Research

236

200

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“…In colorectal adenocarcinoma the Colon Cancer Atlas Network (33) revealed 5.56% UBE2M mutant tumors, but the function of those mutations remain unclear. Two studies found elevated expression of UBE2M in colon adenocarcinoma when compared to normal tissue (34), but again, relevance with regard to treatment efficacy is unclear. Furthermore, no knockout mouse model has been described so far.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer

Stintzing

Heinemann

et al. 2015

Molecular Cancer Therapeutics

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Transmembrane receptors such as the epidermal growth factor receptor (EGFR) are regulated by their turnover, which is dependent on the ubiquitin-proteasome-system (UPS). We tested in two independent study cohorts whether single nucleotide polymorphisms (SNPs) in genes involved in EGFR turnover predict clinical outcome in cetuximab treated metastatic colorectal cancer patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172); SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873); SGIP1 (rs604737; rs6570808; rs7526812); UBE2M (rs895364; rs895374); UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. 153 FOLFIRI plus cetuximab treated patients served as validation set, 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with PFS (logrank-p = 0.005; HR 0.60) within cetuximab treated patients. No association with bevacizumab treated patients (n=168) could be established (p= 0.56, HR: 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC.

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“…The protein annotation and chemoinformatics analysis of the ZIKV-related genes was performed using the canSAR 2.0 integrated knowledgebase, a publically available database [37]. The Browse canSAR analysis tool was used and the ZIKV-associated proteins were batch analyzed for protein annotations, 3D structures, compounds and bioactivity-related information.…”

Section: Methodsmentioning

confidence: 99%

“…A recently described database of ZIKV related genes [35,36] were subjected to chemoinformatics analysis using the canSAR integrated protein annotation tool [37]. Using ligand-based druggability analysis scores, RO5 compliant active hit compounds (IC 50 < 100nM) for 35 ZIKV targets were identified.…”

Section: Introductionmentioning

confidence: 99%

Zika Virus Therapeutic Lead Compounds Discovery Using Chemoinformatics Approaches

Narayanan¹

2016

MOJPB

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The Zika virus disease (ZVD) currently spreading around the globe has no known treatment available. A database of Zika-related genes (N=69) was subjected to chemoinformatics approaches using the canSAR protein annotation tool. Ligand-based druggability analysis of the database of genes identified thirtyfive druggable targets encompassing adhesion molecules, cytokines, enzymes, growth factors and receptors. Eight of these proteins (CCR5, HLA-DRB1, IL6, LTA, PLAT, PPIB, TNF and VEGFA) are current drug targets. Active (IC50< 100nM) Rule of Five (RO5) compliant and toxicophore negative CHEMBL compounds were identified for nine of these Zika virus lead targets (AXL, CASP1, CCL2, CCR5, CTSS, CXCL8, EIF2AK2, NPM1 and TYRO3). The AXL lead gene is a target for an FDA approved antineoplastic kinase inhibitor (Crizotinib/Xalkor). Another FDA approved kinase inhibitor for neoplasms; (Gefitinib) targets the EIF2AK2 lead protein. The protein targets (AXL, CASP1, CCR5, CTSS and RAF1) had highly bioactive compounds available (IC 50 <1nM). CHEMBL compounds with unique protein target specificity were identified for AXL, CCL2, CCR5, CASP1, CTSS, CXCL8/IL8, NPM1/ALK and TYRO3. The RO5 compliant and toxicophore-negative lead compounds identified in the study offer a rationale for rapid verification in Zika virus cell culture models for drug discovery.

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canSAR: updated cancer research and drug discovery knowledgebase

Cited by 76 publications

References 16 publications

Detection, Characterization, and Inhibition of FGFR–TACC Fusions in IDH Wild-type Glioma

Detection, Characterization, and Inhibition of FGFR–TACC Fusions in IDH Wild-type Glioma

Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer

Zika Virus Therapeutic Lead Compounds Discovery Using Chemoinformatics Approaches

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