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1. SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Author

Bland, Philip, Saville, Harry, Wai, Patty T., Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E., Wright, James, Yu, Lu, Mavrommati, Ioanna, Read, Abigail, Peck, Barrie, Allen, Mark, Gazinska, Patrycja, Pemberton, Helen N., Gulati, Aditi, Nash, Sarah, Noor, Farzana, Guppy, Naomi, Roxanis, Ioannis, Pratt, Guy, Oldreive, Ceri, Stankovic, Tatjana, Barlow, Samantha, Kalirai, Helen, Coupland, Sarah E., Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S., Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J., and Natrajan, Rachael

Published
2023
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3. Supplementary Figure S5 from Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer

Author

Hedayat, Somaieh, primary, Cascione, Luciano, primary, Cunningham, David, primary, Schirripa, Marta, primary, Lampis, Andrea, primary, Hahne, Jens C., primary, Tunariu, Nina, primary, Hong, Sung Pil, primary, Marchetti, Silvia, primary, Khan, Khurum, primary, Fontana, Elisa, primary, Angerilli, Valentina, primary, Delrieux, Mia, primary, Nava Rodrigues, Daniel, primary, Procaccio, Letizia, primary, Rao, Sheela, primary, Watkins, David, primary, Starling, Naureen, primary, Chau, Ian, primary, Braconi, Chiara, primary, Fotiadis, Nicos, primary, Begum, Ruwaida, primary, Guppy, Naomy, primary, Howell, Louise, primary, Valenti, Melanie, primary, Cribbes, Scott, primary, Kolozsvari, Bernadett, primary, Kirkin, Vladimir, primary, Lonardi, Sara, primary, Ghidini, Michele, primary, Passalacqua, Rodolfo, primary, Elghadi, Raghad, primary, Magnani, Luca, primary, Pinato, David J., primary, Di Maggio, Federica, primary, Ghelardi, Filippo, primary, Sottotetti, Elisa, primary, Vetere, Guglielmo, primary, Ciracì, Paolo, primary, Vlachogiannis, Georgios, primary, Pietrantonio, Filippo, primary, Cremolini, Chiara, primary, Cortellini, Alessio, primary, Loupakis, Fotios, primary, Fassan, Matteo, primary, and Valeri, Nicola, primary

Published
2024
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4. Supplementary Video S1 from Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer

Author

Hedayat, Somaieh, primary, Cascione, Luciano, primary, Cunningham, David, primary, Schirripa, Marta, primary, Lampis, Andrea, primary, Hahne, Jens C., primary, Tunariu, Nina, primary, Hong, Sung Pil, primary, Marchetti, Silvia, primary, Khan, Khurum, primary, Fontana, Elisa, primary, Angerilli, Valentina, primary, Delrieux, Mia, primary, Nava Rodrigues, Daniel, primary, Procaccio, Letizia, primary, Rao, Sheela, primary, Watkins, David, primary, Starling, Naureen, primary, Chau, Ian, primary, Braconi, Chiara, primary, Fotiadis, Nicos, primary, Begum, Ruwaida, primary, Guppy, Naomy, primary, Howell, Louise, primary, Valenti, Melanie, primary, Cribbes, Scott, primary, Kolozsvari, Bernadett, primary, Kirkin, Vladimir, primary, Lonardi, Sara, primary, Ghidini, Michele, primary, Passalacqua, Rodolfo, primary, Elghadi, Raghad, primary, Magnani, Luca, primary, Pinato, David J., primary, Di Maggio, Federica, primary, Ghelardi, Filippo, primary, Sottotetti, Elisa, primary, Vetere, Guglielmo, primary, Ciracì, Paolo, primary, Vlachogiannis, Georgios, primary, Pietrantonio, Filippo, primary, Cremolini, Chiara, primary, Cortellini, Alessio, primary, Loupakis, Fotios, primary, Fassan, Matteo, primary, and Valeri, Nicola, primary

Published
2024
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5. Supplementary Tables S1-S19 from Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer

Author

Hedayat, Somaieh, primary, Cascione, Luciano, primary, Cunningham, David, primary, Schirripa, Marta, primary, Lampis, Andrea, primary, Hahne, Jens C., primary, Tunariu, Nina, primary, Hong, Sung Pil, primary, Marchetti, Silvia, primary, Khan, Khurum, primary, Fontana, Elisa, primary, Angerilli, Valentina, primary, Delrieux, Mia, primary, Nava Rodrigues, Daniel, primary, Procaccio, Letizia, primary, Rao, Sheela, primary, Watkins, David, primary, Starling, Naureen, primary, Chau, Ian, primary, Braconi, Chiara, primary, Fotiadis, Nicos, primary, Begum, Ruwaida, primary, Guppy, Naomy, primary, Howell, Louise, primary, Valenti, Melanie, primary, Cribbes, Scott, primary, Kolozsvari, Bernadett, primary, Kirkin, Vladimir, primary, Lonardi, Sara, primary, Ghidini, Michele, primary, Passalacqua, Rodolfo, primary, Elghadi, Raghad, primary, Magnani, Luca, primary, Pinato, David J., primary, Di Maggio, Federica, primary, Ghelardi, Filippo, primary, Sottotetti, Elisa, primary, Vetere, Guglielmo, primary, Ciracì, Paolo, primary, Vlachogiannis, Georgios, primary, Pietrantonio, Filippo, primary, Cremolini, Chiara, primary, Cortellini, Alessio, primary, Loupakis, Fotios, primary, Fassan, Matteo, primary, and Valeri, Nicola, primary

