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1. Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

Author

Guo, Christina, Sharp, Adam, Gurel, Bora, Crespo, Mateus, Figueiredo, Ines, Jain, Suneil, Vogl, Ursula, Rekowski, Jan, Rouhifard, Mahtab, Gallagher, Lewis, Yuan, Wei, Carreira, Suzanne, Chandran, Khobe, Paschalis, Alec, Colombo, Ilaria, Stathis, Anastasios, Bertan, Claudia, Seed, George, Goodall, Jane, Raynaud, Florence, Ruddle, Ruth, Swales, Karen E., Malia, Jason, Bogdan, Denisa, Tiu, Crescens, Caldwell, Reece, Aversa, Caterina, Ferreira, Ana, Neeb, Antje, Tunariu, Nina, Westaby, Daniel, Carmichael, Juliet, Fenor de la Maza, Maria Dolores, Yap, Christina, Matthews, Ruth, Badham, Hannah, Prout, Toby, Turner, Alison, Parmar, Mona, Tovey, Holly, Riisnaes, Ruth, Flohr, Penny, Gil, Jesus, Waugh, David, Decordova, Shaun, Schlag, Anna, Calì, Bianca, Alimonti, Andrea, and de Bono, Johann S.

Published
2023
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2. Development and Validation of a New BAG-1L–Specific Antibody to Quantify BAG-1L Protein Expression in Advanced Prostate Cancer

Author

Neeb, Antje, Figueiredo, Ines, Gurel, Bora, Nava Rodrigues, Daniel, Rekowski, Jan, Riisnaes, Ruth, Ferreira, Ana, Miranda, Susana, Crespo, Mateus, Westaby, Daniel, de Los Dolores Fenor de La Maza, Maria, Guo, Christina, Carmichael, Juliet, Grochot, Rafael, Tunariu, Nina, Cato, Andrew C.B., Plymate, Stephen R., de Bono, Johann S., and Sharp, Adam

Published
2023
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4. RNASEH2B loss and PARP inhibition in advanced prostate cancer

Author

Carmichael, Juliet, primary, Figueiredo, Ines, additional, Gurel, Bora, additional, Beije, Nick, additional, Yuan, Wei, additional, Rekowski, Jan, additional, Seed, George, additional, Carreira, Suzanne, additional, Bertan, Claudia, additional, Fenor de la Maza, Maria de Los Dolores, additional, Chandran, Khobe, additional, Neeb, Antje, additional, Welti, Jon, additional, Gallagher, Lewis, additional, Bogdan, Denisa, additional, Crespo, Mateus, additional, Riisnaes, Ruth, additional, Ferreira, Ana, additional, Miranda, Susana, additional, Lu, Jinqiu, additional, Shen, Michael M., additional, Hall, Emma, additional, Porta, Nuria, additional, Westaby, Daniel, additional, Guo, Christina, additional, Grochot, Rafael, additional, Lord, Christopher J., additional, Mateo, Joaquin, additional, Sharp, Adam, additional, and de Bono, Johann, additional

Published
2024
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6. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

Author

Mateo, Joaquin, Carreira, Suzanne, Sandhu, Shahneen, Miranda, Susana, Mossop, Helen, Perez-Lopez, Raquel, Nava Rodrigues, Daniel, Robinson, Dan, Omlin, Aurelius, Tunariu, Nina, Boysen, Gunther, Porta, Nuria, Flohr, Penny, Gillman, Alexa, Figueiredo, Ines, Paulding, Claire, Seed, George, Jain, Suneil, Ralph, Christy, Protheroe, Andrew, Hussain, Syed, Jones, Robert, Elliott, Tony, McGovern, Ursula, Bianchini, Diletta, Goodall, Jane, Zafeiriou, Zafeiris, Williamson, Chris T, Ferraldeschi, Roberta, Riisnaes, Ruth, Ebbs, Bernardette, Fowler, Gemma, Roda, Desamparados, Yuan, Wei, Wu, Yi-Mi, Cao, Xuhong, Brough, Rachel, Pemberton, Helen, A'Hern, Roger, Swain, Amanda, Kunju, Lakshmi P, Eeles, Rosalind, Attard, Gerhardt, Lord, Christopher J, Ashworth, Alan, Rubin, Mark A, Knudsen, Karen E, Feng, Felix Y, Chinnaiyan, Arul M, Hall, Emma, and de Bono, Johann S

Subjects
Genetics, Urologic Diseases, Human Genome, Prostate Cancer, Cancer, Clinical Research, 6.1 Pharmaceuticals, 6.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Adult, Aged, Anemia, Antineoplastic Agents, Ataxia Telangiectasia Mutated Proteins, DNA Repair, Drug Resistance, Neoplasm, Enzyme Inhibitors, Fatigue, Genes, BRCA2, Genes, Tumor Suppressor, Humans, Male, Middle Aged, Mutation, Neoplasm Metastasis, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Prostatic Neoplasms, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundProstate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.MethodsWe conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.ResultsOverall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.ConclusionsTreatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

Published
2015

7. Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010)

Author

Ring, Alistair, primary, Kilburn, Lucy S., additional, Pearson, Alex, additional, Moretti, Laura, additional, Afshari-Mehr, Angelica, additional, Wardley, Andrew M., additional, Gurel, Bora, additional, Macpherson, Iain R., additional, Riisnaes, Ruth, additional, Baird, Richard D., additional, Martin, Sue, additional, Roylance, Rebecca, additional, Johnson, Hannah, additional, Ferreira, Ana, additional, Winter, Matthew C., additional, Dunne, Kathryn, additional, Copson, Ellen, additional, Hickish, Tamas, additional, Burcombe, Russell, additional, Randle, Kat, additional, Serra, Violeta, additional, Llop-Guevara, Alba, additional, Bliss, Judith M., additional, and Turner, Nicholas C., additional

Published
2023
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8. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer

Author

Sharp, Adam, Coleman, Ilsa, Yuan, Wei, Sprenger, Cynthia, Dolling, David, Rodrigues, Daniel Nava, Russo, Joshua W., Figueiredo, Ines, Bertan, Claudia, Seed, George, Riisnaes, Ruth, Uo, Takuma, Neeb, Antje, Welti, Jonathan, Morrissey, Colm, Carreira, Suzanne, Luo, Jun, Nelson, Peter S., Balk, Steven P., True, Lawrence D., de Bono, Johann S., and Plymate, Stephen R.

