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      Response to angiotensin blockade with irbesartan in a patient with metastatic colorectal cancer

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          Abstract

          Personalised oncogenomics analysis revealed potential oncogene addiction of the AP-1 transcriptional complex in a chemo-refractory and MMR-deficient tumor from a patient with metastatic colon cancer. Based on this, treatment with the angiotensin receptor agonist irbesartan was initiated to target the renin–angiotensin system upstream of the AP-1 complex, leading to a profound and durable response.

          Abstract

          Background

          A patient suffering from metastatic colorectal cancer, treatment-related toxicity and resistance to standard chemotherapy and radiation was assessed as part of a personalized oncogenomics initiative to derive potential alternative therapeutic strategies.

          Patients and methods

          Whole-genome and transcriptome sequencing was used to interrogate a metastatic tumor refractory to standard treatments of a patient with mismatch repair-deficient metastatic colorectal cancer.

          Results

          Integrative genomic analysis indicated overexpression of the AP-1 transcriptional complex suggesting experimental therapeutic rationales, including blockade of the renin–angiotensin system. This led to the repurposing of the angiotensin II receptor antagonist, irbesartan, as an anticancer therapy, resulting in the patient experiencing a dramatic and durable response.

          Conclusions

          This case highlights the utility of comprehensive integrative genomic profiling and bioinformatics analysis to provide hypothetical rationales for personalized treatment options.

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          Most cited references21

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          The landscape of microsatellite instability in colorectal and endometrial cancer genomes.

          Microsatellites-simple tandem repeats present at millions of sites in the human genome-can shorten or lengthen due to a defect in DNA mismatch repair. We present here a comprehensive genome-wide analysis of the prevalence, mutational spectrum, and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and whole-genome sequencing data. Recurrent MSI events in coding sequences showed tumor type specificity, elevated frameshift-to-inframe ratios, and lower transcript levels than wild-type alleles. Moreover, genome-wide analysis revealed differences in the distribution of MSI versus point mutations, including overrepresentation of MSI in euchromatic and intronic regions compared to heterochromatic and intergenic regions, respectively, and depletion of MSI at nucleosome-occupied sequences. Our results provide a panoramic view of MSI in cancer genomes, highlighting their tumor type specificity, impact on gene expression, and the role of chromatin organization. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.

            Thalidomide (Thal) achieves responses even in the setting of refractory multiple myeloma (MM). Although increased angiogenesis in MM bone marrow and the antiangiogenic effect of Thal formed the empiric basis for its use in MM, we have shown that Thal and its immunomodulatory analogs (IMiDs) directly induce apoptosis or growth arrest of MM cells, alter adhesion of MM cells to bone marrow stromal cells, inhibit the production of cytokines (interleukin-6 and vascular endothelial growth factor) in bone marrow, and stimulate natural killer cell anti-MM immunity. In the present study, we demonstrate that the IMiDs trigger activation of caspase-8, enhance MM cell sensitivity to Fas-induced apoptosis, and down-regulate nuclear factor (NF)-kappa B activity as well as expression of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein. IMiDs also block the stimulatory effect of insulinlike growth factor-1 on NF-kappa B activity and potentiate the activity of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), dexamethasone, and proteasome inhibitor (PS-341) therapy. These studies both delineate the mechanism of action of IMiDs against MM cells in vitro and form the basis for clinical trials of these agents, alone and coupled with conventional and other novel therapies, to improve outcome in MM.
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              Circulating transforming growth factor-beta in Marfan syndrome.

              Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-beta (TGF-beta). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-beta activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-beta might be mirrored in circulating TGF-beta concentrations. Serum obtained from MFS mutant mice (Fbn1(C1039G/+)) treated with losartan was analyzed for circulating TGF-beta1 concentrations and compared with those from placebo-treated and wild-type mice. Aortic root size was measured by echocardiography. Data were validated in patients with MFS and healthy individuals. In mice, circulating total TGF-beta1 concentrations increased with age and were elevated in older untreated Fbn1(C1039G/+) mice compared with wild-type mice (P=0.01; n=16; mean+/-SEM, 115+/-8 ng/mL versus n=17; mean+/-SEM, 92+/-4 ng/mL). Losartan-treated Fbn1(C1039G/+) mice had lower total TGF-beta1 concentrations compared with age-matched Fbn1(C1039G/+) mice treated with placebo (P=0.01; n=18; 90+/-5 ng/mL), and circulating total TGF-beta1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGF-beta1 levels and aortic root diameters in Fbn1(C1039G/+) and wild-type mice (P=0.002). In humans, circulating total TGF-beta1 concentrations were elevated in patients with MFS compared with control individuals (P<0.0001; n=53; 15+/-1.7 ng/mL versus n=74; 2.5+/-0.4 ng/mL). MFS patients treated with losartan (n=55) or beta-blocker (n=80) showed significantly lower total TGF-beta1 concentrations compared with untreated MFS patients (P< or =0.05). Circulating TGF-beta1 concentrations are elevated in MFS and decrease after administration of losartan, beta-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.
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                Author and article information

                Journal
                Ann Oncol
                Ann. Oncol
                annonc
                annonc
                Annals of Oncology
                Oxford University Press
                0923-7534
                1569-8041
                May 2016
                18 February 2016
                18 February 2016
                : 27
                : 5
                : 801-806
                Affiliations
                [1 ]British Columbia Cancer Agency, Canada's Michael Smith Genome Sciences Centre , Vancouver
                [2 ]Department of Medical Genetics, University of British Columbia , Vancouver
                [3 ]Department of Pathology and Laboratory Medicine, Vancouver General Hospital , Vancouver
                [4 ]Division of Medical Oncology, British Columbia Cancer Agency, Vancouver
                [5 ]Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, Canada
                Author notes
                [* ] Correspondence to: Dr Howard Lim, Division of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6. Tel: +1-604-877-6000 ext 672734; E-mail: hlim@ 123456bccancer.bc.ca
                Article
                mdw060
                10.1093/annonc/mdw060
                4843189
                27022066
                779ed32d-4853-4fd2-a345-b1bc6af2d42f
                © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 30 November 2015
                : 3 February 2016
                : 8 February 2016
                Funding
                Funded by: BC Cancer Foundation
                Funded by: Canada Foundation for Innovation http://dx.doi.org/10.13039/501100000196
                Funded by: University of British Columbia http://dx.doi.org/10.13039/501100005247
                Funded by: Canada Research Chairs program
                Categories
                Original Articles
                Precision Medicine

                Oncology & Radiotherapy
                personalized medicine,ap-1 complex,irbesartan,chemo-refractory colon cancer,rna expression analysis,mismatch repair defective

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