Published
2024
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6. Supplementary Methods S1 from Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer

Author

Hedayat, Somaieh, primary, Cascione, Luciano, primary, Cunningham, David, primary, Schirripa, Marta, primary, Lampis, Andrea, primary, Hahne, Jens C., primary, Tunariu, Nina, primary, Hong, Sung Pil, primary, Marchetti, Silvia, primary, Khan, Khurum, primary, Fontana, Elisa, primary, Angerilli, Valentina, primary, Delrieux, Mia, primary, Nava Rodrigues, Daniel, primary, Procaccio, Letizia, primary, Rao, Sheela, primary, Watkins, David, primary, Starling, Naureen, primary, Chau, Ian, primary, Braconi, Chiara, primary, Fotiadis, Nicos, primary, Begum, Ruwaida, primary, Guppy, Naomy, primary, Howell, Louise, primary, Valenti, Melanie, primary, Cribbes, Scott, primary, Kolozsvari, Bernadett, primary, Kirkin, Vladimir, primary, Lonardi, Sara, primary, Ghidini, Michele, primary, Passalacqua, Rodolfo, primary, Elghadi, Raghad, primary, Magnani, Luca, primary, Pinato, David J., primary, Di Maggio, Federica, primary, Ghelardi, Filippo, primary, Sottotetti, Elisa, primary, Vetere, Guglielmo, primary, Ciracì, Paolo, primary, Vlachogiannis, Georgios, primary, Pietrantonio, Filippo, primary, Cremolini, Chiara, primary, Cortellini, Alessio, primary, Loupakis, Fotios, primary, Fassan, Matteo, primary, and Valeri, Nicola, primary

Published
2024
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7. Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer

Author

Hedayat, Somaieh, primary, Cascione, Luciano, additional, Cunningham, David, additional, Schirripa, Marta, additional, Lampis, Andrea, additional, Hahne, Jens C., additional, Tunariu, Nina, additional, Hong, Sung Pil, additional, Marchetti, Silvia, additional, Khan, Khurum, additional, Fontana, Elisa, additional, Angerilli, Valentina, additional, Delrieux, Mia, additional, Nava Rodrigues, Daniel, additional, Procaccio, Letizia, additional, Rao, Sheela, additional, Watkins, David, additional, Starling, Naureen, additional, Chau, Ian, additional, Braconi, Chiara, additional, Fotiadis, Nicos, additional, Begum, Ruwaida, additional, Guppy, Naomy, additional, Howell, Louise, additional, Valenti, Melanie, additional, Cribbes, Scott, additional, Kolozsvari, Bernadett, additional, Kirkin, Vladimir, additional, Lonardi, Sara, additional, Ghidini, Michele, additional, Passalacqua, Rodolfo, additional, Elghadi, Raghad, additional, Magnani, Luca, additional, Pinato, David J., additional, Di Maggio, Federica, additional, Ghelardi, Filippo, additional, Sottotetti, Elisa, additional, Vetere, Guglielmo, additional, Ciracì, Paolo, additional, Vlachogiannis, Georgios, additional, Pietrantonio, Filippo, additional, Cremolini, Chiara, additional, Cortellini, Alessio, additional, Loupakis, Fotios, additional, Fassan, Matteo, additional, and Valeri, Nicola, additional

Published
2024
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8. MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer

Author

Lampis, Andrea, Hahne, Jens C., Gasparini, Pierluigi, Cascione, Luciano, Hedayat, Somaieh, Vlachogiannis, Georgios, Murgia, Claudio, Fontana, Elisa, Edwards, Joanne, Horgan, Paul G., Terracciano, Luigi, Sansom, Owen J., Martins, Carlos D., Kramer-Marek, Gabriela, Croce, Carlo M., Braconi, Chiara, Fassan, Matteo, and Valeri, Nicola

Published
2021
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10. Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage

Author

Carotenuto, Pietro, Amato, Francesco, Lampis, Andrea, Rae, Colin, Hedayat, Somaieh, Previdi, Maria C., Zito, Domenico, Raj, Maya, Guzzardo, Vincenza, Sclafani, Francesco, Lanese, Andrea, Parisi, Claudia, Vicentini, Caterina, Said-Huntingford, Ian, Hahne, Jens C., Hallsworth, Albert, Kirkin, Vladimir, Young, Kate, Begum, Ruwaida, Wotherspoon, Andrew, Kouvelakis, Kyriakos, Azevedo, Sergio Xavier, Michalarea, Vasiliki, Upstill-Goddard, Rosie, Rao, Sheela, Watkins, David, Starling, Naureen, Sadanandam, Anguraj, Chang, David K., Biankin, Andrew V., Jamieson, Nigel B., Scarpa, Aldo, Cunningham, David, Chau, Ian, Workman, Paul, Fassan, Matteo, Valeri, Nicola, and Braconi, Chiara

