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7 results on '"Bailey, U-M"'

1. Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin

Author

Ho, GY, Kyran, EL, Bedo, J, Wakefield, MJ, Ennis, DP, Mirza, HB, Vandenberg, CJ, Lieschke, E, Farrell, A, Hadla, A, Lim, R, Dall, G, Vince, JE, Chua, NK, Kondrashova, O, Upstill-Goddard, R, Bailey, U-M, Dowson, S, Roxburgh, P, Glasspool, RM, Bryson, G, Biankin, AV, Cooke, SL, Ratnayake, G, McNally, O, Traficante, N, DeFazio, A, Weroha, SJ, Bowtell, DD, McNeish, IA, Papenfuss, AT, Scott, CL, Barker, HE, Ho, GY, Kyran, EL, Bedo, J, Wakefield, MJ, Ennis, DP, Mirza, HB, Vandenberg, CJ, Lieschke, E, Farrell, A, Hadla, A, Lim, R, Dall, G, Vince, JE, Chua, NK, Kondrashova, O, Upstill-Goddard, R, Bailey, U-M, Dowson, S, Roxburgh, P, Glasspool, RM, Bryson, G, Biankin, AV, Cooke, SL, Ratnayake, G, McNally, O, Traficante, N, DeFazio, A, Weroha, SJ, Bowtell, DD, McNeish, IA, Papenfuss, AT, Scott, CL, and Barker, HE

Abstract

UNLABELLED: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. SIGNIFICANCE: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indica

Published
2022

2. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Author

Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, E-M, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, U-M, Jones, M, Moran-Jones, K, Wright, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grutzmann, R, Rahib, L, Johns, A, Pajic, M, Froeling, FEM, Beer, P, Musgrove, EA, Petersen, GM, Ashworth, A, Frame, MC, Crawford, HC, Simeone, DM, Lord, C, Mukhopadhyay, D, Pilarsky, C, Tuveson, DA, Cooke, SL, Jamieson, NB, Morton, JP, Sansom, OJ, Bailey, PJ, Biankin, A, Chang, DK, Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, E-M, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, U-M, Jones, M, Moran-Jones, K, Wright, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grutzmann, R, Rahib, L, Johns, A, Pajic, M, Froeling, FEM, Beer, P, Musgrove, EA, Petersen, GM, Ashworth, A, Frame, MC, Crawford, HC, Simeone, DM, Lord, C, Mukhopadhyay, D, Pilarsky, C, Tuveson, DA, Cooke, SL, Jamieson, NB, Morton, JP, Sansom, OJ, Bailey, PJ, Biankin, A, and Chang, DK

Abstract

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

Published
2021

3. Genomic analyses identify molecular subtypes of pancreatic cancer

Author

Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A. -M., Gingras, M. -C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., Nourse, C., Murtaugh, L. C., Harliwong, I., Idrisoglu, S., Manning, S., Nourbakhsh, E., Wani, S., Fink, L., Holmes, O., Chin, V., Anderson, M. J., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Xu, Q., Wilson, P. J., Cloonan, N., Kassahn, K. S., Taylor, D., Quek, K., Robertson, A., Pantano, L., Mincarelli, L., Sanchez, L. N., Evers, L., Wu, J., Pinese, M., Cowley, M. J., Jones, M. D., Colvin, E. K., Nagrial, A. M., Humphrey, E. S., Chantrill, L. A., Mawson, A., Humphris, J., Chou, A., Pajic, M., Scarlett, C. J., Pinho, A. V., Giry-Laterriere, M., Rooman, I., Samra, J. S., Kench, J. G., Lovell, J. A., Merrett, N. D., Toon, C. W., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Moran-Jones, K., Jamieson, N. B., Graham, J. S., Duthie, F., Oien, K., Hair, J., Grutzmann, R., Maitra, A., Iacobuzio-Donahue, C. A., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Corbo, V., Bassi, C., Rusev, B., Capelli, P., Salvia, R., Tortora, G., Mukhopadhyay, D., Petersen, G. M., Munzy, D. M., Fisher, W. E., Karim, S. A., Eshleman, J. R., Hruban, R. H., Pilarsky, C., Morton, J. P., Sansom, O. J., Scarpa, A., Musgrove, E. A., Bailey, U. -M. H., Hofmann, O., Sutherland, R. L., Wheeler, D. A., Gill, A. J., Gibbs, R. A., Pearson, J. V., Biankin, A. V., Grimmond, S. M., Tortora G. (ORCID:0000-0002-1378-4962), Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A. -M., Gingras, M. -C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., Nourse, C., Murtaugh, L. C., Harliwong, I., Idrisoglu, S., Manning, S., Nourbakhsh, E., Wani, S., Fink, L., Holmes, O., Chin, V., Anderson, M. J., Kazakoff, S., Leonard, C., Newell, F., Waddell, N., Wood, S., Xu, Q., Wilson, P. J., Cloonan, N., Kassahn, K. S., Taylor, D., Quek, K., Robertson, A., Pantano, L., Mincarelli, L., Sanchez, L. N., Evers, L., Wu, J., Pinese, M., Cowley, M. J., Jones, M. D., Colvin, E. K., Nagrial, A. M., Humphrey, E. S., Chantrill, L. A., Mawson, A., Humphris, J., Chou, A., Pajic, M., Scarlett, C. J., Pinho, A. V., Giry-Laterriere, M., Rooman, I., Samra, J. S., Kench, J. G., Lovell, J. A., Merrett, N. D., Toon, C. W., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Moran-Jones, K., Jamieson, N. B., Graham, J. S., Duthie, F., Oien, K., Hair, J., Grutzmann, R., Maitra, A., Iacobuzio-Donahue, C. A., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Corbo, V., Bassi, C., Rusev, B., Capelli, P., Salvia, R., Tortora, G., Mukhopadhyay, D., Petersen, G. M., Munzy, D. M., Fisher, W. E., Karim, S. A., Eshleman, J. R., Hruban, R. H., Pilarsky, C., Morton, J. P., Sansom, O. J., Scarpa, A., Musgrove, E. A., Bailey, U. -M. H., Hofmann, O., Sutherland, R. L., Wheeler, D. A., Gill, A. J., Gibbs, R. A., Pearson, J. V., Biankin, A. V., Grimmond, S. M., and Tortora G. (ORCID:0000-0002-1378-4962)

