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126 results on '"Spanswick, Victoria"'

1. PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer

Author

Propper, David J., Gao, Fangfei, Saunders, Mark P., Sarker, Debashis, Hartley, John A., Spanswick, Victoria J., Lowe, Helen L., Hackett, Louise D., Ng, Tony T., Barber, Paul R., Weitsman, Gregory E., Pearce, Sarah, White, Laura, Lopes, Andre, Forsyth, Sharon, and Hochhauser, Daniel

Published
2023
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2. Protocol for the EACH trial: a multicentre phase II study evaluating the safety and antitumour activity of the combination of avelumab, an anti-PD-L1 agent, and cetuximab, as any line treatment for patients with recurrent/metastatic head and neck squamous cell cancer (HNSCC) in the UK

Author

Ng, Kenrick, primary, Metcalf, Rob, additional, Sacco, Joseph, additional, Kong, Anthony, additional, Wheeler, Graham, additional, Forsyth, Sharon, additional, Bhat, Reshma, additional, Ward, Joseph, additional, Ensell, Leah, additional, Lowe, Helen, additional, Spanswick, Victoria, additional, Hartley, John, additional, White, Laura, additional, Lloyd-Dehler, Elizabeth, additional, and Forster, Martin, additional

Published
2023
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3. Body composition and lung cancer-associated cachexia in TRACERx

Author

Al-Sawaf, Othman, Weiss, Jakob, Skrzypski, Marcin, Lam, Jie Min, Karasaki, Takahiro, Zambrana, Francisco, Kidd, Andrew C, Frankell, Alexander M, Watkins, Thomas BK, Martinez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Huebner, Ariana, Al Bakir, Maise, Sokac, Mateo, Collins, Susie, Veeriah, Selvaraju, Magno, Neil, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Ward, Sophia, Jayanth, Nick, Salgado, Roberto, Bridge, Christopher P, Christiani, David C, Mak, Raymond H, Bay, Camden, Rosenthal, Michael, Sattar, Naveed, Welsh, Paul, Liu, Ying, Perrimon, Norbert, Popuri, Karteek, Beg, Mirza Faisal, McGranahan, Nicholas, Hackshaw, Allan, Breen, Danna M, O'Rahilly, Stephen, Birkbak, Nicolai J, Aerts, Hugo JWL, Jamal-Hanjani, Mariam, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Van Loo, Peter, Szallasi, Zoltan, Kisistok, Judit, Diossy, Miklos, Demeulemeester, Jonas, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Abbosh, Christopher, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Hiley, Crispin T, Moore, David A, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Cadieux, Elizabeth Larose, Lim, Emilia L, Colliver, Emma, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Hartley, John A, Peggs, Karl S, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Grigoriadis, Kristiana, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Hill, Mark S, Dietzen, Michelle, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Pich, Oriol, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Zaccaria, Simone, Hessey, Sonya, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Male, Proteomics, Cachexia, Lung Neoplasms, Antigens, Neoplasm, Carcinoma, Non-Small-Cell Lung, Body Weight, Body Composition, Humans, Neoplasm Recurrence, Local, Muscle, Skeletal, Neoplasm Proteins
Abstract

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

4. The evolution of non-small cell lung cancer metastases in TRACERx

Author

Al Bakir, Maise, Huebner, Ariana, Martinez-Ruiz, Carlos, Grigoriadis, Kristiana, Watkins, Thomas BK, Pich, Oriol, Moore, David A, Veeriah, Selvaraju, Ward, Sophia, Laycock, Joanne, Johnson, Diana, Rowan, Andrew, Razaq, Maryam, Akther, Mita, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Hessey, Sonya, Dietzen, Michelle, Colliver, Emma, Frankell, Alexander, Bunkum, Abigail, Lim, Emilia L, Karasaki, Takahiro, Abbosh, Christopher, Hiley, Crispin T, Hill, Mark S, Cook, Daniel E, Wilson, Gareth A, Salgado, Roberto, Nye, Emma, Stone, Richard Kevin, Fennell, Dean A, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Summers, Yvonne, Lindsay, Colin R, Blackhall, Fiona H, Cave, Judith, Blyth, Kevin G, Nair, Arjun, Ahmed, Asia, Taylor, Magali N, Procter, Alexander James, Falzon, Mary, Lawrence, David, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Papadatos-Pastos, Dionysis, Forster, Martin D, Lee, Siow Ming, Ahmad, Tanya, Quezada, Sergio, Peggs, Karl S, Van Loo, Peter, Dive, Caroline, Hackshaw, Allan, Birkbak, Nicolai J, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Benafif, Sarah, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Krebs, Matthew G, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Puttick, Clare, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Black, James RM, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Clonal Evolution, Cohort Studies, Evolution, Molecular, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Disease Progression, Humans, Neoplasm Metastasis, Neoplasm Recurrence, Local, Clone Cells
Abstract