Subjects
Biology -- Usage, Cancer patients -- Health aspects, Gene expression -- Research, Prostate cancer -- Genetic aspects -- Diagnosis -- Development and progression, Health care industry
Abstract

BACKGROUND. Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue.METHODS. Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, full-length androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined.RESULTS. We demonstrated that AR-V7 protein is rarely expressed (CONCLUSION. This study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology and to confirm the clinical significance of AR-V7.FUNDING. Work at the University of Washington and in the Plymate and Nelson laboratories is supported by the Department of Defense Prostate Cancer Research Program (W81XWH-14-2-0183, W81XWH-12-PCRP-TIA, W81XWH-15-1-0430, and W81XWH-13-2-0070), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the Institute for Prostate Cancer Research, the Veterans Affairs Research Program, the NIH/National Cancer Institute (P01CA163227), and the Prostate Cancer Foundation. Work in the de Bono laboratory was supported by funding from the Movember Foundation/Prostate Cancer UK (CEO13-2-002), the US Department of Defense (W81XWH-13-2-0093), the Prostate Cancer Foundation (20131017 and 20131017-1), Stand Up To Cancer (SU2C-AACR-DT0712), Cancer Research UK (CRM108X-A25144), and the UK Department of Health through an Experimental Cancer Medicine Centre grant (ECMC-CRM064X)., IntroductionProstate cancer (PC) is the most commonly diagnosed noncutaneous cancer and the second leading cause of male cancer-related death in the Western world (1). Androgen receptor (AR) signaling is critical [...]

Published
2019
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9. Abstract CT093: Preliminary evidence of antitumor activity of Ipatasertib (Ipat) and Atezolizumab (A) in glioblastoma (GBM) patients (pts) with PTEN loss in the Phase 1 Ice-CAP trial (NCT03673787)

Author

Tiu, Crescens, primary, Yau, Wing Hing, additional, Welsh, Liam C., additional, Jones, Timothy L., additional, Zachariou, Anna, additional, Prout, Toby, additional, Parmar, Mona, additional, Turner, Alison J., additional, Daly, Robert W., additional, Yap, Christina, additional, Crespo, Mateus, additional, Gurel, Bora, additional, Riisnaes, Ruth M., additional, DeCordova, Shaun A., additional, Swales, Karen E., additional, Banerji, Udai, additional, Minchom, Anna R., additional, Sharp, Adam, additional, de Bono, Johann S., additional, and Lopez, Juanita S., additional

Published
2023
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10. B7-H3 as a Therapeutic Target in Advanced Prostate Cancer

Author

Guo, Christina, Figueiredo, Ines, Gurel, Bora, Neeb, Antje, Seed, George, Crespo, Mateus, Carreira, Suzanne, Rekowski, Jan, Buroni, Lorenzo, Welti, Jon, Bogdan, Denisa, Gallagher, Lewis, Sharp, Adam, Fenor de la Maza, Maria D., Rescigno, Pasquale, Westaby, Daniel, Chandran, Khobe, Riisnaes, Ruth, Ferreira, Ana, Miranda, Susana, and Alimonti, Andrea

Subjects
Prostate cancer, Neuroendocrine, B7-H3, Antibody drug conjugate, DNA damage repair, Adenocarcinoma
Abstract

Background: B7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development of and patient selection for B7-H3 targeted therapies. Objective: To characterise B7-H3 expression in same-patient hormone-sensitive (HSPC) and castration-resistant (CRPC) PC biopsies, associating this with PC genomics, and to evaluate the antitumour activity of an anti–B7-H3 antibody-drug conjugate (ADC) in human CRPC in vitro and in vivo. Design, setting, and participants: We performed immunohistochemistry and next-generation sequencing on a cohort of 98 clinically annotated CRPC biopsies, including 72 patients who also had HSPC biopsies for analyses. We analysed two CRPC transcriptome and exome datasets, and PC scRNASeq datasets. PC organoids (patient-derived xenograft [PDX]-derived organoids [PDX-Os]) were derived from PDXs generated from human CRPC biopsies. Outcome measurements and statistical analysis: We evaluated B7-H3 mRNA expression in relation to a panel of 770 immune-related genes, compared B7-H3 protein expression between same-patient HSPC and CRPC biopsies, determined associations with PC genomic alterations, and evaluated the antitumour activity of DS-7300a, a topoisomerase-1 inhibitor payload anti–B7-H3 ADC, in human PC cell lines, organoids (PDX-Os), and xenografts (PDXs) of different histologies, B7-H3 expressions, and genomics. Results and limitations: B7-H3 was among the most highly expressed immunomodulatory genes in CRPCs. Most CRPCs (93%) expressed B7-H3, and in patients who developed CRPC, B7-H3 expression was frequently expressed at the time of HSPC diagnosis (97%). Conversion from B7-H3 positive to negative, or vice versa, during progression from HSPC to CRPC was uncommon. CRPC with neuroendocrine features were more likely to be B7-H3 negative (28%) than adenocarcinomas. B7-H3 is overexpressed in tumours with defective DNA repair gene (ATM and BRCA2) alterations and is associated with ERG expression, androgen receptor (AR) expression, and AR activity signature. DS7300a had antitumour activity against B7-H3 expressing human PC models including cell lines, PDX-Os, and PDXs of adenocarcinoma and neuroendocrine histology. Conclusions: The frequent overexpression of B7-H3 in CRPC compared with normal tissue and other B7 family members implicates it as a highly relevant therapeutic target in these diseases. Mechanisms driving differences in B7-H3 expression across genomic subsets warrant investigation for understanding the role of B7-H3 in cancer growth and for the clinical development of B7-H3 targeted therapies. Patient summary: B7-H3, a protein expressed on the surface of the most lethal prostate cancers, in particular those with specific mutations, can be targeted using drugs that bind B7-H3. These findings are relevant for the development of such drugs and for deciding which patients to treat with these new drugs., European Urology, 83 (3), ISSN:0302-2838

Published
2023

11. Erratum to 'B7-H3 as a Therapeutic Target in Advanced Prostate Cancer' [Eur Urol 2023;83(3):224–38]

Author

Guo, Christina, Figueiredo, Ines, Gurel, Bora, Neeb, Antje, Seed, George, Crespo, Mateus, Carreira, Suzanne, Rekowski, Jan, Buroni, Lorenzo, Welti, Jon, Bogdan, Denisa, Gallagher, Lewis, Sharp, Adam, Fenor de la Maza, Maria D., Rescigno, Pasquale, Westaby, Daniel, Chandran, Khobe, Riisnaes, Ruth, Ferreira, Ana, Miranda, Susana, and Alimonti, Andrea

Abstract

European Urology, 83 (6), ISSN:0302-2838

Published
2023
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12. SMG8/SMG9 Heterodimer Loss Modulates SMG1 Kinase to Drive ATR Inhibitor Resistance