Published
2016

4. A practical Java tool for small-molecule compound appraisal

Author

Amani, P, Sneyd, T, Preston, S, Young, ND, Mason, L, Bailey, U-M, Baell, J, Camp, D, Gasser, RB, Gorse, A-D, Taylor, P, Hofmann, A, Amani, P, Sneyd, T, Preston, S, Young, ND, Mason, L, Bailey, U-M, Baell, J, Camp, D, Gasser, RB, Gorse, A-D, Taylor, P, and Hofmann, A

Abstract

BACKGROUND: The increased use of small-molecule compound screening by new users from a variety of different academic backgrounds calls for adequate software to administer, appraise, analyse and exchange information obtained from screening experiments. While software and spreadsheet solutions exist, there is a need for software that can be easily deployed and is convenient to use. RESULTS: The Java application cApp addresses this need and aids in the handling and storage of information on small-molecule compounds. The software is intended for the appraisal of compounds with respect to their physico-chemical properties, analysis in relation to adherence to likeness rules as well as recognition of pan-assay interference components and cross-linking with identical entries in the PubChem Compound Database. Results are displayed in a tabular form in a graphical interface, but can also be written in an HTML or PDF format. The output of data in ASCII format allows for further processing of data using other suitable programs. Other features include similarity searches against user-provided compound libraries and the PubChem Compound Database, as well as compound clustering based on a MaxMin algorithm. CONCLUSIONS: cApp is a personal database solution for small-molecule compounds which can handle all major chemical formats. Being a standalone software, it has no other dependency than the Java virtual machine and is thus conveniently deployed. It streamlines the analysis of molecules with respect to physico-chemical properties and drug discovery criteria; cApp is distributed under the GNU Affero General Public License version 3 and available from http://www.structuralchemistry.org/pcsb/. To download cApp, users will be asked for their name, institution and email address. A detailed manual can also be downloaded from this site, and online tutorials are available at http://www.structuralchemistry.org/pcsb/capp.php.

Published
2015

6. Exploring the molecular mechanisms of parasite-host interactions with a view towards new therapeutics and vaccines

Author

Cross, M., Klepzig, E., Dallaston, M., Young, N. D., Bailey, U. -M, Mason, L., Jones, M. K., Robin B. Gasser, and Hofmann, A.

Subjects
Vaccines, Helminths, Helminthiasis, Animals, Humans, General Medicine, Helminth Proteins, Host-Parasite Interactions
Abstract

Despite the massive disease burden worldwide caused by parasitic nematodes and other infectious pathogens, the molecular basis of many infectious diseases caused by these pathogens has been unduly neglected for a long time. Therefore, accelerated progress towards novel therapeutics, and ultimately control of such infectious diseases, is of crucial importance. Capitalising on the wealth of data becoming available from proteomic and genomic studies, new protein targets at the pathogen-host interface can be identified and subjected to protein-based explorations of the molecular basis of pathogen-host interactions. By combining the use of systems and structural biology methodologies, insights into the structural and molecular mechanisms of these interactions can assist in the development of therapeutics and/or vaccines. This brief review examines two different proteins from the body wall of blood flukes - annexins and the stress-induced phosphoprotein 1 - both of which are presently interesting targets for the development of therapeutics.Pomimo ogromnej skali występowania chorób powodowanych przez nicienie pasożytnicze i inne patogeny wywołujące choroby zakaźne, konieczność poznania molekularnych podstaw wielu tych jednostek chorobowych była przez długi czas niesłusznie lekceważona. Z tego względu kluczowe jest przyspieszenie opracowywania nowych terapii i, w rezultacie, skutecznej kontroli wymienionych chorób. Dzięki obszernym danym uzyskiwanym podczas badań proteomicznych i genomowych możliwe jest identyfikowanie nowych białek biorących udział w oddziaływaniach patogen-gospodarz i na ich postawie badanie molekularnych podstaw tych oddziaływań. Połączenie metod z zakresu biologii systemowej i strukturalnej umożliwia z kolei zastosowanie tej wiedzy do opracowywania skutecznych leków i/lub szczepionek. W tym krótkim artykule przeglądowym opisano dwa różne białka obecne w ścianie ciała przywry krwi: aneksyny i indukowaną przez stres fosfoproteinę 1, które są obecnie uznawane za obiecujące cele terapeutyczne.

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