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

5. The evolution of lung cancer and impact of subclonal selection in TRACERx

Author

Frankell, Alexander M, Dietzen, Michelle, Al Bakir, Maise, Lim, Emilia L, Karasaki, Takahiro, Ward, Sophia, Veeriah, Selvaraju, Colliver, Emma, Huebner, Ariana, Bunkum, Abigail, Hill, Mark S, Grigoriadis, Kristiana, Moore, David A, Black, James RM, Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas BK, Naceur-Lombardelli, Cristina, Cook, Daniel E, Salgado, Roberto, Wilson, Gareth A, Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martinez-Ruiz, Carlos, Abbosh, Christopher, Nicholson, Andrew G, Le Quesne, John, Biswas, Dhruva, Rosenthal, Rachel, Puttick, Clare, Hessey, Sonya, Lee, Claudia, Prymas, Paulina, Toncheva, Antonia, Smith, Jon, Xing, Wei, Nicod, Jerome, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Blyth, Kevin G, Fennell, Dean A, Forster, Martin D, Lee, Siow Ming, Falzon, Mary, Hewish, Madeleine, Shackcloth, Michael J, Lim, Eric, Benafif, Sarah, Russell, Peter, Boleti, Ekaterini, Krebs, Matthew G, Lester, Jason F, Papadatos-Pastos, Dionysis, Ahmad, Tanya, Thakrar, Ricky M, Lawrence, David, Navani, Neal, Janes, Sam M, Dive, Caroline, Blackhall, Fiona H, Summers, Yvonne, Cave, Judith, Marafioti, Teresa, Herrero, Javier, Quezada, Sergio A, Peggs, Karl S, Schwarz, Roland F, Van Loo, Peter, Miedema, Daniel M, Birkbak, Nicolai J, Hiley, Crispin T, Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joa, Primrose, Lindsay, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Kaufmann, Tom L, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran L, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Rane, Jayant K, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Danson, Sarah, Robinson, Lily, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Lung Neoplasms, Treatment Outcome, DNA Copy Number Variations, Mutagenesis, Carcinoma, Non-Small-Cell Lung, Mutation, Smoking, Humans, Adenocarcinoma of Lung, Neoplasm Recurrence, Local, Phylogeny
Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

6. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Author

Karasaki, Takahiro, Moore, David A, Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Magno, Neil, Ward, Sophia, Al Bakir, Maise, Watkins, Thomas BK, Grigoriadis, Kristiana, Huebner, Ariana, Hill, Mark S, Frankell, Alexander M, Abbosh, Christopher, Puttick, Clare, Zhai, Haoran, Gimeno-Valiente, Francisco, Saghafinia, Sadegh, Kanu, Nnennaya, Dietzen, Michelle, Pich, Oriol, Lim, Emilia L, Martinez-Ruiz, Carlos, Black, James RM, Biswas, Dhruva, Campbell, Brittany B, Lee, Claudia, Colliver, Emma, Enfield, Katey SS, Hessey, Sonya, Hiley, Crispin T, Zaccaria, Simone, Litchfield, Kevin, Birkbak, Nicolai J, Cadieux, Elizabeth Larose, Demeulemeester, Jonas, Van Loo, Peter, Adusumilli, Prasad R, Tan, Kay See, Cheema, Waseem, Sanchez-Vega, Francisco, Jones, David R, Rekhtman, Natasha, Travis, William D, Hackshaw, Allan, Marafioti, Teresa, Salgado, Roberto, Le Quesne, John, Nicholson, Andrew G, McGranahan, Nicholas, Swanton, Charles, Jamal-Hanjani, Mariam, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Castignani, Carla, Bailey, Chris, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Peggs, Karl S, Selvaraju, Kayalvizhi, Thol, Kerstin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Prymas, Paulina, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
TRACERx Consortium
Abstract

