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García-Vicente L, Martínez-Fernández M, Borja M, Tran V, Álvarez-Vázquez A, Flores-Hernández R, Ding Y, González-Sánchez R, Granados A, McGeever E, Kim YJ, Detweiler A, Mekonen H, Paul S, Pisco AO, Neff NF, Tabernero A. Single-nucleus RNA sequencing reveals a preclinical model for the most common subtype of glioblastoma. Commun Biol 2025; 8:671. [PMID: 40295632 PMCID: PMC12037721 DOI: 10.1038/s42003-025-08092-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
Different glioblastoma (GBM) subtypes have been identified based on the tumor microenvironment (TME). The discovery of new therapies for these hard-to-treat tumors requires a thorough characterization of preclinical models, including their TME, to apply preclinical results to the most similar GBM subtype. Using single-nucleus RNA sequencing (snRNA-seq), we characterized the tumor and TME in an immunocompetent mouse model with intracranially implanted GBM stem cells at different stages and treatments. Visium spatial transcriptomics confirmed the location of annotated cells. This model exhibits GBM targets related to integration into neural circuits - Grik2, Nlgn3, Gap43 or Kcnn4-, immunoevasion - Nt5e, Cd274 or Irf8- and immunosuppression - Csf1r, Arg1, Mrc1 and Tgfb1. The landscape of cytokines, checkpoint ligands and receptors uncovered Mrc1, PD-L1, TIM-3 or B7-H3, among the immunotherapy targets that can be addressed in this model. The comparison with human GBMs unveiled crucial similarities with TMEMed GBM, the most frequent subtype.
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Affiliation(s)
- Laura García-Vicente
- Neuroscience Institute of Castile-Leon (INCYL), iBRAINS-IN-CyL, Department of Biochemistry and Molecular Biology, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - María Martínez-Fernández
- Neuroscience Institute of Castile-Leon (INCYL), iBRAINS-IN-CyL, Department of Biochemistry and Molecular Biology, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | | | | | - Andrea Álvarez-Vázquez
- Neuroscience Institute of Castile-Leon (INCYL), iBRAINS-IN-CyL, Department of Biochemistry and Molecular Biology, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Raquel Flores-Hernández
- Neuroscience Institute of Castile-Leon (INCYL), iBRAINS-IN-CyL, Department of Biochemistry and Molecular Biology, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Yuxin Ding
- Neuroscience Institute of Castile-Leon (INCYL), iBRAINS-IN-CyL, Department of Biochemistry and Molecular Biology, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Raúl González-Sánchez
- Neuroscience Institute of Castile-Leon (INCYL), iBRAINS-IN-CyL, Department of Biochemistry and Molecular Biology, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | | | | | | | | | | | | | | | | | - Arantxa Tabernero
- Neuroscience Institute of Castile-Leon (INCYL), iBRAINS-IN-CyL, Department of Biochemistry and Molecular Biology, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
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2
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Elbialy A, Sood A, Wang SJ, Wang P, Fadiel A, Parwani AV, Huang S, Shvets G, Putluri N, Li J, Liu X. Unveiling racial disparities in prostate cancer using an integrative genomic and transcriptomic analysis. CELL INSIGHT 2025; 4:100238. [PMID: 40104216 PMCID: PMC11914995 DOI: 10.1016/j.cellin.2025.100238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 02/02/2025] [Accepted: 02/03/2025] [Indexed: 03/20/2025]
Abstract
Prostate cancer exhibits significant racial disparities, with African American (AA) individuals showing ∼64% higher incidence and 2.3 times greater mortality rates compared to their Caucasian (CA) counterparts. Understanding the complex interplay of genetic, environmental, lifestyle, socioeconomic, and healthcare access factors is crucial for developing effective interventions to reduce this disproportionate burden. This study aims to uncover the genetic and transcriptomic differences driving these disparities through a comprehensive analysis using RNA sequencing (RNA-seq) and exome sequencing of prostate cancer tissues from both Black and White patients. Our transcriptomics analysis revealed enhanced activity in pathways linked to immune response and cellular interactions in AA prostate cancer samples, with notable regulation by histone-associated transcription factors (HIST1H1A, HIST1H1D, and HIST1H1B) suggests potential involvement of histone modification mechanisms. Additionally, pseudogenes and long non-coding RNAs (lncRNAs) among the regulated genes indicate non-coding elements' role in these disparities. Exome sequencing identified unique variants in AA patient samples within key genes, including TP73 (tumor suppression), XYLB (metabolism), ALDH4A1 (oxidative stress), PTPRB (cellular signaling), and HLA-DRB5 (immune response). These genetic variations likely contribute to disease progression and therapy response disparities. This study highlights the importance of considering genetic and epigenetic variations in developing tailored therapeutic approaches to improve treatment efficacy and reduce mortality rates across diverse populations.