Author

Llorca-Cardenosa, Marta J., primary, Aronson, Lauren I., additional, Krastev, Dragomir B., additional, Nieminuszczy, Jadwiga, additional, Alexander, John, additional, Song, Feifei, additional, Dylewska, Malgorzata, additional, Broderick, Ronan, additional, Brough, Rachel, additional, Zimmermann, Astrid, additional, Zenke, Frank T., additional, Gurel, Bora, additional, Riisnaes, Ruth, additional, Ferreira, Ana, additional, Roumeliotis, Theodoros, additional, Choudhary, Jyoti, additional, Pettitt, Stephen J., additional, de Bono, Johann, additional, Cervantes, Andres, additional, Haider, Syed, additional, Niedzwiedz, Wojciech, additional, Lord, Christopher J., additional, and Chong, Irene Y., additional

Published
2022
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13. A Phase I Trial of CT900, a Novel α-Folate Receptor–Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer

Author

Banerjee, Susana, primary, Michalarea, Vasiliki, additional, Ang, Joo Ern, additional, Ingles Garces, Alvaro, additional, Biondo, Andrea, additional, Funingana, Ionut-Gabriel, additional, Little, Martin, additional, Ruddle, Ruth, additional, Raynaud, Florence, additional, Riisnaes, Ruth, additional, Gurel, Bora, additional, Chua, Sue, additional, Tunariu, Nina, additional, Porter, Joanna C., additional, Prout, Toby, additional, Parmar, Mona, additional, Zachariou, Anna, additional, Turner, Alison, additional, Jenkins, Ben, additional, McIntosh, Stuart, additional, Ainscow, Ed, additional, Minchom, Anna, additional, Lopez, Juanita, additional, de Bono, Johann, additional, Jones, Robert, additional, Hall, Emma, additional, Cook, Natalie, additional, Basu, Bristi, additional, and Banerji, Udai, additional

Published
2022
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14. Systematic study of tissue factor expression in solid tumors

Author

de Bono, Johann S., primary, Harris, Jeffrey R., additional, Burm, Saskia M., additional, Vanderstichele, Adriaan, additional, Houtkamp, Mischa A., additional, Aarass, Saida, additional, Riisnaes, Ruth, additional, Figueiredo, Ines, additional, Nava Rodrigues, Daniel, additional, Christova, Rossitza, additional, Olbrecht, Siel, additional, Niessen, Hans W. M., additional, Ruuls, Sigrid R., additional, Schuurhuis, Danita H., additional, Lammerts van Bueren, Jeroen J., additional, Breij, Esther C. W., additional, and Vergote, Ignace, additional

Published
2022
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15. Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer

Author

Sowalsky, Adam G., primary, Figueiredo, Ines, additional, Lis, Rosina T., additional, Coleman, Ilsa, additional, Gurel, Bora, additional, Bogdan, Denisa, additional, Yuan, Wei, additional, Russo, Joshua W., additional, Bright, John R., additional, Whitlock, Nichelle C., additional, Trostel, Shana Y., additional, Ku, Anson T., additional, Patel, Radhika A., additional, True, Lawrence D., additional, Welti, Jonathan, additional, Jimenez-Vacas, Juan M., additional, Rodrigues, Daniel Nava, additional, Riisnaes, Ruth, additional, Neeb, Antje, additional, Sprenger, Cynthia T., additional, Swain, Amanda, additional, Wilkinson, Scott, additional, Karzai, Fatima, additional, Dahut, William L., additional, Balk, Steven P., additional, Corey, Eva, additional, Nelson, Peter S., additional, Haffner, Michael C., additional, Plymate, Stephen R., additional, de Bono, Johann S., additional, and Sharp, Adam, additional

Published
2022
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16. Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors

Author

Papadatos-Pastos, Dionysis, primary, Yuan, Wei, additional, Pal, Abhijit, additional, Crespo, Mateus, additional, Ferreira, Ana, additional, Gurel, Bora, additional, Prout, Toby, additional, Ameratunga, Malaka, additional, Chénard-Poirier, Maxime, additional, Curcean, Andra, additional, Bertan, Claudia, additional, Baker, Chloe, additional, Miranda, Susana, additional, Masrour, Nahal, additional, Chen, Wentin, additional, Pereira, Rita, additional, Figueiredo, Ines, additional, Morilla, Ricardo, additional, Jenkins, Ben, additional, Zachariou, Anna, additional, Riisnaes, Ruth, additional, Parmar, Mona, additional, Turner, Alison, additional, Carreira, Suzanne, additional, Yap, Christina, additional, Brown, Robert, additional, Tunariu, Nina, additional, Banerji, Udai, additional, Lopez, Juanita, additional, de Bono, Johann, additional, and Minchom, Anna, additional

Published
2022
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18. Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer

Author

Sheehan, Beshara, primary, Neeb, Antje, additional, Buroni, Lorenzo, additional, Paschalis, Alec, additional, Riisnaes, Ruth, additional, Gurel, Bora, additional, Gil, Veronica, additional, Miranda, Susana, additional, Crespo, Mateus, additional, Guo, Christina, additional, Jiménez Vacas, Juan, additional, Figueiredo, Ines, additional, Ferreira, Ana, additional, Welti, Jon, additional, Yuan, Wei, additional, Carreira, Suzanne, additional, Sharp, Adam, additional, and de Bono, Johann, additional

Published
2022
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19. Systematic study of tissue factor expression in solid tumors.

Author

de Bono, Johann S., Harris, Jeffrey R., Burm, Saskia M., Vanderstichele, Adriaan, Houtkamp, Mischa A., Aarass, Saida, Riisnaes, Ruth, Figueiredo, Ines, Nava Rodrigues, Daniel, Christova, Rossitza, Olbrecht, Siel, Niessen, Hans W. M., Ruuls, Sigrid R., Schuurhuis, Danita H., Lammerts van Bueren, Jeroen J., Breij, Esther C. W., and Vergote, Ignace

Published
2023
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20. HER3 Is an Actionable Target in Advanced Prostate Cancer

Author

Gil, Veronica, primary, Miranda, Susana, additional, Riisnaes, Ruth, additional, Gurel, Bora, additional, D'Ambrosio, Mariantonietta, additional, Vasciaveo, Alessandro, additional, Crespo, Mateus, additional, Ferreira, Ana, additional, Brina, Daniela, additional, Troiani, Martina, additional, Sharp, Adam, additional, Sheehan, Beshara, additional, Christova, Rossitza, additional, Seed, George, additional, Figueiredo, Ines, additional, Lambros, Maryou, additional, Dolling, David, additional, Rekowski, Jan, additional, Alajati, Abdullah, additional, Clarke, Matthew, additional, Pereira, Rita, additional, Flohr, Penny, additional, Fowler, Gemma, additional, Boysen, Gunther, additional, Sumanasuriya, Semini, additional, Bianchini, Diletta, additional, Rescigno, Pasquale, additional, Aversa, Caterina, additional, Tunariu, Nina, additional, Guo, Christina, additional, Paschalis, Alec, additional, Bertan, Claudia, additional, Buroni, Lorenzo, additional, Ning, Jian, additional, Carreira, Suzanne, additional, Workman, Paul, additional, Swain, Amanda, additional, Califano, Andrea, additional, Shen, Michael M., additional, Alimonti, Andrea, additional, Neeb, Antje, additional, Welti, Jonathan, additional, Yuan, Wei, additional, and de Bono, Johann, additional