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

11. Supplementary Data from Phase I Pharmacokinetic and Pharmacodynamic Study of SJG-136, a Novel DNA Sequence Selective Minor Groove Cross-linking Agent, in Advanced Solid Tumors

Author

Puzanov, Igor, primary, Lee, Wooin, primary, Chen, Alice P., primary, Calcutt, M. Wade, primary, Hachey, David L., primary, Vermeulen, Wendy L., primary, Spanswick, Victoria J., primary, Liao, Chih-Yi, primary, Hartley, John A., primary, Berlin, Jordan D., primary, and Rothenberg, Mace L., primary

Published
2023
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13. Long-Term Follow-up of AUTO1, a Fast-Off Rate CD19 CAR, in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia and Factors Associated with Durable Response

Author

Roddie, Claire, primary, Dias, Juliana, additional, O’Reilly, Maeve, additional, Mitsikakou, Marina, additional, Charalambous, Eftychia, additional, Green, Louisa, additional, Vaughn, Mhairi, additional, Agliardi, Giulia, additional, Garcia, John, additional, Lewin, Evie, additional, Lowdell, Mark, additional, Marzolini, Maria, additional, Holmes, Helen, additional, Ngai, Yenting, additional, Popova, Bilyana, additional, Wilson, William, additional, Kunaseelan, Sangeetha, additional, Spanswick, Victoria, additional, Lowe, Helen, additional, Ensell, Leah, additional, Hartley, John, additional, Linch, David, additional, Bloor, Adrian J, additional, Irvine, David, additional, Pule, Martin, additional, and Peggs, Karl S., additional

Published
2023
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14. Molecular mechanisms of bioreductive drug activation in solid tumour tissue

Author

Spanswick, Victoria Jane

Subjects
615.1
Abstract

The enzymology of mitomycin C bioactivation was studied in vitro in two solid mouse adenocarcinomas of the colon MAC 16 (high DTD) and MAC 26 (low DTD). Metabolism of mitomycin C by tumour subcellular fractions revealed a novel mitochondrial reductase active under hypoxia in both tumours. DTD and NADPH:cytochrome P-450 reductase activity was confirmed in MAC 16 but not MAC 26. The role of DTD was examined in a tumour homogenate system and was found to play a protective role under hypoxia in MAC 16, predominating over the other enzymes present. MAC 26 showed enhanced hypoxic metabolism due to the presence of the mitochondrial reductase. The studies were extended to a human perspective, using the human colon xenografts HT-29 (high DTD) and BE (low DTD). In vivo studies, again using the MAC tumours, revealed comparable mitomycin C metabolism and antitumour activity in both tumours. Such a result has profound implications on the use of DTD as a target of enzyme-directed bioreactive drug therapy with mitomycin C. The mitomycin C analogue indoloquinone EO9 is a promising new bioreactive drug, although little is known about its metabolism and mechanism of action. The chemical properties of the reactive intermediates of EO9 were studied under controlled conditions via pulse radiolysis, with the aim of proposing a mechanism for its cytotoxicity. Results indicated that whether EO9 undergoes reduction via one-or two-electron reduction, the hydroquinone intermediate, product of two electron reduction via enzymes such as DTD, will predominate and dictate the pattern of cytotoxicity. This suggests a central role of DTD. In vitro metabolism of EO9 by the tumours described above produced a number of metabolites which proved difficult to identify via liquid-chromatography-mass spectroscopy. Unlike mitomycin C and its principle metabolite 2,7-diaminomitosene, no metabolite was found to correlate with metabolic activation under varying oxic and hypoxic conditions in conjunction with DTD activity.

Published
1997

15. Safety, Efficiency and Long-Term Follow-up of AUTO1, a Fast-Off Rate CD19 CAR in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia and Other B-Cell Malignancies

Author

Roddie, Claire, primary, Dias Alves Pinto, Juliana, additional, O'Reilly, Maeve A, additional, Mitsikakou, Marina, additional, Charalambous, Eftychia, additional, Green, Louisa, additional, Vaughan, Mhairi, additional, Agliardi, Giulia, additional, Garcia, John, additional, Lewin, Evie, additional, Lowdell, Mark W., additional, Marzolini, Maria A V, additional, Wood, Leigh, additional, Holmes, Helen, additional, Ngai, Yenting, additional, Popova, Bilyana, additional, Wilson, William, additional, Kunaseelan, Sangeetha, additional, Spanswick, Victoria, additional, Lowe, Helen, additional, Ensell, Leah, additional, Hartley, John A., additional, Morley, Simon, additional, Linch, David C., additional, Bloor, Adrian, additional, Irvine, David A., additional, Pule, Martin, additional, and Peggs, Karl S, additional