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Affiliation(s)
- Abdalla Elbialy
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Computational Oncology Unit, The University of Chicago Comprehensive Cancer Center, 900 E 57th Street, KCBD Bldg., STE 4144, Chicago, IL, 60637, USA
| | - Akshay Sood
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Department of Urology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Shang-Jui Wang
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Peng Wang
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Department of Medicine, College of Medicine, The Ohio State University, Columbus, OH, 3210, USA
| | - Ahmed Fadiel
- Computational Oncology Unit, The University of Chicago Comprehensive Cancer Center, 900 E 57th Street, KCBD Bldg., STE 4144, Chicago, IL, 60637, USA
| | - Anil V Parwani
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Departments of Pathology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Steven Huang
- School of Applied and Engineering Physics, Cornell University, Ithaca, NY, 14850, USA
| | - Gennady Shvets
- School of Applied and Engineering Physics, Cornell University, Ithaca, NY, 14850, USA
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jenny Li
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Departments of Pathology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Xuefeng Liu
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Departments of Pathology, Urology, and Radiation Oncology, College of Medicine, The Ohio StateUniversity, Columbus, OH, 43210, USA
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3
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Constantin C, Matvienko D, László C, Scabia V, Battista L, Binz PA, Bruce SJ, Brisken C. Mimicking women's endocrine milieu in mice for women's health-related studies. NPJ WOMEN'S HEALTH 2025; 3:13. [PMID: 39991042 PMCID: PMC11845318 DOI: 10.1038/s44294-025-00060-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 01/30/2025] [Indexed: 02/25/2025]
Abstract
To improve preclinical studies and their translation, patient-derived xenografts (PDXs) are increasingly used. They have human-specific tumor characteristics and reflect intra and inter-tumor heterogeneity. However, the endocrine milieu differs between humans and host mice. In light of sex-specific cancer biology and a rise in endocrine-related cancers there is an urgent need to correctly reflect the hormonal milieu in PDX models. We show that female mice of NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) strain widely used for PDXs has 17-β-estradiol (E2) and testosterone (T) levels comparable to C57Bl6 females but higher progesterone (P4) levels. E2 levels are comparable, T levels are lower and P4 levels higher than those observed in postmenopausal women. Ovariectomy increases T to levels observed in postmenopausal women. Subcutaneous E2 and combined E2/P4 silicon pellets provide NSG females with premenopausal ovarian hormone levels. These procedures humanize the endocrine environment of experimental animals, improving PDX relevance in women's health-related research.
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Affiliation(s)
- Céline Constantin
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Lonza AG, Visp, Switzerland
| | - Daria Matvienko
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Csaba László
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- PMI R&D Philip Morris Products S.A., Neuchâtel, Switzerland
| | - Valentina Scabia
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- International Cancer Prevention Institute, Route de la Corniche 8, Epalinges, Switzerland
| | - Laura Battista
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Pierre-Alain Binz
- Clinical Chemistry Laboratory, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
- Institut Central des Hopitaux du Valais, Sion, Switzerland
| | - Stephen J. Bruce
- Clinical Chemistry Laboratory, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Cathrin Brisken
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
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4
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El-Tanani M, Rabbani SA, El-Tanani Y, Matalka II, Khalil IA. Bridging the gap: From petri dish to patient - Advancements in translational drug discovery. Heliyon 2025; 11:e41317. [PMID: 39811269 PMCID: PMC11730937 DOI: 10.1016/j.heliyon.2024.e41317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 12/13/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Translational research serves as the bridge between basic research and practical applications in clinical settings. The journey from "bench to bedside" is fraught with challenges and complexities such as the often-observed disparity between how compounds behave in a laboratory setting versus in the complex systems of living organisms. The challenge is further compounded by the limited ability of in vitro models to mimic the specific biochemical environment of human tissues. This article explores and details the recent advancements and innovative approaches that are increasingly successful in bridging the gap between laboratory research and patient care. These advancements include, but are not limited to, sophisticated in vitro models such as organ-on-a-chip and computational models that utilize artificial intelligence to predict drug efficacy and safety. The article aims to showcase how these technologies improve the predictability of drug performance in human bodies and significantly speed up the drug development process. Furthermore, it discusses the role of biomarker discovery in preparation of more targeted and personalized therapy approaches and covers the impact of regulatory changes designed to facilitate drug approvals. Additionally, by providing detailed case studies of successful applications, we illustrate the practical impacts of these innovations on drug discovery and patient care.
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Affiliation(s)
- Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Syed Arman Rabbani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | | | - Ismail I. Matalka
- Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
- Department of Pathology and Microbiology, Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Ikramy A. Khalil
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
- Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
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5
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Smith MA, Houghton PJ, Lock RB, Maris JM, Gorlick R, Kurmasheva RT, Li XN, Teicher BA, Chuang JH, Dela Cruz FS, Dyer MA, Kung AL, Lloyd MW, Mossé YP, Stearns TM, Stewart EA, Bult CJ, Erickson SW. Lessons learned from 20 years of preclinical testing in pediatric cancers. Pharmacol Ther 2024; 264:108742. [PMID: 39510293 DOI: 10.1016/j.pharmthera.2024.108742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/24/2024] [Accepted: 10/29/2024] [Indexed: 11/15/2024]
Abstract
Programs for preclinical testing of targeted cancer agents in murine models of childhood cancers have been supported by the National Cancer Institute (NCI) since 2004. These programs were established to work collaboratively with industry partners to address the paucity of targeted agents for pediatric cancers compared with the large number of agents developed and approved for malignancies primarily affecting adults. The distinctive biology of pediatric cancers and the relatively small numbers of pediatric cancer patients are major challenges for pediatric oncology drug development. These factors are exacerbated by the division of cancers into multiple subtypes that are further sub-classified by their genomic properties. The imbalance between the large number of candidate agents and small patient populations requires careful prioritization of agents developed for adult cancers for clinical evaluation in children with cancer. The NCI-supported preclinical pediatric programs have published positive and negative results of efficacy testing for over 100 agents to aid the pediatric research community in identifying the most promising candidates to move forward for clinical testing in pediatric oncology. Here, we review and summarize lessons learned from two decades of experience with the design and execution of preclinical trials of antineoplastic agents in murine models of childhood cancers.