Published
2021
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11. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers

Author

Vlachogiannis, Georgios, Hedayat, Somaieh, Vatsiou, Alexandra, Jamin, Yann, Fernández-Mateos, Javier, Khan, Khurum, Lampis, Andrea, Eason, Katherine, Huntingford, Ian, Burke, Rosemary, Rata, Mihaela, Koh, Dow-Mu, Tunariu, Nina, Collins, David, Hulkki-Wilson, Sanna, Ragulan, Chanthirika, Spiteri, Inmaculada, Moorcraft, Sing Yu, Chau, Ian, Rao, Sheela, Watkins, David, Fotiadis, Nicos, Bali, Maria, Darvish-Damavandi, Mahnaz, Lote, Hazel, Eltahir, Zakaria, Smyth, Elizabeth C., Begum, Ruwaida, Clarke, Paul A., Hahne, Jens C., Dowsett, Mitchell, de Bono, Johann, Workman, Paul, Sadanandam, Anguraj, Fassan, Matteo, Sansom, Owen J., Eccles, Suzanne, Starling, Naureen, Braconi, Chiara, Sottoriva, Andrea, Robinson, Simon P., Cunningham, David, and Valeri, Nicola

Published
2018

12. MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma

Author

Lampis, Andrea, Carotenuto, Pietro, Vlachogiannis, Georgios, Cascione, Luciano, Hedayat, Somaieh, Burke, Rosemary, Clarke, Paul, Bosma, Else, Simbolo, Michele, Scarpa, Aldo, Yu, Sijia, Cole, Rebecca, Smyth, Elizabeth, Mateos, Javier Fernández, Begum, Ruwaida, Hezelova, Blanka, Eltahir, Zakaria, Wotherspoon, Andrew, Fotiadis, Nicos, Bali, Maria Antonietta, Nepal, Chirag, Khan, Khurum, Stubbs, Mark, Hahne, Jens C., Gasparini, Pierluigi, Guzzardo, Vincenza, Croce, Carlo M., Eccles, Suzanne, Fassan, Matteo, Cunningham, David, Andersen, Jesper B., Workman, Paul, Valeri, Nicola, and Braconi, Chiara

Published
2018
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13. Supplementary Table S4 from Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial

Author

Khan, Khurum H., primary, Cunningham, David, primary, Werner, Benjamin, primary, Vlachogiannis, Georgios, primary, Spiteri, Inmaculada, primary, Heide, Timon, primary, Mateos, Javier Fernandez, primary, Vatsiou, Alexandra, primary, Lampis, Andrea, primary, Damavandi, Mahnaz Darvish, primary, Lote, Hazel, primary, Huntingford, Ian Said, primary, Hedayat, Somaieh, primary, Chau, Ian, primary, Tunariu, Nina, primary, Mentrasti, Giulia, primary, Trevisani, Francesco, primary, Rao, Sheela, primary, Anandappa, Gayathri, primary, Watkins, David, primary, Starling, Naureen, primary, Thomas, Janet, primary, Peckitt, Clare, primary, Khan, Nasir, primary, Rugge, Massimo, primary, Begum, Ruwaida, primary, Hezelova, Blanka, primary, Bryant, Annette, primary, Jones, Thomas, primary, Proszek, Paula, primary, Fassan, Matteo, primary, Hahne, Jens C., primary, Hubank, Michael, primary, Braconi, Chiara, primary, Sottoriva, Andrea, primary, and Valeri, Nicola, primary

Published
2023
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14. Supplementary Data from Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial

Author

Khan, Khurum H., primary, Cunningham, David, primary, Werner, Benjamin, primary, Vlachogiannis, Georgios, primary, Spiteri, Inmaculada, primary, Heide, Timon, primary, Mateos, Javier Fernandez, primary, Vatsiou, Alexandra, primary, Lampis, Andrea, primary, Damavandi, Mahnaz Darvish, primary, Lote, Hazel, primary, Huntingford, Ian Said, primary, Hedayat, Somaieh, primary, Chau, Ian, primary, Tunariu, Nina, primary, Mentrasti, Giulia, primary, Trevisani, Francesco, primary, Rao, Sheela, primary, Anandappa, Gayathri, primary, Watkins, David, primary, Starling, Naureen, primary, Thomas, Janet, primary, Peckitt, Clare, primary, Khan, Nasir, primary, Rugge, Massimo, primary, Begum, Ruwaida, primary, Hezelova, Blanka, primary, Bryant, Annette, primary, Jones, Thomas, primary, Proszek, Paula, primary, Fassan, Matteo, primary, Hahne, Jens C., primary, Hubank, Michael, primary, Braconi, Chiara, primary, Sottoriva, Andrea, primary, and Valeri, Nicola, primary

Published
2023
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15. Supplementary Tables from Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial

