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1. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis

Author

Angela Rita Elia, Penny Flohr, Martina Troiani, Silke Gillessen, Matteo Grioni, Maria Rescigno, Alberto Briganti, Daniela Bossi, Simone Mosole, Lorenzo Buroni, Christina Guo, Christian Jobin, Anna Palmisano, Eugenia D’Antonio, Mirko Minini, Antonio Esposito, Antje Neeb, Emiliano Pasquini, Pasquale Rescigno, Jonathan Welti, Bianca Calì, Gladys Martinetti Lucchini, Jacopo Troisi, Nicolò Pernigoni, Andrea Alimonti, Giuseppe Attanasio, Sara Merler, Andrea Rinaldi, Josee Gauthier, Jean-Philippe Theurillat, Ajinkya Revandkar, Raad Z. Gharaibeh, Johann S. de Bono, Matteo Ferrari, Elena Zagato, Ricardo Pereira Mestre, Marco Bolis, Joanne Hunt, Fabio Grassi, Matteo Bellone, Arianna Calcinotto, Pernigoni, N., Zagato, E., Calcinotto, A., Troiani, M., Mestre, R. P., Cali, B., Attanasio, G., Troisi, J., Minini, M., Mosole, S., Revandkar, A., Pasquini, E., Elia, A. R., Bossi, D., Rinaldi, A., Rescigno, P., Flohr, P., Hunt, J., Neeb, A., Buroni, L., Guo, C., Welti, J., Ferrari, M., Grioni, M., Gauthier, J., Gharaibeh, R. Z., Palmisano, A., Lucchini, G. M., D'Antonio, E., Merler, S., Bolis, M., Grassi, F., Esposito, A., Bellone, M., Briganti, A., Rescigno, M., Theurillat, J. -P., Jobin, C., Gillessen, S., de Bono, J., and Alimonti, A.

Subjects
Aged, Aged, 80 and over, Androgen Antagonists, Androgens, Animals, Anti-Bacterial Agents, Bacteria, Cell Line, Tumor, Fecal Microbiota Transplantation, Gastrointestinal Microbiome, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Middle Aged, Neoplasms, Experimental, Prevotella, Prostatic Neoplasms, Castration-Resistant, Symbiosis, Xenograft Model Antitumor Assays, Host Microbial Interactions, Microbial metabolism, Gut flora, Castration-Resistant, SCID, Inbred C57BL, urologic and male genital diseases, Cell Line, Microbiology, Experimental, Prostate cancer, Neoplasms, 80 and over, medicine, Tumor, Multidisciplinary, biology, Host (biology), Prostatic Neoplasms, biology.organism_classification, medicine.disease, Commensalism, Inbred NOD
Abstract

The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.