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Affiliation(s)
- Malcolm A Smith
- National Cancer Institute, Bethesda, MD, United States of America.
| | - Peter J Houghton
- The University of Texas Health at San Antonio, TX, United States of America
| | - Richard B Lock
- Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - John M Maris
- The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Richard Gorlick
- The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | | | - Xiao-Nan Li
- Lurie Children's Hospital, Northwestern University Feiberg School of Medicine, Chicago, IL, United States of America
| | | | - Jeffrey H Chuang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America
| | - Filemon S Dela Cruz
- Memorial Sloan Kettering Cancer Center, New York City, NY, United States of America
| | - Michael A Dyer
- St. Jude Children's Research Hospital, Memphis, TN, United States of America
| | - Andrew L Kung
- Memorial Sloan Kettering Cancer Center, New York City, NY, United States of America
| | - Michael W Lloyd
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, United States of America
| | - Yael P Mossé
- The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Timothy M Stearns
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, United States of America
| | - Elizabeth A Stewart
- St. Jude Children's Research Hospital, Memphis, TN, United States of America
| | - Carol J Bult
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, United States of America
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Monjaras-Avila CU, Luque-Badillo AC, Bacon JVM, Wyatt AW, So A, Chavez-Munoz C. A novel approach to engineering three-dimensional bladder tumor models for drug testing. Sci Rep 2024; 14:26883. [PMID: 39506094 PMCID: PMC11542063 DOI: 10.1038/s41598-024-78440-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024] Open
Abstract
Bladder cancer (BCa) poses a significant health challenge, particularly affecting men with higher incidence and mortality rates. Addressing the need for improved predictive models in BCa treatment, this study introduces an innovative 3D in vitro patient-derived bladder cancer tumor model, utilizing decellularized pig bladders as scaffolds. Traditional 2D cell cultures, insufficient in replicating tumor microenvironments, have driven the development of sophisticated 3D models. The study successfully achieved pig bladder decellularization through multiple cycles of immersion in salt solutions, resulting in notable macroscopic and histological changes. This process confirmed the removal of cellular components while preserving the native extracellular matrix (ECM). Quantitative analysis demonstrated the efficacy of decellularization, with a remarkable reduction in DNA concentration, signifying the removal of over 95% of cellular material. In the development of the in vitro bladder cancer model, muscle invasive bladder cancer patients' cells were cultured within decellularized pig bladders, yielding a three-dimensional cancer model. Optimal results were attained using an air-liquid interface technique, with cells injected directly into the scaffold at three distinct time points. Histological evaluations showcased characteristics resembling in vivo tumors derived from bladder cancer patients' cells. To demonstrate the 3D cancer model's effectiveness as a drug screening platform, the study treated it with Cisplatin (Cis), Gemcitabine (Gem), and a combination of both drugs. Comprehensive cell viability assays and histological analyses illustrated changes in cell survival and proliferation. The model exhibited promising correlations with clinical outcomes, boasting an 83.3% reliability rate in predicting treatment responses. Comparison with traditional 2D cultures and spheroids underscored the 3D model's superiority in reliability, with an 83.3% predictive capacity compared to 50% for spheroids and 33.3% for 2D culture. Acknowledging limitations, such as the absence of immune and stromal components, the study suggests avenues for future improvements. In conclusion, this innovative 3D bladder cancer model, combining decellularization and patient-derived cells, marks a significant advancement in preclinical drug testing. Its potential for predicting treatment outcomes and capturing patient-specific responses opens new avenues for personalized medicine in bladder cancer therapeutics. Future refinements and validations with larger patient cohorts hold promise for revolutionizing BCa research and treatment strategies.
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Affiliation(s)
- C U Monjaras-Avila
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - A C Luque-Badillo
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - J V M Bacon
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - A W Wyatt
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
- Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - A So
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - C Chavez-Munoz
- Department of Medicine, Faculty of Medicine, University of British Columbia, H.B. 2660 Oak Street, Vancouver, BC, V6H3Z6, Canada.
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Miera-Maluenda M, Pérez-Torres M, Mañas A, Rubio-San-Simón A, Butjosa-Espín M, Ruiz-Duran P, Seoane JA, Moreno L, Segura MF. Advances in the approaches used to repurpose drugs for neuroblastoma. Expert Opin Drug Discov 2024; 19:1309-1319. [PMID: 39258785 DOI: 10.1080/17460441.2024.2402413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 09/05/2024] [Indexed: 09/12/2024]
Abstract
INTRODUCTION Neuroblastoma (NB) remains a challenging pediatric malignancy with limited treatment options, particularly for high-risk cases. Drug repurposing offers a convenient and cost-effective strategy for treating rare diseases like NB. Using existing drugs with known safety profiles accelerates the availability of new treatments, reduces development costs, and mitigates risks, offering hope for improved patient outcomes in challenging conditions. AREAS COVERED This review provides an overview of the advances in approaches used to repurpose drugs for NB therapy. The authors discuss strategies employed in drug repurposing, including computational and experimental methods, and rational drug design, highlighting key examples of repurposed drugs with promising clinical results. Additionally, the authors examine the challenges and opportunities associated with drug repurposing in NB and discuss future directions and potential areas for further research. EXPERT OPINION The fact that only one new drug has been approved in the last 30 years for the treatment of neuroblastoma plus a significant proportion of high-risk NB patients that remain uncurable, evidences the need for new fast and cost-effective alternatives. Drug repurposing may accelerate the treatment development process while reducing expenses and risks. This approach can swiftly bring effective NB therapies to market, enhancing survival rates and patient quality of life.