Author

Khan, Khurum H., primary, Cunningham, David, primary, Werner, Benjamin, primary, Vlachogiannis, Georgios, primary, Spiteri, Inmaculada, primary, Heide, Timon, primary, Mateos, Javier Fernandez, primary, Vatsiou, Alexandra, primary, Lampis, Andrea, primary, Damavandi, Mahnaz Darvish, primary, Lote, Hazel, primary, Huntingford, Ian Said, primary, Hedayat, Somaieh, primary, Chau, Ian, primary, Tunariu, Nina, primary, Mentrasti, Giulia, primary, Trevisani, Francesco, primary, Rao, Sheela, primary, Anandappa, Gayathri, primary, Watkins, David, primary, Starling, Naureen, primary, Thomas, Janet, primary, Peckitt, Clare, primary, Khan, Nasir, primary, Rugge, Massimo, primary, Begum, Ruwaida, primary, Hezelova, Blanka, primary, Bryant, Annette, primary, Jones, Thomas, primary, Proszek, Paula, primary, Fassan, Matteo, primary, Hahne, Jens C., primary, Hubank, Michael, primary, Braconi, Chiara, primary, Sottoriva, Andrea, primary, and Valeri, Nicola, primary

Published
2023
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16. Data from Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial

Author

Khan, Khurum H., primary, Cunningham, David, primary, Werner, Benjamin, primary, Vlachogiannis, Georgios, primary, Spiteri, Inmaculada, primary, Heide, Timon, primary, Mateos, Javier Fernandez, primary, Vatsiou, Alexandra, primary, Lampis, Andrea, primary, Damavandi, Mahnaz Darvish, primary, Lote, Hazel, primary, Huntingford, Ian Said, primary, Hedayat, Somaieh, primary, Chau, Ian, primary, Tunariu, Nina, primary, Mentrasti, Giulia, primary, Trevisani, Francesco, primary, Rao, Sheela, primary, Anandappa, Gayathri, primary, Watkins, David, primary, Starling, Naureen, primary, Thomas, Janet, primary, Peckitt, Clare, primary, Khan, Nasir, primary, Rugge, Massimo, primary, Begum, Ruwaida, primary, Hezelova, Blanka, primary, Bryant, Annette, primary, Jones, Thomas, primary, Proszek, Paula, primary, Fassan, Matteo, primary, Hahne, Jens C., primary, Hubank, Michael, primary, Braconi, Chiara, primary, Sottoriva, Andrea, primary, and Valeri, Nicola, primary

Published
2023
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17. Supplementary Data from miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial

Author

Anandappa, Gayathri, primary, Lampis, Andrea, primary, Cunningham, David, primary, Khan, Khurum H., primary, Kouvelakis, Kyriakos, primary, Vlachogiannis, Georgios, primary, Hedayat, Somaieh, primary, Tunariu, Nina, primary, Rao, Sheela, primary, Watkins, David, primary, Starling, Naureen, primary, Braconi, Chiara, primary, Darvish-Damavandi, Mahnaz, primary, Lote, Hazel, primary, Thomas, Janet, primary, Peckitt, Clare, primary, Kalaitzaki, Ria, primary, Khan, Nasir, primary, Fotiadis, Nicos, primary, Rugge, Massimo, primary, Begum, Ruwaida, primary, Rana, Isma, primary, Bryant, Annette, primary, Hahne, Jens C., primary, Chau, Ian, primary, Fassan, Matteo, primary, and Valeri, Nicola, primary

Published
2023
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18. Abstract P6-10-05: Mutations in the RNA Splicing Factor SF3B1 drive endocrine therapy resistance and confer a targetable replication stress response defect through PARP inhibition

Author

Bland, Phil, primary, Saville, Harry, additional, Read, Abigail, additional, Wai, Patty, additional, Muirhead, Gareth, additional, Curnow, Lucinda, additional, Nieminuszczy, Jadwiga, additional, Ravindran, Nivedita, additional, John, Marie, additional, Hedayat, Somaieh, additional, Barker, Holly, additional, Wright, James, additional, Yu, Lu, additional, Mavrommati, Ioanna, additional, Peck, Barrie, additional, Allen, Mark, additional, Gazinska, Patrycja, additional, Pemberton, Helen, additional, Gulati, Aditi, additional, Nash, Sarah, additional, Noor, Farzana, additional, Guppy, Naomi, additional, Roxanis, Ioannis, additional, Barlow, Samantha, additional, Kalirai, Helen, additional, Coupland, Sarah, additional, Broderick, Ronan, additional, Alsafadi, Samar, additional, Houy, Alexandre, additional, Stern, Marc-Henri, additional, Pettit, Stephen, additional, Choudhary, Jyoti, additional, Haider, Syed, additional, Niedzwiedz, Wojciech, additional, Lord, Christopher, additional, and Natrajan, Rachael, additional

Published
2023
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20. SF3B1hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Author