Published
2021

2. Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors

Author

Pasquale Rescigno, Lorenzo Buroni, Amanda Swain, Nicolás Herranz, Bora Gurel, Ruth Riisnaes, Alejandro Athie, Jan Rekowski, Natalia Castro, Wei Yuan, Christopher J. Lord, Adam Sharp, J. Carmichael, Sara Arce-Gallego, Joan Carles, Diletta Bianchini, Macarena Gonzalez, Ana Ferreira, Suzanne Carreira, Antje Neeb, Jesús Gil, Verena Wagner, George Seed, Alec Paschalis, Cristina Suarez, Daniel Nava Rodrigues, Veronica Gil, Maria de Los Dolores Fenor de la Maza, Caterina Aversa, Ines Figueiredo, Jian Ning, Irene Casanova-Salas, Johann S. de Bono, Teresa Casals, Rafael Morales-Barrera, Claudia Bertan, Joaquin Mateo, Sarai Cordoba, Khobe Chandran, Susana Miranda, Jon Welti, Violeta Serra, Institut Català de la Salut, [Neeb A, Miranda S, Buroni L, Yuan W] The Institute of Cancer Research, London, UK. [Herranz N, Arce-Gallego S, Serra V] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Athie A, Casals T, Casanova-Salas I, Cordoba S, Castro N] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Gonzalez M, Morales-Barrera R, Suarez C, Carles J, Mateo J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, Genome instability, ADN - Reparació, Synthetic lethality, 030232 urology & nephrology, Medicaments antineoplàstics - Ús terapèutic, Ataxia Telangiectasia Mutated Proteins, DNA damage response, Chemical Phenomena::Biochemical Phenomena::DNA Repair [PHENOMENA AND PROCESSES], Prostate cancer, 0302 clinical medicine, Prostate, Tumor Cells, Cultured, Medicine, fenómenos químicos::fenómenos bioquímicos::reparación del ADN [FENÓMENOS Y PROCESOS], medicine.diagnostic_test, OLAPARIB, Urology & Nephrology, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, DNA-REPAIR, Immunohistochemistry, Life Sciences & Biomedicine, Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [DISEASES], DNA repair, Urology, Poly(ADP-ribose) Polymerase Inhibitors, ATR inhibition, 03 medical and health sciences, Biopsy, Humans, terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Neoplasm Staging, Retrospective Studies, Science & Technology, Pròstata - Càncer, business.industry, PARP inhibition, Prostatic Neoplasms, 1103 Clinical Sciences, Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine.disease, Telomere, neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata [ENFERMEDADES], ATM, Cancer research, business
Abstract

Inhibició de l’ATR; Resposta de danys a l’ADN; Càncer de pròstata Inhibición de ATR; Respuesta al daño del ADN; Cancer de prostata ATR inhibition; DNA damage response; Prostate cancer Background Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond. Objective To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset. Design, setting, and participants We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model. Outcome measurements and statistical analysis ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models. Results and limitations Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models. Conclusions ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition. We gratefully acknowledge research funding for this work from Cancer Research UK, Prostate Cancer UK, the Movember Foundation through the London Movember Centre of Excellence ( CEO13_2-002 ), the Prostate Cancer Foundation (including Young Investigator Awards to Joaquin Mateo, Pasquale Rescigno, and Adam Sharp), Stand Up To Cancer, and the UK Department of Health through an Experimental Cancer Medicine Centre grant. Professor Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator; research at the Royal Marsden Hospital is supported by a Biomedical Research Centre grant. Part of this work was also funded by a Deparment of Defense CDMRP Impact Award (W81XWH-18-1-0756) to Joaquin Mateo and by Instituto de Salud Carlos III through Grant FI19/00280 to Sara Arce-Gallego, Grant CP19/00170 to Nicolás Herranz, and Grant PI18/01384 to Joaquin Mateo. The authors affiliated to VHIO acknowledge the “la Caixa” Foundation ( ID 100010434 ) for funding under agreement LCF/PR/PR17/51120011 and funding from Fundacion FERO and Moventia . This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 837900 . The funding organisations had no role in the design, conduction or data analysis of this project, neither in the manuscript preparation.

Published
2021
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3. BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity.

Author

Westaby D, Jiménez-Vacas JM, Figueiredo I, Rekowski J, Pettinger C, Gurel B, Lundberg A, Bogdan D, Buroni L, Neeb A, Padilha A, Taylor J, Zeng W, Das S, Hobern E, Riisnaes R, Crespo M, Miranda S, Ferreira A, Hanratty BP, Nava Rodrigues D, Bertan C, Seed G, Fenor de La Maza MLD, Guo C, Carmichael J, Grochot R, Chandran K, Stavridi A, Varkaris A, Stylianou N, Hollier BG, Tunariu N, Balk SP, Carreira S, Yuan W, Nelson PS, Corey E, Haffner M, de Bono J, and Sharp A

Subjects
Male, Humans, Animals, Cell Line, Tumor, Receptors, Androgen metabolism, Receptors, Androgen genetics, Mice, DNA Methylation, Epithelial-Mesenchymal Transition, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Lineage, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplasm Proteins biosynthesis, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant metabolism, Gene Expression Regulation, Neoplastic
Abstract

The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response.