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Affiliation(s)
- Marta Miera-Maluenda
- Childhood Cancer and Blood Disorders Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - María Pérez-Torres
- Department of Pediatric Oncology and Hematology, Vall D'Hebron University Hospital, Barcelona, Spain
| | - Adriana Mañas
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- IdiPAZ-CNIO Pediatric Onco-Hematology Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Alba Rubio-San-Simón
- Pediatric Oncology and Hematology Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Maria Butjosa-Espín
- Cancer Computational Biology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Paula Ruiz-Duran
- Childhood Cancer and Blood Disorders Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jose A Seoane
- Cancer Computational Biology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Lucas Moreno
- Childhood Cancer and Blood Disorders Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Pediatric Oncology and Hematology, Vall D'Hebron University Hospital, Barcelona, Spain
| | - Miguel F Segura
- Childhood Cancer and Blood Disorders Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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Janitri V, ArulJothi KN, Ravi Mythili VM, Singh SK, Prasher P, Gupta G, Dua K, Hanumanthappa R, Karthikeyan K, Anand K. The roles of patient-derived xenograft models and artificial intelligence toward precision medicine. MedComm (Beijing) 2024; 5:e745. [PMID: 39329017 PMCID: PMC11424683 DOI: 10.1002/mco2.745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 08/22/2024] [Accepted: 08/22/2024] [Indexed: 09/28/2024] Open
Abstract
Patient-derived xenografts (PDX) involve transplanting patient cells or tissues into immunodeficient mice, offering superior disease models compared with cell line xenografts and genetically engineered mice. In contrast to traditional cell-line xenografts and genetically engineered mice, PDX models harbor the molecular and biologic features from the original patient tumor and are generationally stable. This high fidelity makes PDX models particularly suitable for preclinical and coclinical drug testing, therefore better predicting therapeutic efficacy. Although PDX models are becoming more useful, the several factors influencing their reliability and predictive power are not well understood. Several existing studies have looked into the possibility that PDX models could be important in enhancing our knowledge with regard to tumor genetics, biomarker discovery, and personalized medicine; however, a number of problems still need to be addressed, such as the high cost and time-consuming processes involved, together with the variability in tumor take rates. This review addresses these gaps by detailing the methodologies to generate PDX models, their application in cancer research, and their advantages over other models. Further, it elaborates on how artificial intelligence and machine learning were incorporated into PDX studies to fast-track therapeutic evaluation. This review is an overview of the progress that has been done so far in using PDX models for cancer research and shows their potential to be further improved in improving our understanding of oncogenesis.
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Affiliation(s)
| | - Kandasamy Nagarajan ArulJothi
- Department of Genetic Engineering, College of Engineering and TechnologySRM Institute of Science and TechnologyChengalpattuTamil NaduIndia
| | - Vijay Murali Ravi Mythili
- Department of Genetic Engineering, College of Engineering and TechnologySRM Institute of Science and TechnologyChengalpattuTamil NaduIndia
| | - Sachin Kumar Singh
- School of Pharmaceutical SciencesLovely Professional UniversityPhagwaraPunjabIndia
| | - Parteek Prasher
- Department of ChemistryUniversity of Petroleum & Energy Studies, Energy AcresDehradunIndia
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of PharmacyChitkara UniversityRajpuraPunjabIndia
| | - Kamal Dua
- Faculty of Health, Australian Research Center in Complementary and Integrative, MedicineUniversity of Technology SydneyUltimoNSWAustralia
- Discipline of Pharmacy, Graduate School of HealthUniversity of Technology SydneyUltimoNSWAustralia
| | - Rakshith Hanumanthappa
- JSS Banashankari Arts, Commerce, and SK Gubbi Science CollegeKarnatak UniversityDharwadKarnatakaIndia
| | - Karthikeyan Karthikeyan
- Centre of Excellence in PCB Design and Analysis, Department of Electronics and Communication EngineeringM. Kumarasamy College of EngineeringKarurTamil NaduIndia
| | - Krishnan Anand
- Department of Chemical Pathology, School of Pathology, Office of the Dean, Faculty of Health SciencesUniversity of the Free StateBloemfonteinSouth Africa
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Abstract
Metastasis is the ultimate and often lethal stage of cancer. Metastasis occurs in three phases that may vary across individuals: First, dissemination from the primary tumor. Second, tumor dormancy at the metastatic site where micrometastatic cancer cells remain quiescent or, in dynamic cycles of proliferation and elimination, remaining clinically undetectable. Finally, cancer cells are able to overcome microenvironmental constraints for outgrowth, or the formation of clinically detectable macrometastases that colonize distant organs and are largely incurable. A variety of approaches have been used to model metastasis to elucidate molecular mechanisms and identify putative therapeutic targets. In particular, metastatic dormancy has been challenging to model in vivo due to the sparse numbers of cancer cells in micrometastasis nodules and the long latency times required for tumor outgrowth. Here, we review state-of-the art genetically engineered mouse, syngeneic, and patient-derived xenograft approaches for modeling metastasis and dormancy. We describe the advantages and limitations of various metastasis models, novel findings enabled by such approaches, and highlight opportunities for future improvement.