Bland, Philip, Saville, Harry, Wai, Patty T., Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E., Wright, James, Yu, Lu, Mavrommati, Ioanna, Read, Abigail, Peck, Barrie, Allen, Mark, Gazinska, Patrycja, Pemberton, Helen N., Gulati, Aditi, Nash, Sarah, Noor, Farzana, Guppy, Naomi, Roxanis, Ioannis, Pratt, Guy, Oldreive, Ceri, Stankovic, Tatjana, Barlow, Samantha, Kalirai, Helen, Coupland, Sarah E., Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S., Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J., and Natrajan, Rachael

Abstract

SF3B1hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUTcells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUTcancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

Published
2023
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21. Modulation of biliary cancer chemo‐resistance through microRNA‐mediated rewiring of the expansion of CD133+ cells

Author

Carotenuto, Pietro, Hedayat, Somaieh, Fassan, Matteo, Cardinale, Vincenzo, Lampis, Andrea, Guzzardo, Vincenza, Vicentini, Caterina, Scarpa, Aldo, Cascione, Luciano, Costantini, Daniele, Carpino, Guido, Alvaro, Domenico, Ghidini, Michele, Trevisani, Francesco, Te Poele, Robert, Salati, Massimiliano, Ventura, Sofia, Vlachogiannis, Georgios, Hahne, Jens C, Boulter, Luke, Forbes, Stuart J, Guest, Rachel, Cillo, Umberto, Said‐Huntingford, Ian, Begum, Ruwaida, Smyth, Elizabeth, Michalarea, Vasiliki, Cunningham, David, Rimassa, Lorenza, Santoro, Armando, Roncalli, Massimo, Kirnkin, Vladimir, Clarke, Paul, Workman, Paul, Valeri, Nicola, and Braconi, Chiara

Abstract

Background and aims:\ud Changes in single microRNA (MIR) expression have been associated with chemo‐resistance in Biliary Tract Cancer (BTC). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy.\ud \ud Approach and Results:\ud High‐throughput‐screening of 997 LNA‐MIR‐inhibitors was performed in 6 CCA cell lines treated with Cisplatin‐Gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with miRvana probes. MIR and gene expression was assessed by TaqMan‐assay, RNA‐sequencing and in‐situ‐hybridization in 4 indepedent cohorts of human BTC. Knock‐out of microRNA was achieved by CRISPR‐CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in‐vitro and in‐vivo.\ud \ud High‐throughput‐screening revealed that MIR1249‐inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTC. In validation experiments, MIR1249‐inhibition did not alter cell viability in untreated or DMSO‐treated cells; however it did increase CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem niche of human BTC, as well as in CD133+ chemo‐resistant CCLP cells. MIR1249 modulated the chemotherapy‐induced enrichment of CD133+ cells by controlling their clonal expansion via the Wnt‐regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of Cancer‐Stem‐Cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumour shrinkage after exposure to weekly CG, while WT models showed only stable disease over treatment.\ud \ud Conclusions:\ud MIR1249 mediates resistance to CG in BTC and may be tested as a novel target for therapeutics.

Published
2020

22. EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers

Author

Smyth, Elizabeth C, primary, Vlachogiannis, Georgios, additional, Hedayat, Somaieh, additional, Harbery, Alice, additional, Hulkki-Wilson, Sanna, additional, Salati, Massimiliano, additional, Kouvelakis, Kyriakos, additional, Fernandez-Mateos, Javier, additional, Cresswell, George D, additional, Fontana, Elisa, additional, Seidlitz, Therese, additional, Peckitt, Clare, additional, Hahne, Jens C, additional, Lampis, Andrea, additional, Begum, Ruwaida, additional, Watkins, David, additional, Rao, Sheela, additional, Starling, Naureen, additional, Waddell, Tom, additional, Okines, Alicia, additional, Crosby, Tom, additional, Mansoor, Was, additional, Wadsley, Jonathan, additional, Middleton, Gary, additional, Fassan, Matteo, additional, Wotherspoon, Andrew, additional, Braconi, Chiara, additional, Chau, Ian, additional, Vivanco, Igor, additional, Sottoriva, Andrea, additional, Stange, Daniel E, additional, Cunningham, David, additional, and Valeri, Nicola, additional

Published
2020
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23. Abstract 5720: MicroRNA deregulation of the serine synthesis pathway controls intrinsic and non-cell autonomous mechanism of resistance to Regorafenib in metastatic colorectal cancer (mCRC)

Author

Hedayat, Somaieh, primary, Lampis, Andrea, additional, Vlachogiannis, George, additional, Khan, khurum, additional, Marchetti, Silvia, additional, Fassan, Matteo, additional, Ghidini, Michele, additional, Begum, Ruwaida, additional, Schirripa, Marta, additional, Passalacqua, Rodolfo, additional, Cunningham, David, additional, Loupakis, Fotios, additional, and Valeri, Nicola, additional

Published
2020
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24. Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