Published
2021
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21. Preliminary evidence of antitumour activity of Ipatasertib (Ipat) and Atezolizumab (ATZ) in glioblastoma patients (pts) with PTEN loss from the Phase 1 Ice-CAP trial (NCT03673787)

Author

Tiu, Crescens, primary, Welsh, Liam, additional, Jones, Timothy, additional, Zachariou, Anna, additional, Prout, Toby, additional, Turner, Alison, additional, Daly, Rob, additional, Tunariu, Nina, additional, Riisnaes, Ruth, additional, Gurel, Bora, additional, Crespo, Mateus, additional, Carreira, Suzanne, additional, Vivanco, Igor, additional, Jenkins, Ben, additional, Yap, Christina, additional, Minchom, Anna, additional, Banerji, Udai, additional, deBono, Johann, additional, and Lopez, Juanita, additional

Published
2021
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22. PD-L1 quantification across tumor types using the reverse phase protein microarray: implications for precision medicine

Author

Baldelli, Elisa, primary, Hodge, K Alex, additional, Bellezza, Guido, additional, Shah, Neil J, additional, Gambara, Guido, additional, Sidoni, Angelo, additional, Mandarano, Martina, additional, Ruhunusiri, Chamodya, additional, Dunetz, Bryant, additional, Abu-Khalaf, Maysa, additional, Wulfkuhle, Julia, additional, Gallagher, Rosa I, additional, Liotta, Lance, additional, de Bono, Johann, additional, Mehra, Niven, additional, Riisnaes, Ruth, additional, Ravaggi, Antonella, additional, Odicino, Franco, additional, Sereni, Maria Isabella, additional, Blackburn, Matthew, additional, Zupa, Angela, additional, Improta, Giuseppina, additional, Demsko, Perry, additional, Crino', Lucio, additional, Ludovini, Vienna, additional, Giaccone, Giuseppe, additional, Petricoin, Emanuel F, additional, and Pierobon, Mariaelena, additional

Published
2021
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23. Abstract LB035: B7-H3 as a therapeutic target in prostate cancer

Author

Guo, Christina, primary, Figueiredo, Ines, additional, Gurel, Bora, additional, Crespo, Matues, additional, Rekowski, Jan, additional, Carreira, Suzanne, additional, Neeb, Antje, additional, Sharp, Adam, additional, Fenor de la Maza, Maria D., additional, Rescigno, Pasquale, additional, Chandran, Khobe, additional, Ferreira, Ana, additional, Riisnaes, Ruth, additional, Miranda, Susana, additional, Pereira, Rita, additional, Gil, Veronica, additional, Seed, George, additional, Bertan, Claudia, additional, Baker, Chloe, additional, Yuan, Wei, additional, and de Bono, Johann S., additional

Published
2021
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24. Abstract CT120: Results of the glioblastoma multiforme (GBM) cohort of phase 1 trial Ice-CAP (NCT03673787): Preliminary evidence of antitumour activity of Ipatasertib (Ipa) and Atezolizumab (A) in patients (pts) with PTEN loss

Author

Tiu, Crescens, primary, Biondo, Andrea, additional, Welsh, Liam C., additional, Jones, Timothy L., additional, Zachariou, Anna, additional, Prout, Toby, additional, Turner, Alison J., additional, Daly, Robert, additional, Vivanco, Igor, additional, Yap, Christina, additional, Jenkins, Ben, additional, Crespo, Mateus, additional, Riisnaes, Ruth, additional, Carreira, Suzanne, additional, Gurel, Bora, additional, Tunariu, Nina, additional, Minchom, Anna, additional, Banerji, Udai, additional, de Bono, Johann S., additional, and Lopez, Juanita S., additional

Published
2021
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25. HER3 expression and MEK activation in non-small-cell lung carcinoma

Author

Manickavasagar, Thubeena, primary, Yuan, Wei, additional, Carreira, Suzanne, additional, Gurel, Bora, additional, Miranda, Susana, additional, Ferreira, Ana, additional, Crespo, Mateus, additional, Riisnaes, Ruth, additional, Baker, Chloe, additional, O’Brien, Mary, additional, Bhosle, Jaishree, additional, Popat, Sanjay, additional, Banerji, Udai, additional, Lopez, Juanita, additional, Bono, Johann de, additional, and Minchom, Anna, additional

Published
2021
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26. PD-L1 quantification across tumor types using the reverse phase protein microarray: implications for precision medicine

Author

Baldelli, Elisa, Hodge, K Alex, Bellezza, Guido, Shah, Neil J, Gambara, Guido, Sidoni, Angelo, Mandarano, Martina, Ruhunusiri, Chamodya, Dunetz, Bryant, Abu-Khalaf, Maysa, Wulfkuhle, Julia, Gallagher, Rosa I, Liotta, Lance, de Bono, Johann, Mehra, Niven, Riisnaes, Ruth, Ravaggi, Antonella, Odicino, Franco, Sereni, Maria Isabella, Blackburn, Matthew, Zupa, Angela, Improta, Giuseppina, Demsko, Perry, Crino', Lucio, Ludovini, Vienna, Giaccone, Giuseppe, Petricoin, Emanuel F, Pierobon, Mariaelena, Baldelli, Elisa, Hodge, K Alex, Bellezza, Guido, Shah, Neil J, Gambara, Guido, Sidoni, Angelo, Mandarano, Martina, Ruhunusiri, Chamodya, Dunetz, Bryant, Abu-Khalaf, Maysa, Wulfkuhle, Julia, Gallagher, Rosa I, Liotta, Lance, de Bono, Johann, Mehra, Niven, Riisnaes, Ruth, Ravaggi, Antonella, Odicino, Franco, Sereni, Maria Isabella, Blackburn, Matthew, Zupa, Angela, Improta, Giuseppina, Demsko, Perry, Crino', Lucio, Ludovini, Vienna, Giaccone, Giuseppe, Petricoin, Emanuel F, and Pierobon, Mariaelena