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Affiliation(s)
- Ahmed Mahmoud
- Program in Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Karuna Ganesh
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
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10
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Kunkel MW, Coussens NP, Morris J, Taylor RC, Dexheimer TS, Jones EM, Doroshow JH, Teicher BA. HTS384 NCI60: The Next Phase of the NCI60 Screen. Cancer Res 2024; 84:2403-2416. [PMID: 38861359 PMCID: PMC11292194 DOI: 10.1158/0008-5472.can-23-3031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 02/20/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024]
Abstract
The NCI60 human tumor cell line screen has been in operation as a service to the cancer research community for more than 30 years. The screen operated with 96-well plates, a 2-day exposure period to test agents, and following cell fixation, a visible absorbance endpoint by the protein-staining dye sulforhodamine B. In this study, we describe the next phase of this important cancer research tool, the HTS384 NCI60 screen. Although the cell lines remain the same, the updated screen is performed with 384-well plates, a 3-day exposure period to test agents, and a luminescent endpoint to measure cell viability based upon cellular ATP content. In this study, a library of 1,003 FDA-approved and investigational small-molecule anticancer agents was screened by the two NCI60 assays. The datasets were compared with a focus on targeted agents with at least six representatives in the library. For many agents, including inhibitors of EGFR, BRAF, MEK, ERK, and PI3K, the patterns of GI50 values were very similar between the screens with strong correlations between those patterns within the dataset from each screen. However, for some groups of targeted agents, including mTOR, BET bromodomain, and NAMPRTase inhibitors, there were limited or no correlations between the two datasets, although the patterns of GI50 values and correlations between those patterns within each dataset were apparent. Beginning in January 2024, the HTS384 NCI60 screen became the free screening service of the NCI to facilitate drug discovery by the cancer research community. Significance: The new NCI60 cell line screen HTS384 shows robust patterns of response to oncology agents and substantial overlap with the classic screen, providing an updated tool for studying therapeutic agents. See related commentary by Colombo and Corsello, p. 2397.
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Affiliation(s)
- Mark W. Kunkel
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
| | - Nathan P. Coussens
- Molecular Pharmacology Laboratories, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
| | - Joel Morris
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
| | - Ronald C. Taylor
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
| | - Thomas S. Dexheimer
- Molecular Pharmacology Laboratories, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
| | - Eric M. Jones
- Molecular Pharmacology Laboratories, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
| | - James H. Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
| | - Beverly A. Teicher
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
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11
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Petrescu DI, Yustein JT, Dasgupta A. Preclinical models for the study of pediatric solid tumors: focus on bone sarcomas. Front Oncol 2024; 14:1388484. [PMID: 39091911 PMCID: PMC11291195 DOI: 10.3389/fonc.2024.1388484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 07/01/2024] [Indexed: 08/04/2024] Open
Abstract
Sarcomas comprise between 10-15% of all pediatric malignancies. Osteosarcoma and Ewing sarcoma are the two most common pediatric bone tumors diagnosed in children and young adults. These tumors are commonly treated with surgery and/or radiation therapy and combination chemotherapy. However, there is a strong need for the development and utilization of targeted therapeutic methods to improve patient outcomes. Towards accomplishing this goal, pre-clinical models for these unique malignancies are of particular importance to design and test experimental therapeutic strategies prior to being introduced to patients due to their origination site and propensity to metastasize. Pre-clinical models offer several advantages for the study of pediatric sarcomas with unique benefits and shortcomings dependent on the type of model. This review addresses the types of pre-clinical models available for the study of pediatric solid tumors, with special attention to the bone sarcomas osteosarcoma and Ewing sarcoma.
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Affiliation(s)
- D. Isabel Petrescu
- Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Jason T. Yustein
- Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
| | - Atreyi Dasgupta
- The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Texas Children’s Cancer and Hematology Centers, Houston, TX, United States
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12
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Takahashi Y, Morimura R, Tsukamoto K, Gomi S, Yamada A, Mizukami M, Naito Y, Irie S, Nagayama S, Shinozaki E, Yamaguchi K, Fujita N, Kitano S, Katayama R, Matsusaki M. In vitro throughput screening of anticancer drugs using patient-derived cell lines cultured on vascularized three-dimensional stromal tissues. Acta Biomater 2024; 183:111-129. [PMID: 38801868 DOI: 10.1016/j.actbio.2024.05.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 05/06/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
The development of high-throughput anticancer drug screening methods using patient-derived cancer cell (PDC) lines that maintain their original characteristics in an in vitro three-dimensional (3D) culture system poses a significant challenge to achieving personalized cancer medicine. Because stromal tissue plays a critical role in the composition and maintenance of the cancer microenvironment, in vitro 3D-culture using reconstructed stromal tissues has attracted considerable attention. Here, a simple and unique in vitro 3D-culture method using heparin and collagen together with fibroblasts and endothelial cells to fabricate vascularized 3D-stromal tissues for in vitro culture of PDCs is reported. Whereas co-treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, and 5-fluorouracil significantly reduced the survival rate of 3D-cultured PDCs to 30%, separate addition of each drug did not induce comparable strong cytotoxicity, suggesting the possibility of evaluating the combined effect of anticancer drugs and angiogenesis inhibitors. Surprisingly, drug evaluation using eight PDC lines with the 3D-culture method resulted in a drug efficacy concordance rate of 75% with clinical outcomes. The model is expected to be applicable to in vitro throughput drug screening for the development of personalized cancer medicine. STATEMENT OF SIGNIFICANCE: To replicate the cancer microenvironment, we constructed a cancer-stromal tissue model in which cancer cells are placed above and inside stromal tissue with vascular network structures derived from vascular endothelial cells in fibroblast tissue using CAViTs method. Using this method, we were able to reproduce the invasion and metastasis processes of cancer cells observed in vivo. Using patient-derived cancer cells, we assessed the possibility of evaluating the combined effect with an angiogenesis inhibitor. Further, primary cancer cells also grew on the stromal tissues with the normal medium. These data suggest that the model may be useful for new in vitro drug screening and personalized cancer medicine.