Published
2022
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16. PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer

Author

Propper, David J., primary, Gao, Fangfei, additional, Saunders, Mark P., additional, Sarker, Debashis, additional, Hartley, John A., additional, Spanswick, Victoria J., additional, Lowe, Helen L., additional, Hackett, Louise D., additional, Ng, Tony T., additional, Barber, Paul R., additional, Weitsman, Gregory E., additional, Pearce, Sarah, additional, White, Laura, additional, Lopes, Andre, additional, Forsyth, Sharon, additional, and Hochhauser, Daniel, additional

Published
2022
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17. Safety and Efficacy of AUTO1, a Fast-Off Rate CD19 CAR in Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma (B-NHL) and Chronic Lymphocytic Leukaemia (CLL)

Author

Roddie, Claire, primary, Dias, Juliana, additional, O'Reilly, Maeve A, additional, Cadinanos Garai, Amaia, additional, Green, Louisa, additional, Abbasian, Mahnaz, additional, Mitsikakou, Marina, additional, Vaughan, Mhairi, additional, Meyer Cantinho Pereira, Vitoria, additional, Marzolini, Maria A V, additional, Wood, Leigh, additional, Olejnik, Joanna, additional, Ngai, Yenting, additional, Popova, Bilyana, additional, Wilson, William, additional, Spanswick, Victoria, additional, Lowe, Helen, additional, Ensell, Leah, additional, Hartley, John A., additional, Farzaneh, Farzin, additional, Lowdell, Mark W., additional, Linch, David C., additional, Pule, Martin, additional, and Peggs, Karl S, additional

Published
2021
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19. Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Author

Roddie, Claire, primary, Dias, Juliana, additional, O'Reilly, Maeve A., additional, Abbasian, Mahnaz, additional, Cadinanos-Garai, Amaia, additional, Vispute, Ketki, additional, Bosshard-Carter, Leticia, additional, Mitsikakou, Marina, additional, Mehra, Vedika, additional, Roddy, Harriet, additional, Hartley, John A., additional, Spanswick, Victoria, additional, Lowe, Helen, additional, Popova, Bilyana, additional, Clifton-Hadley, Laura, additional, Wheeler, Graham, additional, Olejnik, Joanna, additional, Bloor, Adrian, additional, Irvine, David, additional, Wood, Leigh, additional, Marzolini, Maria A. V., additional, Domning, Sabine, additional, Farzaneh, Farzin, additional, Lowdell, Mark W., additional, Linch, David C., additional, Pule, Martin A., additional, and Peggs, Karl S., additional

Published
2021
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21. ALLCAR19: Updated Data Using AUTO1, a Novel Fast-Off Rate CD19 CAR in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia and Other B-Cell Malignancies

Author

Roddie, Claire, primary, O'Reilly, Maeve A, additional, Marzolini, Maria A V, additional, Wood, Leigh, additional, Dias, Juliana, additional, Cadinanos Garai, Amaia, additional, Bosshard, Leticia, additional, Abbasian, Mahnaz, additional, Lowdell, Mark W., additional, Wheeler, Graham, additional, Olejnik, Joanna, additional, Popova, Bilyana, additional, Clifton-Hadley, Laura, additional, Pathak, Yashma, additional, Spanswick, Victoria, additional, Lowe, Helen, additional, Hartley, John A., additional, Syed, Farhatullah, additional, Qasim, Waseem, additional, Farzaneh, Farzin, additional, Linch, David C., additional, Pule, Martin, additional, and Peggs, Karl S, additional

Published
2020
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22. 277 - Long-Term Follow-up of AUTO1, a Fast-Off Rate CD19 CAR, in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia and Factors Associated with Durable Response

Author

Roddie, Claire, Dias, Juliana, O’Reilly, Maeve, Mitsikakou, Marina, Charalambous, Eftychia, Green, Louisa, Vaughn, Mhairi, Agliardi, Giulia, Garcia, John, Lewin, Evie, Lowdell, Mark, Marzolini, Maria, Holmes, Helen, Ngai, Yenting, Popova, Bilyana, Wilson, William, Kunaseelan, Sangeetha, Spanswick, Victoria, Lowe, Helen, Ensell, Leah, Hartley, John, Linch, David, Bloor, Adrian J, Irvine, David, Pule, Martin, and Peggs, Karl S.