Abstract

BACKGROUND: Anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-L1) agents are broadly used in first-line and second-line treatment across different tumor types. While immunohistochemistry-based assays are routinely used to assess PD-L1 expression, their clinical utility remains controversial due to the partial predictive value and lack of standardized cut-offs across antibody clones. Using a high throughput immunoassay, the reverse phase protein microarray (RPPA), coupled with a fluorescence-based detection system, this study compared the performance of six anti-PD-L1 antibody clones on 666 tumor samples. METHODS: PD-L1 expression was measured using five antibody clones (22C3, 28-8, CAL10, E1L3N and SP142) and the therapeutic antibody atezolizumab on 222 lung, 71 ovarian, 52 prostate and 267 breast cancers, and 54 metastatic lesions. To capture clinically relevant variables, our cohort included frozen and formalin-fixed paraffin-embedded samples, surgical specimens and core needle biopsies. Pure tumor epithelia were isolated using laser capture microdissection from 602 samples. Correlation coefficients were calculated to assess concordance between antibody clones. For two independent cohorts of patients with lung cancer treated with nivolumab, RPPA-based PD-L1 measurements were examined along with response to treatment. RESULTS: Median-center PD-L1 dynamic ranged from 0.01 to 39.37 across antibody clones. Correlation coefficients between the six antibody clones were heterogeneous (range: -0.48 to 0.95) and below 0.50 in 61% of the comparisons. In nivolumab-treated patients, RPPA-based measurement identified a subgroup of tumors, where low PD-L1 expression equated to lack of response. CONCLUSIONS: Continuous RPPA-based measurements capture a broad dynamic range of PD-L1 expression in human specimens and heterogeneous concordance levels between antibody clones. This high throughput immunoassay can potentially identify subgroups of tumors in wh

Published
2021

27. JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer

Author

Paschalis, Alec, primary, Welti, Jonathan, additional, Neeb, Antje J., additional, Yuan, Wei, additional, Figueiredo, Ines, additional, Pereira, Rita, additional, Ferreira, Ana, additional, Riisnaes, Ruth, additional, Rodrigues, Daniel Nava, additional, Jiménez-Vacas, Juan M., additional, Kim, Soojin, additional, Uo, Takuma, additional, Micco, Patrizio Di, additional, Tumber, Anthony, additional, Islam, Md. Saiful, additional, Moesser, Marc A., additional, Abboud, Martine, additional, Kawamura, Akane, additional, Gurel, Bora, additional, Christova, Rossitza, additional, Gil, Veronica S., additional, Buroni, Lorenzo, additional, Crespo, Mateus, additional, Miranda, Susana, additional, Lambros, Maryou B., additional, Carreira, Suzanne, additional, Tunariu, Nina, additional, Alimonti, Andrea, additional, Al-Lazikani, Bissan, additional, Schofield, Christopher J., additional, Plymate, Stephen R., additional, Sharp, Adam, additional, and de Bono, Johann S., additional

Published
2021
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28. Characterizing CDK12-Mutated Prostate Cancers

Author

Rescigno, Pasquale, primary, Gurel, Bora, additional, Pereira, Rita, additional, Crespo, Mateus, additional, Rekowski, Jan, additional, Rediti, Mattia, additional, Barrero, Maialen, additional, Mateo, Joaquin, additional, Bianchini, Diletta, additional, Messina, Carlo, additional, Fenor de la Maza, Maria D., additional, Chandran, Khobe, additional, Carmichael, Juliet, additional, Guo, Christina, additional, Paschalis, Alec, additional, Sharp, Adam, additional, Seed, George, additional, Figueiredo, Ines, additional, Lambros, Maryou, additional, Miranda, Susana, additional, Ferreira, Ana, additional, Bertan, Claudia, additional, Riisnaes, Ruth, additional, Porta, Nuria, additional, Yuan, Wei, additional, Carreira, Suzanne, additional, and de Bono, Johann S., additional

Published
2021
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29. Abstract CT143: Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers

Author

Shinde, Rajiv, primary, Terbuch, Angelika, additional, Little, Martin, additional, Caldwell, Reece, additional, Kurup, Roopa, additional, Riisnaes, Ruth, additional, Crespo, Mateus, additional, Ruddle, Ruth, additional, Gurel, Bora, additional, Stewart, Adam, additional, King, Jenny, additional, Parmar, Mona, additional, Turner, Alison, additional, Raynaud, Florence, additional, Mahmud, Muneeb, additional, Yap, Christina, additional, Pachter, Jonathan A., additional, Mills, Gordon B., additional, Minchom, Anna, additional, Lopez, Juanita, additional, Banerjee, Susana N., additional, de Bono, Johann S., additional, Krebs, Matthew, additional, and Banerji, Udai, additional

Published
2020
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30. Abstract CT129: HyPeR: A phase 1, dose escalation and expansion trial of guadecitabine (SGI-110), a second-generation hypomethylating agent in combination with pembrolizumab (MK3475) in patients with refractory solid tumors

Author

Papadatos-Pastos, Dionysis, primary, Pal, Abhijit, additional, Akay, Melek, additional, Ameratunga, Malaka, additional, Mithra, Sanjena, additional, Ang, Joo-Ern, additional, Levva, Sofia, additional, Caldwell, Reece, additional, Riisnaes, Ruth, additional, Crespo, Mateus, additional, Yuan, Wei, additional, Seed, George, additional, Gurel, Bora, additional, Figueiredo, Ines, additional, Pereira, Rita, additional, Miranda, Susana, additional, Ferreira, Anna, additional, Carreira, Suzanne, additional, Bertan, Claudia, additional, Baker, Chloe, additional, Morilla, Ricardo, additional, Brown, Robert, additional, Masrour, Nahal, additional, Prout, Toby, additional, Zachariou, Anna, additional, Turner, Alison, additional, Parmar, Mona, additional, Van de Velde, Mark, additional, Jenkins, Ben, additional, Yap, Christina, additional, Tunariu, Nina, additional, Banerji, Udai, additional, Lopez, Juanita, additional, Minchom, Anna, additional, and De Bono, Johann, additional

Published
2020
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31. Abstract LB-075: CDK12-mutated lethal prostate cancers: How hot are these tumors

Author

Gurel, Bora, primary, Rescigno, Pasquale, additional, Yuan, Wei, additional, Pereira, Rita, additional, Crespo, Mateus, additional, Rediti, Mattia, additional, Figueiredo, Ines, additional, Barrero, Maialen, additional, Bianchini, Diletta, additional, Fenor de la Maza, Maria D., additional, Chandran, Khobe, additional, Carmichael, Juliet, additional, Paschalis, Alec, additional, Sharp, Adam, additional, Seed, George, additional, Riisnaes, Ruth, additional, Bertan, Claudia, additional, Carreira, Suzanne, additional, and De Bono, Johann S., additional

Published
2020
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32. Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab

Author

Minchom, Anna, primary, Yuan, Wei, additional, Crespo, Mateus, additional, Gurel, Bora, additional, Figueiredo, Ines, additional, Wotherspoon, Andrew, additional, Miranda, Susana, additional, Riisnaes, Ruth, additional, Ferreira, Ana, additional, Bertan, Claudia, additional, Pereira, Rita, additional, Clarke, Matt, additional, Baker, Chloe, additional, Ang, Joo Ern, additional, Fotiadis, Nicos, additional, Tunariu, Nina, additional, Carreira, Suzanne, additional, Popat, Sanjay, additional, O'Brien, Mary, additional, Banerji, Udai, additional, de Bono, Johann, additional, and Lopez, Juanita, additional

Published
2020
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33. Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer

Author

Slovin, Susan, primary, Hussain, Syed, additional, Saad, Fred, additional, Garcia, Jorge, additional, Picus, Joel, additional, Ferraldeschi, Roberta, additional, Crespo, Mateus, additional, Flohr, Penelope, additional, Riisnaes, Ruth, additional, Lin, Chihche, additional, Keer, Harold, additional, Oganesian, Aram, additional, Workman, Paul, additional, and de Bono, Johann, additional

Published
2019
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34. Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss

Author

de Bono, Johann S., primary, De Giorgi, Ugo, additional, Rodrigues, Daniel Nava, additional, Massard, Christophe, additional, Bracarda, Sergio, additional, Font, Albert, additional, Arranz Arija, Jose Angel, additional, Shih, Kent C., additional, Radavoi, George Daniel, additional, Xu, Na, additional, Chan, Wai Y., additional, Ma, Han, additional, Gendreau, Steven, additional, Riisnaes, Ruth, additional, Patel, Premal H., additional, Maslyar, Daniel J., additional, and Jinga, Viorel, additional

Published
2019
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35. RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer

Author

Nava Rodrigues, Daniel, primary, Casiraghi, Nicola, additional, Romanel, Alessandro, additional, Crespo, Mateus, additional, Miranda, Susana, additional, Rescigno, Pasquale, additional, Figueiredo, Ines, additional, Riisnaes, Ruth, additional, Carreira, Suzanne, additional, Sumanasuriya, Semini, additional, Gasperini, Paola, additional, Sharp, Adam, additional, Mateo, Joaquin, additional, Makay, Alan, additional, McNair, Christopher, additional, Schiewer, Matthew, additional, Knudsen, Karen, additional, Boysen, Gunther, additional, Demichelis, Francesca, additional, and de Bono, Johann S., additional

Published
2019
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36. Circulating Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition

Author

Goodall, Jane, Mateo, Joaquin, Yuan, Wei, Mossop, Helen, Porta, Nuria, Miranda, Susana, Perez-Lopez, Raquel, Dolling, David, Robinson, Dan, Sandhu, Shahneen, Fowler, Gemma, Ebbs, Berni, Flohr, Penny, Seed, George, Rodrigues, Daniel Nava, Boysen, Gunther, Bertan, Claudia, Atkin, Mark, Clarke, Matthew, Crespo, Mateus, Figueiredo, Ines, Riisnaes, Ruth, Sumanasuriya, Semini, Rescigno, Pasquale, Zafeiriou, Zafeiris, Sharp, Adam, Tunariu, Nina, Bianchini, Diletta, Gillman, Alexa, Lord, Christopher J, Hall, Emma, Chinnaiyan, Arul M., Carreira, Suzanne, and de Bono, Johann S.

Subjects
Male, Humans, Prostatic Neoplasms, DNA, Poly(ADP-ribose) Polymerase Inhibitors, Cell-Free Nucleic Acids, Article, Biomarkers
Abstract

Biomarkers for a more precise patient care are needed in metastatic prostate cancer (mPC). We have reported a Phase II trial (TOPARP-A) of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib in mPC, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole exome sequencing of serial circulating-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95%CI 0.06-0.56 p=0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (Chi-squared p

Published
2017

37. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer

Author

Sharp, Adam, primary, Coleman, Ilsa, additional, Yuan, Wei, additional, Sprenger, Cynthia, additional, Dolling, David, additional, Rodrigues, Daniel Nava, additional, Russo, Joshua W., additional, Figueiredo, Ines, additional, Bertan, Claudia, additional, Seed, George, additional, Riisnaes, Ruth, additional, Uo, Takuma, additional, Neeb, Antje, additional, Welti, Jonathan, additional, Morrissey, Colm, additional, Carreira, Suzanne, additional, Luo, Jun, additional, Nelson, Peter S., additional, Balk, Steven P., additional, True, Lawrence D., additional, de Bono, Johann S., additional, and Plymate, Stephen R., additional

Published
2018
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38. Single-Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis

Author

Lambros, Maryou B., primary, Seed, George, additional, Sumanasuriya, Semini, additional, Gil, Veronica, additional, Crespo, Mateus, additional, Fontes, Mariane, additional, Chandler, Rob, additional, Mehra, Niven, additional, Fowler, Gemma, additional, Ebbs, Berni, additional, Flohr, Penny, additional, Miranda, Susana, additional, Yuan, Wei, additional, Mackay, Alan, additional, Ferreira, Ana, additional, Pereira, Rita, additional, Bertan, Claudia, additional, Figueiredo, Ines, additional, Riisnaes, Ruth, additional, Rodrigues, Daniel Nava, additional, Sharp, Adam, additional, Goodall, Jane, additional, Boysen, Gunther, additional, Carreira, Suzanne, additional, Bianchini, Diletta, additional, Rescigno, Pasquale, additional, Zafeiriou, Zafeiris, additional, Hunt, Joanne, additional, Moloney, Deirdre, additional, Hamilton, Lucy, additional, Neves, Rui P., additional, Swennenhuis, Joost, additional, Andree, Kiki, additional, Stoecklein, Nikolas H., additional, Terstappen, Leon W.M.M., additional, and de Bono, Johann S., additional

Published
2018
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39. SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity

Author

Boysen, Gunther, primary, Rodrigues, Daniel N., additional, Rescigno, Pasquale, additional, Seed, George, additional, Dolling, David, additional, Riisnaes, Ruth, additional, Crespo, Mateus, additional, Zafeiriou, Zafeiris, additional, Sumanasuriya, Semini, additional, Bianchini, Diletta, additional, Hunt, Joanne, additional, Moloney, Deirdre, additional, Perez-Lopez, Raquel, additional, Tunariu, Nina, additional, Miranda, Susana, additional, Figueiredo, Inês, additional, Ferreira, Ana, additional, Christova, Rossitza, additional, Gil, Veronica, additional, Aziz, Sara, additional, Bertan, Claudia, additional, de Oliveira, Flavia M., additional, Atkin, Mark, additional, Clarke, Matthew, additional, Goodall, Jane, additional, Sharp, Adam, additional, MacDonald, Theresa, additional, Rubin, Mark A., additional, Yuan, Wei, additional, Barbieri, Christopher E., additional, Carreira, Suzanne, additional, Mateo, Joaquin, additional, and de Bono, Johann S., additional