Published
2024
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4. Multiplexed live-cell imaging for drug responses in patient-derived organoid models of cancer.

Author

Colling KE, Symons EL, Buroni L, Sumanisiri HK, Andrew-Udoh J, Witt E, Losh HA, Morrison AM, Leslie KK, Dunnill CJ, De Bono JS, and Thiel KW

Abstract

Patient-derived organoid (PDO) models of cancer are a multifunctional research system that better recapitulates human disease as compared to cancer cell lines. PDO models can be generated by culturing patient tumor cells in extracellular basement membrane extracts (BME) and plating as three-dimensional domes. However, commercially available reagents that have been optimized for phenotypic assays in monolayer cultures often are not compatible with BME. Herein we describe a method to plate PDO models and assess drug effects using an automated live-cell imaging system. In addition, we apply fluorescent dyes that are compatible with kinetic measurements to simultaneously quantitate cell health and apoptosis. Image capture can be customized to occur at regular time intervals over several days. Users can analyze drug effects in individual Z-plane images or a Z Projection of serial images from multiple focal planes. Using masking, specific parameters of interest are calculated, such as PDO number, area, and fluorescence intensity. We provide proof-of-concept data demonstrating the effect of cytotoxic agents on cell health, apoptosis and viability. This automated kinetic imaging platform can be expanded to other phenotypic readouts to understand diverse therapeutic effects in PDO models of cancer.

Published
2023
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5. Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer.

Author

Sheehan B, Neeb A, Buroni L, Paschalis A, Riisnaes R, Gurel B, Gil V, Miranda S, Crespo M, Guo C, Jiménez Vacas J, Figueiredo I, Ferreira A, Welti J, Yuan W, Carreira S, Sharp A, and de Bono J

Subjects
Animals, Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Male, Mice, Treatment Outcome, Xenograft Model Antitumor Assays, Antigens, Surface genetics, Antigens, Surface metabolism, Antineoplastic Agents therapeutic use, DNA Damage, Glutamate Carboxypeptidase II genetics, Glutamate Carboxypeptidase II metabolism, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics
Abstract

Purpose: Prostate-specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)-PSMA-617 are affecting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression, raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies and therefore hypothesized that DNA damage upregulates PSMA expression., Experimental Design: To test this relationship between PSMA and DNA damage we conducted a screen of 147 anticancer agents (NCI/NIH FDA-approved anticancer "Oncology Set") and treated tumor cells with repeated ionizing irradiation., Results: The topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, were identified from the screen to upregulate PSMA protein expression in castration-resistant LNCaP95 cells; this result was validated in vitro in LNCaP, LNCaP95, and 22Rv1 cell lines and in vivo using an mCRPC patient-derived xenograft model CP286 identified to have heterogeneous PSMA expression. As double-strand DNA break induction by topoisomerase-2 inhibitors upregulated PSMA, we next studied the impact of ionizing radiation on PSMA expression; this also upregulated PSMA protein expression in a dose-dependent fashion., Conclusions: The results presented herein are the first, to our knowledge, to demonstrate that PSMA is upregulated in response to double-strand DNA damage by anticancer treatment. These data support the study of rational combinations that maximize the antitumor activity of PSMA-targeted therapeutic strategies by upregulating PSMA., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2022
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6. HER3 Is an Actionable Target in Advanced Prostate Cancer.