Published
2023
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25. Automated Manufacture of Matched Donor-Derived Allogeneic CD19 CAR T-Cells for Relapsed/Refractory B-ALL Following Allogeneic Stem Cell Transplantation: Toxicity, Efficacy and the Important Role of Lymphodepletion

Author

Roddie, Claire, primary, O'Reilly, Maeve A, primary, Marzolini, Maria A V, primary, Wood, Leigh, primary, Dias Alves Pinto, Juliana, primary, Abbasian, Mahnaz, primary, Vispute, Ketki, primary, Bosshard, Leticia, primary, Lowdell, Mark W., primary, Wheeler, Graham, primary, Day, Alex, primary, Popova, Bilyana, primary, Champion, Kim, primary, Pathak, Yashma, primary, Gali, Alexia, primary, Mahmoud, Nasir, primary, Spanswick, Victoria, primary, Lowe, Helen, primary, Hartley, John A., primary, Farzaneh, Farzin, primary, Nickolay, Lauren, primary, Syed, Fahetullah, primary, Qasim, Waseem, primary, Linch, David C., primary, Pule, Martin, primary, and Peggs, Karl S, primary

Published
2019
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26. AUTO1, a Novel Fast Off CD19CAR Delivers Durable Remissions and Prolonged CAR T Cell Persistence with Low CRS or Neurotoxicity in Adult ALL

Author

Roddie, Claire, primary, O'Reilly, Maeve A, primary, Marzolini, Maria A V, primary, Wood, Leigh, primary, Dias Alves Pinto, Juliana, primary, Abbasian, Mahnaz, primary, Vispute, Ketki, primary, Lowdell, Mark W., primary, Wheeler, Graham, primary, Olejnik, Joanna, primary, Popova, Bilyana, primary, Champion, Kim, primary, Gali, Alexia, primary, Pathak, Yashma, primary, Spanswick, Victoria, primary, Lowe, Helen, primary, Hartley, John A., primary, Farzaneh, Farzin, primary, Linch, David C., primary, Pule, Martin, primary, and Peggs, Karl S, primary

Published
2019
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28. Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples

Author

Spanswick Victoria J, Lowe Helen L, Newton Claire, Bingham John P, Bagnobianchi Alessia, Kiakos Konstantinos, Craddock Charles, Ledermann Jonathan A, Hochhauser Daniel, and Hartley John A

Subjects
DNA interstrand cross-linking, Acquired drug resistance, DNA repair, DNA cross-linking agent, Melphalan, Cisplatin, Multiple myeloma, Ovarian cancer, DNA damage response, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background DNA interstrand cross-links (ICLs) are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma) and solid tumours (ovarian cancer) that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the ‘unhooking’ step is common to all ICLs. Methods Using a modification of the single cell gel electrophoresis (Comet) assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. Results Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The RAD51 foci response was both drug and cell line specific. Real time PCR studies highlighted differences in the damage response to melphalan and cisplatin following equi-ICL forming doses. Conclusions These data suggest that the mechanisms by which melphalan and cisplatin-induced ICLs are ‘unhooked’ in vitro are distinct, and the mechanisms of clinical acquired resistance involving repair of ICLs, are drug specific.

Published
2012
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29. EACH: A randomised phase II study evaluating the safety and anti-tumour activity of the combination of avelumab and cetuximab relative to avelumab monotherapy in recurrent/metastatic head and neck squamous cell cancer.

Author

Forster, Martin David, primary, Sacco, Joseph J., additional, Kong, Anthony Hee, additional, Wheeler, Graham, additional, Forsyth, Sharon, additional, Bhat, Reshma, additional, Blair, Kameka, additional, Lowe, Helen, additional, Spanswick, Victoria J, additional, Ensell, Leah, additional, Hartley, John A., additional, and White, Laura, additional

Published
2019
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32. Additional file 1: Table S1. of Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

Author

Mellinas-Gomez, Maria, Spanswick, Victoria, Paredes-Moscosso, Solange, Robson, Matthew, R. Pedley, Thurston, David, Baines, Stephen, Stell, Anneliese, and Hartley, John