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Affiliation(s)
- Yuki Takahashi
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama 345-8508, Japan; Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Rii Morimura
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama 345-8508, Japan; Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Kei Tsukamoto
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama 345-8508, Japan
| | - Sayaka Gomi
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama 345-8508, Japan
| | - Asuka Yamada
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama 345-8508, Japan; Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
| | - Miki Mizukami
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama 345-8508, Japan
| | - Yasuyuki Naito
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama 345-8508, Japan; Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
| | - Shinji Irie
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
| | - Satoshi Nagayama
- Department of Colorectal Surgery, Gastroenterological Cancer Center, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan; Department of Surgery, Uji Tokushukai Medical Center, Kyoto 611-0041, Japan
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Naoya Fujita
- Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Shiro Kitano
- Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama 345-8508, Japan; Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan.
| | - Ryohei Katayama
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
| | - Michiya Matsusaki
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan; Department of Applied Chemistry Graduate School of Engineering Osaka University, Osaka 565-0871, Japan.
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13
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Yadav R, Mahajan S, Singh H, Mehra NK, Madan J, Doijad N, Singh PK, Guru SK. Emerging In Vitro and In Vivo Models: Hope for the Better Understanding of Cancer Progression and Treatment. Adv Biol (Weinh) 2024; 8:e2300487. [PMID: 38581078 DOI: 10.1002/adbi.202300487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/04/2024] [Indexed: 04/07/2024]
Abstract
Various cancer models have been developed to aid the understanding of the underlying mechanisms of tumor development and evaluate the effectiveness of various anticancer drugs in preclinical studies. These models accurately reproduce the critical stages of tumor initiation and development to mimic the tumor microenvironment better. Using these models for target validation, tumor response evaluation, resistance modeling, and toxicity comprehension can significantly enhance the drug development process. Herein, various in vivo or animal models are presented, typically consisting of several mice and in vitro models ranging in complexity from transwell models to spheroids and CRISPR-Cas9 technologies. While in vitro models have been used for decades and dominate the early stages of drug development, they are still limited primary to simplistic tests based on testing on a single cell type cultivated in Petri dishes. Recent advancements in developing new cancer therapies necessitate the generation of complicated animal models that accurately mimic the tumor's complexity and microenvironment. Mice make effective tumor models as they are affordable, have a short reproductive cycle, exhibit rapid tumor growth, and are simple to manipulate genetically. Human cancer mouse models are crucial to understanding the neoplastic process and basic and clinical research improvements. The following review summarizes different in vitro and in vivo metastasis models, their advantages and disadvantages, and their ability to serve as a model for cancer research.
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Affiliation(s)
- Rachana Yadav
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Srushti Mahajan
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, 500037, India
| | - Hoshiyar Singh
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Neelesh Kumar Mehra
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, 500037, India
| | - Jitender Madan
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, 500037, India
| | - Nandkumar Doijad
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Pankaj Kumar Singh
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, 500037, India
| | - Santosh Kumar Guru
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
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14
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Rubahamya B, Dong S, Thurber GM. Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data. SCIENCE ADVANCES 2024; 10:eadk1894. [PMID: 38820153 PMCID: PMC11141632 DOI: 10.1126/sciadv.adk1894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 04/29/2024] [Indexed: 06/02/2024]
Abstract
Antibody drug conjugates (ADCs) have made impressive strides in the clinic in recent years with 11 Food and Drug Administration approvals, including 6 for the treatment of patients with solid tumors. Despite this success, the development of new agents remains challenging with a high failure rate in the clinic. Here, we show that current approved ADCs for the treatment of patients with solid tumors can all show substantial efficacy in some mouse models when administered at a similar weight-based [milligrams per kilogram (mg/kg)] dosing in mice that is tolerated in the clinic. Mechanistically, equivalent mg/kg dosing results in a similar drug concentration in the tumor and a similar tissue penetration into the tumor due to the unique delivery features of ADCs. Combined with computational approaches, which can account for the complex distribution within the tumor microenvironment, these scaling concepts may aid in the evaluation of new agents and help design therapeutics with maximum clinical efficacy.
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Affiliation(s)
- Baron Rubahamya
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shujun Dong
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Greg M. Thurber
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
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15
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Sharma MP, Shukla S, Misra G. Recent advances in breast cancer cell line research. Int J Cancer 2024; 154:1683-1693. [PMID: 38230499 DOI: 10.1002/ijc.34849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/06/2023] [Accepted: 12/19/2023] [Indexed: 01/18/2024]
Abstract
Breast cancer, a formidable global health challenge, needs continuous translational research to understand the complexity of mechanisms and improve therapeutic and diagnostic strategies. Breast cancer cell lines are of paramount importance as they significantly contribute to the initial stage of research to understand cancer biology. This review provides insights into targeted therapies and immunotherapies that have emerged using in vitro models and microbiome analysis. It focuses on therapeutic development using cell lines and the limitations of tumor heterogeneity and microenvironment. We explore the evolving landscape of breast cancer cell lines from two-dimensional (2-D) cultures to patient-derived xenograft (PDX) models advancing both fundamental and translational research. Patient-derived xenografts, cell line-derived xenografts (CDX), three-dimensional (3-D) cultures, organoids, and circulating tumor cells (CTC) models provide promising alternatives that capture the intricacies of the tumor microenvironment. This review bridges the gap between traditional cell lines and newer developments exploring the therapeutic and diagnostic advancements and needs for cell lines to expedite the progress in breast cancer research and treatment.