Author

Khan, Khurum, Rata, Mihaela, Cunningham, David, Koh, Dow-Mu, Tunariu, Nina, Hahne, Jens C., Vlachogiannis, George, Hedayat, Somaieh, Marchetti, Silvia, Lampis, Andrea, Damavandi, Mahnaz Darvish, Lote, Hazel, Rana, Isma, Williams, Anja, Eccles, Suzanne A., Fontana, Elisa, Collins, David, Eltahir, Zakaria, Rao, Sheela, Watkins, David, Starling, Naureen, Thomas, Jan, Kalaitzaki, Eleftheria, Fotiadis, Nicos, Begum, Ruwaida, Bali, Maria, Rugge, Massimo, Temple, Eleanor, Fassan, Matteo, Chau, Ian, Braconi, Chiara, and Valeri, Nicola

Subjects
Adult, Male, liquid biopsy, Colon, anti-angiogenic treatment, DCE-MRI, Pyridines, Phenylurea Compounds, colorectal cancer, cancer therapeutics, regorafenib, Kaplan-Meier Estimate, Middle Aged, Magnetic Resonance Imaging, Treatment Outcome, Humans, Female, Prospective Studies, Colorectal Neoplasms, Biomarkers, Aged
Abstract

Objective: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.\ud \ud Design: Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.\ud \ud Results: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).\ud \ud Conclusions: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

Published
2017

25. MicroRNA 31-3p expression and benefit from anti-EGFR inhibitors in metastatic colorectal cancer patients enrolled in the prospective phase II PROSPECT-C trial

Author

Anandappa, Gayathri, Lampis, Andrea, Cunningham, David, Khan, Khurum H., Kouvelakis, Kyriakos, Vlachogiannis, Georgios, Hedayat, Somaieh, Tunariu, Nina, Rao, Sheela, Watkins, David, Starling, Naureen, Braconi, Chiara, Darvish-Damavandi, Mahnaz, Lote, Hazel, Thomas, Janet, Peckitt, Clare, Kalaitzaki, Ria, Khan, Nasir, Fotiadis, Nicos, Rugge, Massimo, Begum, Ruwaida, Rana, Isma, Bryant, Annette, Hahne, Jens C., Chau, Ian, Fassan, Matteo, and Valeri, Nicola

Subjects
Male, Gene Expression, Middle Aged, Prognosis, Immunohistochemistry, ErbB Receptors, MicroRNAs, Antineoplastic Agents, Immunological, Treatment Outcome, Retreatment, Biomarkers, Tumor, Humans, Female, Molecular Targeted Therapy, Colorectal Neoplasms, Tomography, X-Ray Computed, In Situ Hybridization, Aged
Abstract

Purpose: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs. Experimental Design: miR-31-3p was tested by in situ hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and RAS status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination. Results: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer). Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.

Published
2019

26. EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

Author

Smyth, Elizabeth C., Vlachogiannis, Georgios, Hedayat, Somaieh, Harbery, Alice, Hulkki-Wilson, Sanna, Salati, Massimiliano, Kouvelakis, Kyriakos, Fernandez-Mateos, Javier, Cresswell, George D., Fontana, Elisa, Seidlitz, Therese, Peckitt, Clare, Hahne, Jens C., Lampis, Andrea, Begum, Ruwaida, Watkins, David, Rao, Sheela, Starling, Naureen, Waddell, Tom, and Okines, Alicia

Subjects
ESOPHAGEAL cancer, EPIDERMAL growth factor receptors, RECTAL cancer, CELL-free DNA
Published
2021
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27. Abstract LB-305: Circulating miR-652-3p as a biomarker of resistance to regorafenib in metastatic colorectal cancer patients

Author

Hedayat, Somaieh, primary, Khan, Khurum, additional, Cunningham, David, additional, Vlachogiannis, George, additional, Lampis, Andrea, additional, Marchetti, Silvia, additional, Fassan, Matteo, additional, Begum, Ruwaida, additional, Schirripa, Marta, additional, Loupakis, Fotios Fotios, additional, and Valeri, Nicola, additional

Published
2019
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28. Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease

Author

Colombano, Giampiero, primary, Caldwell, John J., additional, Matthews, Thomas P., additional, Bhatia, Chitra, additional, Joshi, Amar, additional, McHardy, Tatiana, additional, Mok, Ngai Yi, additional, Newbatt, Yvette, additional, Pickard, Lisa, additional, Strover, Jade, additional, Hedayat, Somaieh, additional, Walton, Michael I., additional, Myers, Stephanie M., additional, Jones, Alan M., additional, Saville, Harry, additional, McAndrew, Craig, additional, Burke, Rosemary, additional, Eccles, Suzanne A., additional, Davies, Faith E., additional, Bayliss, Richard, additional, and Collins, Ian, additional

Published
2019
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29. Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial

Author

Khan, Khurum H., primary, Cunningham, David, additional, Werner, Benjamin, additional, Vlachogiannis, Georgios, additional, Spiteri, Inmaculada, additional, Heide, Timon, additional, Mateos, Javier Fernandez, additional, Vatsiou, Alexandra, additional, Lampis, Andrea, additional, Damavandi, Mahnaz Darvish, additional, Lote, Hazel, additional, Huntingford, Ian Said, additional, Hedayat, Somaieh, additional, Chau, Ian, additional, Tunariu, Nina, additional, Mentrasti, Giulia, additional, Trevisani, Francesco, additional, Rao, Sheela, additional, Anandappa, Gayathri, additional, Watkins, David, additional, Starling, Naureen, additional, Thomas, Janet, additional, Peckitt, Clare, additional, Khan, Nasir, additional, Rugge, Massimo, additional, Begum, Ruwaida, additional, Hezelova, Blanka, additional, Bryant, Annette, additional, Jones, Thomas, additional, Proszek, Paula, additional, Fassan, Matteo, additional, Hahne, Jens C., additional, Hubank, Michael, additional, Braconi, Chiara, additional, Sottoriva, Andrea, additional, and Valeri, Nicola, additional

Published
2018
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30. HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target

Author

Fok, Jacqueline H.L., primary, Hedayat, Somaieh, additional, Zhang, Lei, additional, Aronson, Lauren I., additional, Mirabella, Fabio, additional, Pawlyn, Charlotte, additional, Bright, Michael D., additional, Wardell, Christopher P., additional, Keats, Jonathan J., additional, De Billy, Emmanuel, additional, Rye, Carl S., additional, Chessum, Nicola E.A., additional, Jones, Keith, additional, Morgan, Gareth J., additional, Eccles, Suzanne A., additional, Workman, Paul, additional, and Davies, Faith E., additional

Published
2018
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31. Metastatic colorectal cancer (mCRC) patient derived organoids (PDOs) as a preclinical tool to understand mechanisms of resistance to anti-angiogenic drugs

Author

Hedayat, Somaieh, primary, Vlachogiannis, George, additional, Jamin, Yann, additional, Khan, Khurum, additional, Fernandez-mateos, Javier, additional, Hahne, Jens C., additional, Rata, Michaela, additional, Koh, Dow-Ku, additional, Tunariu, Nina, additional, Collins, David, additional, Bali, Monia, additional, Chau, Ian, additional, Rao, Sheela, additional, Watkins, David, additional, Sterling, Naureen, additional, Fotoadis, Nicos, additional, Huntingford, Ian, additional, Gegum, Ruwaida, additional, Rana, Isma, additional, Rugge, Massimo, additional, Braconi, Chiara, additional, Fassan, Matteo, additional, Eccles, Suzanne, additional, Robinson, Simon P., additional, Cunningham, David, additional, and Valeri, Nicola, additional

Published
2018
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32. Metastatic colorectal cancer (mCRC) patient derived organoids (PDOs) as a preclinical tool to understand mechanisms of resistance to anti-angiogenic drugs

Author

Hedayat, Somaieh, primary, Vlachogiannis, George, additional, Jamin, Yann, additional, Khan, Khurum, additional, Fernandez-mateos, Javier, additional, Hahne, Jens C., additional, Rata, Michaela, additional, Koh, Dow-Ku, additional, Tunariu, Nina, additional, Collins, David, additional, Bali, Monia, additional, Chau, Ian, additional, Rao, Sheela, additional, Watkins, David, additional, Sterling, Naureen, additional, Fotoadis, Nicos, additional, Huntingford, Ian, additional, Gegum, Ruwaida, additional, Rana, Isma, additional, Rugge, Massimo, additional, Braconi, Chiara, additional, Fassan, Matteo, additional, Eccles, Suzanne, additional, Robinson, Simon P., additional, Cunningham, David, additional, and Valeri, Nicola, additional

Published
2017
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33. Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells

Author

Ferraldeschi, Roberta, primary, Welti, Jonathan, additional, Powers, Marissa V., additional, Yuan, Wei, additional, Smyth, Tomoko, additional, Seed, George, additional, Riisnaes, Ruth, additional, Hedayat, Somaieh, additional, Wang, Hannah, additional, Crespo, Mateus, additional, Nava Rodrigues, Daniel, additional, Figueiredo, Ines, additional, Miranda, Susana, additional, Carreira, Suzanne, additional, Lyons, John F., additional, Sharp, Swee, additional, Plymate, Stephen R., additional, Attard, Gerhardt, additional, Wallis, Nicola, additional, Workman, Paul, additional, and de Bono, Johann S., additional

Published
2016
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34. Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study.

Author

Khurum Khan, Rata, Mihaela, Cunningham, David, Dow-Mu Koh, Tunariu, Nina, Hahne, Jens C., Vlachogiannis, George, Hedayat, Somaieh, Marchetti, Silvia, Lampis, Andrea, Damavandi, Mahnaz Darvish, Lote, Hazel, Rana, Isma, Williams, Anja, Eccles, Suzanne A., Fontana, Elisa, Collins, David, Eltahir, Zakaria, Rao, Sheela, and Watkins, David

Subjects
COLON cancer treatment, REGORAFENIB, METASTASIS, FUNCTIONAL imaging sensors, ANTINEOPLASTIC agents
Published
2018
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36. Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