Abstract

Specific culture media and supplements required for optimum canine cell lines growth. EMEM - Eagle’s Minimal Essential Medium, DMEM - Dulbecco’s Modified Eagle Medium, RPMI - Royal Park Memorial Institute Medium, FBS – foetal bovine serum, NEAA – non-essential amino acids. Table S2. The effect of SG2000 on the survival of LMeC xenografted mice following different SG2000 dosage regimes. Table S3. The effect of SG2000 on the survival of CMeC-1 xenografted mice following different SG2000 dosage regimes. Figure S1. In vitro cytotoxicity of SG2000 against 12 canine tumour cell lines and two canine normal cell lines. Cell viability was assessed using the SRB assay (except for cell line C2 which was assessed using the MTT assay). Results shown are the mean (± SEM) calculated from three independent experiments, expressed as a percentage absorbance at A540 nm compared to untreated control cells. A) 1 h exposure to SG2000 followed by 96 h post-incubation in drug-free medium. B) Continuous (96 h) exposure to SG2000. (PDF 404 kb)

Published
2015
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33. Long-Term Efficacy and Safety of Obecabtagene Autoleucel (obe-cel) in Adult Patients (pts) with Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia ([R/R B-ALL]; Pooled Analysis from ALLCAR19 and FELIX Phase Ib Studies) or Other B-cell Malignancies (ALLCAR19 Extension Study)

Author

Roddie, Claire, Tholouli, Eleni, Shaughnessy, Paul, Jabbour, Elias, Logan, Aaron C., Hodby, Katharine, Mountjoy, Luke, Bloor, Adrian John Clifton, Irvine, David, Linch, David C., Orchard, Kim H., Wilson, William, Popova, Bilyana, Dias, Juliana, Agliardi, Giulia, Spanswick, Victoria, Lowe, Helen, Mitsikakou, Marina, Charalambous, Eftychia, Dawes, Joanna, Raymond, Meera, Hu, Yanqing, Brugger, Wolfram, Pule, Martin A., Park, Jae H., and Peggs, Karl

Abstract

Background:Obe-cel is an autologous CD19 chimeric antigen receptor (CAR) T cell product designed to reduce toxicity and improve persistence through a fast off-rate CD19 binding domain. The clinical activity of obe-cel has been explored in adults with R/R B-ALL in a Phase I study (ALLCAR19, NCT02935257; Roddie C et al. J Clin Oncol 2021) and a Phase Ib/II study (FELIX, NCT04404660; Roddie C et al. J Clin Oncol 2023;41[16 Suppl]:7000). Additionally, obe-cel has been tested in pts with R/R B-cell chronic lymphocytic leukemia (B-CLL) and R/R B-cell non-Hodgkin lymphoma (B-NHL) (ALLCAR19 extension; Roddie C et al. Blood 2022;140[1 Suppl]:7452-3). Pts from the ALLCAR19 and FELIX Phase Ib studies are in long-term follow up (≥22 mos), and the ALLCAR19 extension has been recruiting for 3 years. We report an analysis of long-term efficacy and safety data from the ALLCAR19 and FELIX Phase Ib studies, as well as data from the ALLCAR19 extension.

Published
2023
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34. Development of a Phase 1 Study Evaluating the Activity of Modular CAR T for Multiple Myeloma (MCARTY) Targeting BCMA and CD19 for Improved Persistence

Author

Lee, Lydia Sarah Hui, Lim, Wen Chean, Mactier, Catriona, Dias Alves Pinto, Juliana, Pereira, Vitoria, Vaughan, Mhairi, Green, Louisa, Lewin, Evie, Garcia, John, Agliardi, Giulia, Pathak, Yashma, Jannoo, Riaz, Wood, Leigh, Popova, Bilyana, Holmes, Helen, Thomas, Simon, Spanswick, Victoria, Wilson, William, Parrish, Christopher, Popat, Rakesh, Roddie, Claire, Yong, Kwee, and Pule, Martin A.

Abstract

BCMA directed CAR T cell therapy for multiple myeloma (MM) shows promise, but very long-term survival may be limited. Notably, BCMA CAR T persistence in MM is shorter than that seen in with CD19 CAR T cells in B cell malignancies where long-term CD19 CAR T persistence is associated with durable responses. Shorter BCMA CAR T persistence may be explained by the lower surface density of BCMA on tumour compared with that of CD19. Alternatively, CD19 CAR T persistence may be driven by recognition of continuous emergence of newly differentiated B cells.