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Affiliation(s)
- Manika P Sharma
- Molecular Diagnostics and COVID-19 Kit Testing Laboratory, National Institute of Biologicals (Ministry of Health and Family Welfare), Noida, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Supriya Shukla
- Molecular Diagnostics and COVID-19 Kit Testing Laboratory, National Institute of Biologicals (Ministry of Health and Family Welfare), Noida, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Gauri Misra
- Molecular Diagnostics and COVID-19 Kit Testing Laboratory, National Institute of Biologicals (Ministry of Health and Family Welfare), Noida, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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16
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Daley JD, Mukherjee E, Tufino AC, Bailey N, Bhaskar S, Periyapatna N, MacFawn I, Kunning S, Hinck C, Bruno T, Olson AC, McAllister-Lucas LM, Hinck AP, Cooper K, Bao R, Cillo AR, Bailey KM. Immunocompetent murine model of Ewing sarcoma reveals role for TGFβ inhibition to enhance immune infiltrates in Ewing tumors during radiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.07.592974. [PMID: 38766091 PMCID: PMC11100684 DOI: 10.1101/2024.05.07.592974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Ewing sarcoma (ES) is an aggressive cancer diagnosed in adolescents and young adults. The fusion oncoprotein (EWSR1::FLI1) that drives Ewing sarcoma is known to downregulate TGFBR2 expression (part of the TGFβ receptor). Because TGFBR2 is downregulated, it was thought that TGFβ likely plays an inconsequential role in Ewing biology. However, the expression of TGFβ in the Ewing tumor immune microenvironment (TIME) and functional impact of TGFβ in the TIME remains largely unknown given the historical lack of immunocompetent preclinical models. Here, we use single-cell RNAseq analysis of human Ewing tumors to show that immune cells, such as NK cells, are the largest source of TGFβ production in human Ewing tumors. We develop a humanized (immunocompetent) mouse model of ES and demonstrate distinct TME signatures and metastatic potential in these models as compared to tumors developed in immunodeficient mice. Using this humanized model, we study the effect of TGFβ inhibition on the Ewing TME during radiation therapy, a treatment that both enhances TGFβ activation and is used to treat aggressive ES. Utilizing a trivalent ligand TGFβ TRAP to inhibit TGFβ, we demonstrate that in combination with radiation, TGFβ inhibition both increases ES immune cell infiltration and decreases lung metastatic burden in vivo . The culmination of these data demonstrates the value of humanized models to address immunobiologic preclinical questions in Ewing sarcoma and suggests TGFβ inhibition as a promising intervention during radiation therapy to promote metastatic tumor control.
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17
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Petersen ME, Brant MG, Lasalle M, Das S, Duan R, Wong J, Ding T, Wu KJ, Siddappa D, Fang C, Zhang W, Wu AML, Hirkala-Schaefer T, Garnett GAE, Fung V, Yang L, Hernandez Rojas A, Lawn SO, Barnscher SD, Rich JR, Colombo R. Design and Evaluation of ZD06519, a Novel Camptothecin Payload for Antibody Drug Conjugates. Mol Cancer Ther 2024; 23:606-618. [PMID: 38354417 PMCID: PMC11063767 DOI: 10.1158/1535-7163.mct-23-0822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/08/2024] [Accepted: 02/09/2024] [Indexed: 02/16/2024]
Abstract
In recent years, the field of antibody drug conjugates (ADC) has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs incorporating camptothecin-based topoisomerase I inhibitor payloads. Herein, we present the development of a novel camptothecin ZD06519 (FD1), which has been specifically designed for its application as an ADC payload. A panel of camptothecin analogs with different substituents at the C-7 and C-10 positions of the camptothecin core was prepared and tested in vitro. Selected compounds spanning a range of potency and hydrophilicity were elaborated into drug-linkers, conjugated to trastuzumab, and evaluated in vitro and in vivo. ZD06519 was selected on the basis of its favorable properties as a free molecule and as an antibody conjugate, which include moderate free payload potency (∼1 nmol/L), low hydrophobicity, strong bystander activity, robust plasma stability, and high-monomeric ADC content. When conjugated to different antibodies using a clinically validated MC-GGFG-based linker, ZD06519 demonstrated impressive efficacy in multiple cell line-derived xenograft models and noteworthy tolerability in healthy mice, rats, and non-human primates.
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Affiliation(s)
- Mark E. Petersen
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Michael G. Brant
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Manuel Lasalle
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Samir Das
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Renee Duan
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Jodi Wong
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Tong Ding
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Kaylee J. Wu
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Dayananda Siddappa
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Chen Fang
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Wen Zhang
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Alex M. L. Wu
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | | | - Graham A. E. Garnett
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Vincent Fung
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Luying Yang
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | | | - Samuel O. Lawn
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Stuart D. Barnscher
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Jamie R. Rich
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
| | - Raffaele Colombo
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, British Columbia, Canada
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18
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Stribbling SM, Beach C, Ryan AJ. Orthotopic and metastatic tumour models in preclinical cancer research. Pharmacol Ther 2024; 257:108631. [PMID: 38467308 PMCID: PMC11781865 DOI: 10.1016/j.pharmthera.2024.108631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 02/27/2024] [Accepted: 03/08/2024] [Indexed: 03/13/2024]
Abstract
Mouse models of disease play a pivotal role at all stages of cancer drug development. Cell-line derived subcutaneous tumour models are predominant in early drug discovery, but there is growing recognition of the importance of the more complex orthotopic and metastatic tumour models for understanding both target biology in the correct tissue context, and the impact of the tumour microenvironment and the immune system in responses to treatment. The aim of this review is to highlight the value that orthotopic and metastatic models bring to the study of tumour biology and drug development while pointing out those models that are most likely to be encountered in the literature. Important developments in orthotopic models, such as the increasing use of early passage patient material (PDXs, organoids) and humanised mouse models are discussed, as these approaches have the potential to increase the predictive value of preclinical studies, and ultimately improve the success rate of anticancer drugs in clinical trials.