Author

Khan, Khurum, Rata, Mihaela, Cunningham, David, Koh, Dow-Mu, Tunariu, Nina, Hahne, Jens C, Vlachogiannis, George, Hedayat, Somaieh, Marchetti, Silvia, Lampis, Andrea, Damavandi, Mahnaz Darvish, Lote, Hazel, Rana, Isma, Williams, Anja, Eccles, Suzanne A, Fontana, Elisa, Collins, David, Eltahir, Zakaria, Rao, Sheela, Watkins, David, Starling, Naureen, Thomas, Jan, Kalaitzaki, Eleftheria, Fotiadis, Nicos, Begum, Ruwaida, Bali, Maria, Rugge, Massimo, Temple, Eleanor, Fassan, Matteo, Chau, Ian, Braconi, Chiara, and Valeri, Nicola

Abstract

ObjectiveRegorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.DesignPatients with RASmutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RASmutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.ResultsTwenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RASmutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).ConclusionsCombining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

Published
2018
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37. Abstract 2433: In vitro and in vivo antitumor activity of the next generation HSP90 inhibitor, AT13387, in both hormone-sensitive and castration-resistant prostate cancer models.

Author

Ferraldeschi, Roberta, primary, Hedayat, Somaieh, additional, Smyth, Tomoko, additional, Wallis, Nicola, additional, Lyons, John, additional, Riisnaes, Ruth, additional, Crespo, Mateus, additional, Nava Rodrigues, Daniel, additional, Miranda, Susana, additional, Sharp, Swee, additional, Attard, Gerhardt, additional, Eccles, Suzanne, additional, Workman, Paul, additional, and de Bono, Johann, additional

Published
2013
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39. Modulation of Biliary Cancer Chemo-Resistance Through MicroRNA-Mediated Rewiring of the Expansion of CD133+ Cells.

Author

Carotenuto P, Hedayat S, Fassan M, Cardinale V, Lampis A, Guzzardo V, Vicentini C, Scarpa A, Cascione L, Costantini D, Carpino G, Alvaro D, Ghidini M, Trevisani F, Te Poele R, Salati M, Ventura S, Vlachogiannis G, Hahne JC, Boulter L, Forbes SJ, Guest RV, Cillo U, Said-Huntingford I, Begum R, Smyth E, Michalarea V, Cunningham D, Rimassa L, Santoro A, Roncalli M, Kirkin V, Clarke P, Workman P, Valeri N, and Braconi C

Subjects
Antineoplastic Agents pharmacology, CRISPR-Cas Systems, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Deoxycytidine pharmacology, Drug Discovery, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic, High-Throughput Screening Assays methods, Humans, Xenograft Model Antitumor Assays, Gemcitabine, Biliary Tract Neoplasms drug therapy, Biliary Tract Neoplasms metabolism, Biliary Tract Neoplasms pathology, Cholangiocarcinoma drug therapy, Cholangiocarcinoma metabolism, Cholangiocarcinoma pathology, Cisplatin pharmacology, Deoxycytidine analogs & derivatives, MicroRNAs antagonists & inhibitors, MicroRNAs metabolism
Abstract

Background and Aims: Changes in single microRNA (miRNA) expression have been associated with chemo-resistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy., Approach and Results: High-throughput screening (HTS) of 997 locked nucleic acid miRNA inhibitors was performed in six cholangiocarcinoma cell lines treated with cisplatin and gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with mirVana probes. MicroRNA and gene expression was assessed by TaqMan assay, RNA-sequencing, and in situ hybridization in four independent cohorts of human BTCs. Knockout of microRNA was achieved by CRISPR-CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in vitro and in vivo. HTS revealed that MIR1249 inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTCs. In validation experiments, MIR1249 inhibition did not alter cell viability in untreated or dimethyl sulfoxide-treated cells; however, it did increase the CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem cell niche of human BTCs as well as in CD133+ chemo-resistant CCLP cells. MIR1249 modulated the chemotherapy-induced enrichment of CD133+ cells by controlling their clonal expansion through the Wnt-regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of cancer stem cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumor shrinkage after exposure to weekly CG, whereas wild-type models showed only stable disease over treatment., Conclusions: MIR1249 mediates resistance to CG in BTCs and may be tested as a target for therapeutics., (© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Published
2020
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40. miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial.

Author

Anandappa G, Lampis A, Cunningham D, Khan KH, Kouvelakis K, Vlachogiannis G, Hedayat S, Tunariu N, Rao S, Watkins D, Starling N, Braconi C, Darvish-Damavandi M, Lote H, Thomas J, Peckitt C, Kalaitzaki R, Khan N, Fotiadis N, Rugge M, Begum R, Rana I, Bryant A, Hahne JC, Chau I, Fassan M, and Valeri N

Subjects
Aged, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological adverse effects, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Colorectal Neoplasms diagnosis, Colorectal Neoplasms mortality, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Female, Humans, Immunohistochemistry, In Situ Hybridization, Male, Middle Aged, Molecular Targeted Therapy, Prognosis, Retreatment, Tomography, X-Ray Computed, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Gene Expression, MicroRNAs genetics
Abstract

Purpose: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs., Experimental Design: miR-31-3p was tested by in situ hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and RAS status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination., Results: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer)., Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs., (©2019 American Association for Cancer Research.)

Published
2019
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