G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells.

G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells.

J Am Chem Soc. 2013 Jun 19;

Authors: McLuckie KI, Di Antonio M, Zecchini H, Xian J, Caldas C, Krippendorff BF, Tannahill D, Lowe C, Balasubramanian S

Abstract
Synthetic lethality is a genetic concept in which cell death is induced by the combination of mutations in two sensitive genes, while mutation of either gene alone is not sufficient to affect cell survival. Synthetic lethality can be also achieved "chemically" by combination of drug-like molecules targeting distinct but cooperative pathways. Previously, we reported that the small molecule pyridostatin (PDS) stabilizes G-quadruplexes in cells and elicits a DNA damage response (DDR) by causing the formation of DNA double strand breaks (DSB). We hypothesize that cell death mediated by ligand-induced G-quadruplex stabilization could be potentiated in cells deficient in DNA damage repair genes. Here, we demonstrated that PDS acts synergistically both with NU7441, an inhibitor of the DNA-PK kinase crucial for non-homologous end joining (NHEJ) repair of DNA DSBs, and BRCA2-deficient cells that are genetically impaired in homologous recombination-mediated DSB repair (HR). G-quadruplex targeting ligands have potential as cancer therapeutic agents, acting synergistically with inhibition or mutation of the DNA damage repair machinery.

PMID: 23782415 [PubMed - as supplied by publisher]

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Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

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Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

Cancer Metastasis Rev. 2012 Dec;31(3-4):807-14

Authors: Suda K, Mizuuchi H, Maehara Y, Mitsudomi T

Abstract
Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NF?B pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.

PMID: 22736441 [PubMed - indexed for MEDLINE]

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Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

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Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

Abstract
Abstract The limited efficacy of endocrine therapy and chemotherapy has stimulated several researches aimed to detect novel molecularly target therapies for advanced, persistent or recurrent endometrial cancer. Prior attempts to block vascular endothelial growth factor (VEGF) with sunitinib, sorafenib and thalidomide have obtained disappointing results. Bevacizumab has shown a promising activity in a phase II study. The percentages of patients with progression-free survival ?6 months were similar for endometrioid (35%) and serous carcinoma (36%), but the number of cases was too small to assess the relevance of histological type for response to bevacizumab. In a phase II study, aflibercept was administered every 2 weeks to women with recurrent or persistent disease after chemotherapy. Forty-one percent of the patients were progression-free at 6 months, but 32% of the women had been removed from study because of toxicity. The detection of activating mutations of Fibroblast Growth Factor Receptor (FGFR)-2 in primary endometrial carcinoma has generated a new avenue for the development of molecularly target agents. Dovitinib, a tyrosine kinase inhibitor targeting both VEGF receptor (VEGFR) and FGFRs, is under clinical investigation in different malignancies including endometrial cancer.

PMID: 23767831 [PubMed - as supplied by publisher]

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Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis.

Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis.

PLoS One. 2013;8(6):e65166

Authors: Qi WX, Huang YJ, Yao Y, Shen Z, Min DL

Abstract
BACKGROUND: Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined.
METHODS: We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.
RESULTS: A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3-2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21-8.67, p?=?0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed.
CONCLUSION: With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

PMID: 23785409 [PubMed - in process]

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Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis.

Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis.

PLoS One. 2013;8(6):e65166

Authors: Qi WX, Huang YJ, Yao Y, Shen Z, Min DL

Abstract
BACKGROUND: Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined.
METHODS: We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.
RESULTS: A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3-2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21-8.67, p?=?0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed.
CONCLUSION: With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

PMID: 23785409 [PubMed - in process]

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Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Related Articles

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

Abstract
Abstract The limited efficacy of endocrine therapy and chemotherapy has stimulated several researches aimed to detect novel molecularly target therapies for advanced, persistent or recurrent endometrial cancer. Prior attempts to block vascular endothelial growth factor (VEGF) with sunitinib, sorafenib and thalidomide have obtained disappointing results. Bevacizumab has shown a promising activity in a phase II study. The percentages of patients with progression-free survival ?6 months were similar for endometrioid (35%) and serous carcinoma (36%), but the number of cases was too small to assess the relevance of histological type for response to bevacizumab. In a phase II study, aflibercept was administered every 2 weeks to women with recurrent or persistent disease after chemotherapy. Forty-one percent of the patients were progression-free at 6 months, but 32% of the women had been removed from study because of toxicity. The detection of activating mutations of Fibroblast Growth Factor Receptor (FGFR)-2 in primary endometrial carcinoma has generated a new avenue for the development of molecularly target agents. Dovitinib, a tyrosine kinase inhibitor targeting both VEGF receptor (VEGFR) and FGFRs, is under clinical investigation in different malignancies including endometrial cancer.

PMID: 23767831 [PubMed - as supplied by publisher]

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Image-based high-throughput screening for inhibitors of angiogenesis.

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Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

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