Author

Gil V, Miranda S, Riisnaes R, Gurel B, D'Ambrosio M, Vasciaveo A, Crespo M, Ferreira A, Brina D, Troiani M, Sharp A, Sheehan B, Christova R, Seed G, Figueiredo I, Lambros M, Dolling D, Rekowski J, Alajati A, Clarke M, Pereira R, Flohr P, Fowler G, Boysen G, Sumanasuriya S, Bianchini D, Rescigno P, Aversa C, Tunariu N, Guo C, Paschalis A, Bertan C, Buroni L, Ning J, Carreira S, Workman P, Swain A, Califano A, Shen MM, Alimonti A, Neeb A, Welti J, Yuan W, and de Bono J

Subjects
Animals, Antineoplastic Agents, Immunological pharmacology, Apoptosis, Biomarkers, Tumor genetics, Camptothecin pharmacology, Cell Proliferation, Follow-Up Studies, Humans, Male, Mice, Inbred NOD, Mice, SCID, Neuregulin-1 genetics, Organoids drug effects, Organoids metabolism, Prognosis, Prospective Studies, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Receptor, ErbB-3 genetics, Receptor, ErbB-3 metabolism, Survival Rate, Tumor Cells, Cultured, Tumor Microenvironment, Xenograft Model Antitumor Assays, Mice, Antibodies, Monoclonal, Humanized pharmacology, Biomarkers, Tumor metabolism, Camptothecin analogs & derivatives, Neuregulin-1 metabolism, Organoids pathology, Prostatic Neoplasms pathology, Receptor, ErbB-3 antagonists & inhibitors
Abstract

It has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting ERBB receptors as a therapeutic strategy for prostate cancer has been ineffective clinically. However, we show here that membranous HER3 protein is commonly highly expressed in lethal prostate cancer, associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated that the HER3 ligand NRG1 is detectable primarily in tumor-infiltrating myelomonocytic cells in human prostate cancer; this observation was confirmed using single-cell RNA sequencing of human prostate cancer biopsies and murine transgenic prostate cancer models. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids with high HER3 expression as well as mouse prostate cancer organoids, recombinant NRG1 enhanced proliferation and survival. Supernatant from murine bone marrow-derived macrophages and myeloid-derived suppressor cells promoted murine prostate cancer organoid growth in vitro , which could be reversed by a neutralizing anti-NRG1 antibody and ERBB inhibition. Targeting HER3, especially with the HER3-directed antibody-drug conjugate U3-1402, exhibited antitumor activity against HER3-expressing prostate cancer. Overall, these data indicate that HER3 is commonly overexpressed in lethal prostate cancer and can be activated by NRG1 secreted by myelomonocytic cells in the tumor microenvironment, supporting HER3-targeted therapeutic strategies for treating HER3-expressing advanced CRPC. SIGNIFICANCE: HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2021
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7. JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.

Author

Paschalis A, Welti J, Neeb AJ, Yuan W, Figueiredo I, Pereira R, Ferreira A, Riisnaes R, Rodrigues DN, Jiménez-Vacas JM, Kim S, Uo T, Micco PD, Tumber A, Islam MS, Moesser MA, Abboud M, Kawamura A, Gurel B, Christova R, Gil VS, Buroni L, Crespo M, Miranda S, Lambros MB, Carreira S, Tunariu N, Alimonti A, Al-Lazikani B, Schofield CJ, Plymate SR, Sharp A, and de Bono JS

Subjects
Alternative Splicing, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cohort Studies, Enzyme Inhibitors therapeutic use, Gene Expression Regulation, Neoplastic, Humans, Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors, Jumonji Domain-Containing Histone Demethylases genetics, Male, Molecular Targeted Therapy, Oxygenases genetics, Oxygenases physiology, Prognosis, Prostatic Neoplasms, Castration-Resistant diagnosis, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant mortality, Protein Isoforms genetics, Protein Isoforms metabolism, Receptors, Androgen chemistry, Receptors, Androgen metabolism, Retrospective Studies, Jumonji Domain-Containing Histone Demethylases physiology, Prostatic Neoplasms, Castration-Resistant genetics, Receptors, Androgen genetics
Abstract

Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased ( P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival ( P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. SIGNIFICANCE: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention., (©2021 American Association for Cancer Research.)

Published
2021
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