Published
2018
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40. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer

Author

Rodrigues, Daniel Nava, primary, Rescigno, Pasquale, additional, Liu, David, additional, Yuan, Wei, additional, Carreira, Suzanne, additional, Lambros, Maryou B., additional, Seed, George, additional, Mateo, Joaquin, additional, Riisnaes, Ruth, additional, Mullane, Stephanie, additional, Margolis, Claire, additional, Miao, Diana, additional, Miranda, Susana, additional, Dolling, David, additional, Clarke, Matthew, additional, Bertan, Claudia, additional, Crespo, Mateus, additional, Boysen, Gunther, additional, Ferreira, Ana, additional, Sharp, Adam, additional, Figueiredo, Ines, additional, Keliher, Daniel, additional, Aldubayan, Saud, additional, Burke, Kelly P., additional, Sumanasuriya, Semini, additional, Fontes, Mariane Sousa, additional, Bianchini, Diletta, additional, Zafeiriou, Zafeiris, additional, Mendes, Larissa Sena Teixeira, additional, Mouw, Kent, additional, Schweizer, Michael T., additional, Pritchard, Colin C., additional, Salipante, Stephen, additional, Taplin, Mary-Ellen, additional, Beltran, Himisha, additional, Rubin, Mark A., additional, Cieslik, Marcin, additional, Robinson, Dan, additional, Heath, Elizabeth, additional, Schultz, Nikolaus, additional, Armenia, Joshua, additional, Abida, Wassim, additional, Scher, Howard, additional, Lord, Christopher, additional, D’Andrea, Alan, additional, Sawyers, Charles L., additional, Chinnaiyan, Arul M., additional, Alimonti, Andrea, additional, Nelson, Peter S., additional, Drake, Charles G., additional, Van Allen, Eliezer M., additional, and de Bono, Johann S., additional

Published
2018
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41. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer

Author

Nava Rodrigues, Daniel, primary, Rescigno, Pasquale, additional, Liu, David, additional, Yuan, Wei, additional, Carreira, Suzanne, additional, Lambros, Maryou B., additional, Seed, George, additional, Mateo, Joaquin, additional, Riisnaes, Ruth, additional, Mullane, Stephanie, additional, Margolis, Claire, additional, Miao, Diana, additional, Miranda, Susana, additional, Dolling, David, additional, Clarke, Matthew, additional, Bertan, Claudia, additional, Crespo, Mateus, additional, Boysen, Gunther, additional, Ferreira, Ana, additional, Sharp, Adam, additional, Figueiredo, Ines, additional, Keliher, Daniel, additional, Aldubayan, Saud, additional, Burke, Kelly P., additional, Sumanasuriya, Semini, additional, Fontes, Mariane Sousa, additional, Bianchini, Diletta, additional, Zafeiriou, Zafeiris, additional, Teixeira Mendes, Larissa Sena, additional, Mouw, Kent, additional, Schweizer, Michael T., additional, Pritchard, Colin C., additional, Salipante, Stephen, additional, Taplin, Mary-Ellen, additional, Beltran, Himisha, additional, Rubin, Mark A., additional, Cieslik, Marcin, additional, Robinson, Dan, additional, Heath, Elizabeth, additional, Schultz, Nikolaus, additional, Armenia, Joshua, additional, Abida, Wassim, additional, Scher, Howard, additional, Lord, Christopher, additional, D’Andrea, Alan, additional, Sawyers, Charles L., additional, Chinnaiyan, Arul M., additional, Alimonti, Andrea, additional, Nelson, Peter S., additional, Drake, Charles G., additional, Van Allen, Eliezer M., additional, and de Bono, Johann S., additional

Published
2018
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42. Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification

Author

Seed, George, primary, Yuan, Wei, additional, Mateo, Joaquin, additional, Carreira, Suzanne, additional, Bertan, Claudia, additional, Lambros, Maryou, additional, Boysen, Gunther, additional, Ferraldeschi, Roberta, additional, Miranda, Susana, additional, Figueiredo, Ines, additional, Riisnaes, Ruth, additional, Crespo, Mateus, additional, Rodrigues, Daniel Nava, additional, Talevich, Eric, additional, Robinson, Dan R., additional, Kunju, Lakshmi P., additional, Wu, Yi-Mi, additional, Lonigro, Robert, additional, Sandhu, Shahneen, additional, Chinnaiyan, Arul M., additional, and de Bono, Johann S., additional

Published
2017
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43. Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer

Author

Cato, Laura, primary, Neeb, Antje, additional, Sharp, Adam, additional, Buzón, Victor, additional, Ficarro, Scott B, additional, Yang, Linxiao, additional, Muhle-Goll, Claudia, additional, Kuznik, Nane C, additional, Riisnaes, Ruth, additional, Nava Rodrigues, Daniel, additional, Armant, Olivier, additional, Gourain, Victor, additional, Adelmant, Guillaume, additional, Ntim, Emmanuel A, additional, Westerling, Thomas, additional, Dolling, David, additional, Rescigno, Pasquale, additional, Figueiredo, Ines, additional, Fauser, Friedrich, additional, Wu, Jennifer, additional, Rottenberg, Jaice T, additional, Shatkina, Liubov, additional, Ester, Claudia, additional, Luy, Burkhard, additional, Puchta, Holger, additional, Troppmair, Jakob, additional, Jung, Nicole, additional, Bräse, Stefan, additional, Strähle, Uwe, additional, Marto, Jarrod A, additional, Nienhaus, Gerd Ulrich, additional, Al-Lazikani, Bissan, additional, Salvatella, Xavier, additional, de Bono, Johann S, additional, Cato, Andrew CB, additional, and Brown, Myles, additional

Published
2017
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44. Abstract 4679: Mismatch repair defects in lethal prostate cancer

Author

Rescigno, Pasquale, primary, Rodrigues, Daniel Nava, additional, Yuan, Wei, additional, Carreira, Suzanne, additional, Lambros, Maryou, additional, Seed, George, additional, Riisnaes, Ruth, additional, Miranda, Susana, additional, Dolling, David, additional, Clarke, Matthew, additional, Crespo, Mateus, additional, Bertan, Claudia, additional, Boysen, Gunther, additional, Mateo, Joaquin, additional, Ferreira, Ana, additional, Sharp, Adam, additional, Figueiredo, Ines, additional, Sumanasuriya, Semini, additional, Fontes, Mariane Sousa, additional, Bianchini, Diletta, additional, Zafeiriou, Zafeiris, additional, and Bono, Johann Sebastian de, additional