Published
2023
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35. ORCA-2: A phase I study of olaparib in addition to cisplatin-based concurrent chemoradiotherapy for patients with high risk locally advanced squamous cell carcinoma of the head and neck.

Author

Forster, Martin David, primary, Mendes, Ruheena, additional, Harrington, Kevin J., additional, Guerrero Urbano, Teresa, additional, Baines, Helen, additional, Spanswick, Victoria J, additional, Ensell, Leah, additional, Hartley, John A., additional, Adeleke, Sola, additional, Gougis, Paul, additional, Leader, David, additional, McDowell, Cathy, additional, Lopes, Andre, additional, Teague, Jonathan, additional, Forsyth, Sharon, additional, and Beare, Sandy, additional

Published
2016
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36. γ-H2AX foci formation as a pharmacodynamic marker of DNA damage produced by DNA cross-linking agents: results from two Phase I clinical trials of SJG-136 (SG2000)

Author

Wu, Jenny, Clingen, Peter H, Spanswick, Victoria J, Mellinas-Gomez, Maria, Meyer, Tim, Puzanov, Igor, Jodrell, Duncan, Hochhauser, Daniel, and Hartley, John A

Subjects
Histones, Benzodiazepinones, Pharmacogenetics, Humans, Pyrroles, Comet Assay, Lymphocytes, Fibroblasts, Article, DNA Damage
Abstract

PURPOSE: To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs. EXPERIMENTAL DESIGN: γ-H2AX foci formation was validated pre-clinically in comparison to the comet assay, and evaluated pharmacodynamically in two Phase I studies of different dosing schedules of the novel cross-linking agent SJG-136 (SG2000). RESULTS: The measurement of γ-H2AX foci in human fibroblasts and lymphocytes in vitro was >10-fold more sensitive than comet assay measurement of cross-linking, with peak γ-H2AX response 24 hours after the peak of cross-linking. In lymphocytes from a Phase I study (3-weekly schedule), γ-H2AX foci were detectable 1 hour following the end of administration and in all patients maximum response was observed at 24 hours. Significant levels of foci were still evident at days 8 and 15 consistent with the known persistence of the DNA damage produced by this agent. In two tumor biopsy samples, foci were detected 4 hours post-infusion with levels higher than in lymphocytes. Extensive foci formation was also observed prior to the third dose in cycle 1 in lymphocytes from a second Phase I study (daily × 3 schedule). These foci also persisted with a significant level evident prior to the second cycle (day 21). An increased γ-H2AX response was observed during the second cycle consistent with a cumulative pharmacodynamic effect. No clear relationship between foci formation and administered drug dose was observed. CONCLUSION: This is the first use of γ-H2AX as a pharmacodynamic response to a DNA cross-linking agent in a clinical trial setting.

Published
2012

43. Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitroand in clinical acquired resistant tumour samples

Author

Spanswick, Victoria J, primary, Lowe, Helen L, additional, Newton, Claire, additional, Bingham, John P, additional, Bagnobianchi, Alessia, additional, Kiakos, Konstantinos, additional, Craddock, Charles, additional, Ledermann, Jonathan A, additional, Hochhauser, Daniel, additional, and Hartley, John A, additional

Published
2012
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45. Phase I Pharmacokinetic and Pharmacodynamic Study of SJG-136, a Novel DNA Sequence Selective Minor Groove Cross-linking Agent, in Advanced Solid Tumors

Author

Puzanov, Igor, primary, Lee, Wooin, additional, Chen, Alice P., additional, Calcutt, M. Wade, additional, Hachey, David L., additional, Vermeulen, Wendy L., additional, Spanswick, Victoria J., additional, Liao, Chih-Yi, additional, Hartley, John A., additional, Berlin, Jordan D., additional, and Rothenberg, Mace L., additional

Published
2011
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49. Quinone Oxidoreductase-2–Mediated Prodrug Cancer Therapy

Author

Middleton, Mark R., primary, Knox, Richard, additional, Cattell, Emma, additional, Oppermann, Udo, additional, Midgley, Rachel, additional, Ali, Raghib, additional, Auton, Tim, additional, Agarwal, Roshan, additional, Anderson, David, additional, Sarker, Debashis, additional, Judson, Ian, additional, Osawa, Tsuyoshi, additional, Spanswick, Victoria J., additional, Davies, Scot, additional, Hartley, John A., additional, and Kerr, David J., additional

Published
2010
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