Published
2017
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45. First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer

Author

Blagden, Sarah, Omlin, Aurelius, Olmin, Aurelius, Josephs, Debra, Stavraka, Chara, Zivi, Andrea, Pinato, David J, Anthoney, Alan, Decordova, Shaun, Swales, Karen, Riisnaes, Ruth, Pope, Lorna, Noguchi, Kohei, Shiokawa, Rie, Inatani, Michiyasu, Prince, Jenny, Jones, Keith, Twelves, Chris, Spicer, James, and Banerji, Udai

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Maximum Tolerated Dose, Nausea, Class I Phosphatidylinositol 3-Kinases, Administration, Oral, Antineoplastic Agents, Pharmacology, Gastroenterology, Article, Breast cancer, Pharmacokinetics, Internal medicine, Neoplasms, medicine, Humans, Neoplasm Metastasis, Adverse effect, Stomatitis, Aged, Sulfonamides, Dose-Response Relationship, Drug, business.industry, Cancer, Middle Aged, medicine.disease, Pyrimidines, Treatment Outcome, Oncology, Pharmacodynamics, Positron-Emission Tomography, Toxicity, Female, medicine.symptom, business, Tomography, X-Ray Computed
Abstract

Purpose: This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of CH5132799. Experimental Design: Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily or twice daily in 28-day cycles. Results: Thirty-eight patients with solid tumors received CH5132799 at 2 to 96 mg once daily or 48 to 72 mg twice daily. The MTD was 48 mg on the twice-daily schedule but was not reached on the once daily schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea, and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/mL and 1,550 ng·h/mL, respectively, consistent with efficacious exposure based on preclinical modeling. Reduction in SUVmax with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in 5 of 7 patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pretreated patient with triple-negative breast cancer had marked improvement in her cutaneous skin lesions lasting six cycles. Conclusion: CH5132799 is well tolerated at the MTD dose of 48 mg twice daily. At this dose, the drug had a favorable PK and PD profile and preliminary evidence of clinical activity. Clin Cancer Res; 20(23); 5908–17. ©2014 AACR.

Published
2014

46. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate

Author

Ferraldeschi, Roberta, Nava Rodrigues, Daniel, Riisnaes, Ruth, Miranda, Susana, Figueiredo, Ines, Rescigno, Pasquale, Ravi, Praful, Pezaro, Carmel, Omlin, Aurelius, Lorente, David, Zafeiriou, Zafeiris, Mateo, Joaquin, Altavilla, Amelia, Sideris, Spyridon, Bianchini, Diletta, Grist, Emily, Thway, Khin, Perez Lopez, Raquel, Tunariu, Nina, Parker, Chris, Dearnaley, David, Reid, Alison, Attard, Gerhardt, and de Bono, Johann

Subjects
Male, PTEN, Time Factors, Urology, Prostate Cancer, Abiraterone Acetate, PTEN Phosphohydrolase, Prostatic Neoplasms, Androgen Antagonists, Antineoplastic Agents, Middle Aged, Immunohistochemistry, Disease-Free Survival, Prostatic Neoplasms, Castration-Resistant, Treatment Outcome, Risk Factors, Antineoplastic Combined Chemotherapy Protocols, Humans, Aged, Retrospective Studies
Abstract

Background Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer. Objective To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression. Design, setting, and participants We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis. Outcome measurements and statistical analysis The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses. Results and limitations A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19–2.55; p = 0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12–2.28; p = 0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis. Conclusions Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted. Patient summary PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression., Take Home Message Loss of PTEN expression is associated with shorter median survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate.

Published
2014

47. Abstract 4965: Analytic validation and clinical qualification of a novel immunohistochemical assay for AR-V7 protein expression in metastatic prostate cancer

Author

Nava Rodrigues, Daniel, primary, Welti, Jon, additional, Sharp, Adam, additional, Sun, Shihua, additional, Riisnaes, Ruth, additional, Figueiredo, Ines, additional, Zafeiriou, Zafeiris, additional, Rescigno, Pasquale, additional, de Bono, Johann S., additional, and Plymate, Stephen R., additional

Published
2016
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48. 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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49. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate

Author

Ferraldeschi, Roberta, Nava Rodrigues, Daniel, Riisnaes, Ruth, Miranda, Susana, Figueiredo, Ines, Rescigno, Pasquale, Ravi, Praful, Pezaro, Carmel, Omlin, Aurelius, Lorente, David, Zafeiriou, Zafeiris, Mateo, Joaquin, Altavilla, Amelia, Sideris, Spyridon, Bianchini, Diletta, Grist, Emily, Thway, Khin, Perez Lopez, Raquel, Tunariu, Nina, Parker, Chris, Dearnaley, David, Reid, Alison, Attard, Gerhardt, de Bono, Johann, Ferraldeschi, Roberta, Nava Rodrigues, Daniel, Riisnaes, Ruth, Miranda, Susana, Figueiredo, Ines, Rescigno, Pasquale, Ravi, Praful, Pezaro, Carmel, Omlin, Aurelius, Lorente, David, Zafeiriou, Zafeiris, Mateo, Joaquin, Altavilla, Amelia, Sideris, Spyridon, Bianchini, Diletta, Grist, Emily, Thway, Khin, Perez Lopez, Raquel, Tunariu, Nina, Parker, Chris, Dearnaley, David, Reid, Alison, Attard, Gerhardt, and de Bono, Johann

Abstract

BACKGROUND: Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer. OBJECTIVE: To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses. RESULTS AND LIMITATIONS: A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19-2.55; p=0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12-2.28; p=0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis. CONCLUSIONS: Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted. PATIENT SUMMARY: PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancer

Published
2015

50. Abstract PR14: Phase I trial of first-in-class ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor VX-970 as monotherapy (mono) or in combination with carboplatin (CP) in advanced cancer patients (pts) with preliminary evidence of target modulation and antitumor activity

Author

Yap, Timothy A., primary, Luken, Maria J. de Miguel, additional, O'Carrigan, Brent, additional, Roda, Desam, additional, Papadatos-Pastos, Dionysis, additional, Lorente, David, additional, Tunariu, Nina, additional, Lopez, Raquel Perez, additional, Gayle, Sasha, additional, Riisnaes, Ruth, additional, Figueiredo, Ines, additional, Miranda, Susana, additional, Carreira, Suzanne, additional, Yang, Fang, additional, Karan, Sharon, additional, Penney, Marina, additional, Pollard, John, additional, Molife, L. Rhoda, additional, Banerji, Udai, additional, Asmal, Mohammed, additional, Fields, Scott Z., additional, and Bono, Johann S. de, additional

Published
2015
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