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Affiliation(s)
- Stephen M Stribbling
- Department of Chemistry, University College London, Gower Street, London WC1E 6BT, UK.
| | - Callum Beach
- Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Anderson J Ryan
- Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK; Fast Biopharma, Aston Rowant, Oxfordshire, OX49 5SW, UK.
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19
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Soufizadeh P, Mansouri V, Ahmadbeigi N. A review of animal models utilized in preclinical studies of approved gene therapy products: trends and insights. Lab Anim Res 2024; 40:17. [PMID: 38649954 PMCID: PMC11034049 DOI: 10.1186/s42826-024-00195-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 02/18/2024] [Accepted: 02/23/2024] [Indexed: 04/25/2024] Open
Abstract
Scientific progress heavily relies on rigorous research, adherence to scientific standards, and transparent reporting. Animal models play a crucial role in advancing biomedical research, especially in the field of gene therapy. Animal models are vital tools in preclinical research, allowing scientists to predict outcomes and understand complex biological processes. The selection of appropriate animal models is critical, considering factors such as physiological and pathophysiological similarities, availability, and ethical considerations. Animal models continue to be indispensable tools in preclinical gene therapy research. Advancements in genetic engineering and model selection have improved the fidelity and relevance of these models. As gene therapy research progresses, careful consideration of animal models and transparent reporting will contribute to the development of effective therapies for various genetic disorders and diseases. This comprehensive review explores the use of animal models in preclinical gene therapy studies for approved products up to September 2023. The study encompasses 47 approved gene therapy products, with a focus on preclinical trials. This comprehensive analysis serves as a valuable reference for researchers in the gene therapy field, aiding in the selection of suitable animal models for their preclinical investigations.
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Affiliation(s)
- Parham Soufizadeh
- Gene Therapy Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Biomedical Research Institute, University of Tehran, Tehran, Iran
| | - Vahid Mansouri
- Gene Therapy Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Naser Ahmadbeigi
- Gene Therapy Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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20
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Lewis MT, Caldas C. The Power and Promise of Patient-Derived Xenografts of Human Breast Cancer. Cold Spring Harb Perspect Med 2024; 14:a041329. [PMID: 38052483 PMCID: PMC10982691 DOI: 10.1101/cshperspect.a041329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
In 2016, a group of researchers engaged in the development of patient-derived xenografts (PDXs) of human breast cancer provided a comprehensive review of the state of the field. In that review, they summarized the clinical problem that PDXs might address, the technical approaches to their generation (including a discussion of host animals and transplant conditions tested), and presented transplantation success (take) rates across groups and across transplantation conditions. At the time, there were just over 500 unique PDX models created by these investigators representing all three clinically defined subtypes (ER+, HER2+, and TNBC). Today, many of these PDX resources have at least doubled in size, and several more PDX development groups now exist, such that there may be well upward of 1000 PDX models of human breast cancer in existence worldwide. They also presented a series of open questions for the field. Many of these questions have been addressed. However, several remain open, or only partially addressed. Herein, we revisit these questions, and recount the progress that has been made in a number of areas with respect to generation, characterization, and use of PDXs in translational research, and re-present questions that remain open. These open questions, and others, are now being addressed not only by individual investigators, but also large, well-funded consortia including the PDXNet program of the National Cancer Institute in the United States, and the EuroPDX Consortium, an organization of PDX developers across Europe. Finally, we discuss the new opportunities in PDX-based research.
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Affiliation(s)
- Michael T Lewis
- Baylor College of Medicine, The Lester and Sue Smith Breast Center, Departments of Molecular and Cellular Biology and Radiology, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Carlos Caldas
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom
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21
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Suzuki T, Henshaw MJ, Yanagi T, Aoshima K. Current understanding of comparative pathology and prospective research approaches for canine hemangiosarcoma. Res Vet Sci 2024; 167:105120. [PMID: 38150941 DOI: 10.1016/j.rvsc.2023.105120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 12/11/2023] [Accepted: 12/18/2023] [Indexed: 12/29/2023]
Abstract
Hemangiosarcoma (HSA) is a malignant tumor originating from endothelial cells. HSA typically develops in dogs, but is rare in other animals, including humans. Although surgery and chemotherapy are conventional treatments for HSA, neither treatment can significantly improve patient prognosis. To develop novel and effective therapeutics, a deeper understanding of HSA pathogenesis must be acquired. However, the limited research tools for HSA have been unable to make a breakthrough; therefore, it is crucial to widely utilize or establish novel research tools such as patient-derived xenograft models, organoids, and chicken embryo xenograft models. The pathogenesis of the human counterpart of HSA, angiosarcoma (AS), also remains incompletely understood, preventing the extrapolation of findings from humans to dogs, unlike other diseases. In this review, we summarize the clinicopathological and morphological features of HSA, and then we discuss the current understanding of the molecular pathology of HSA. Finally, we highlight promising research tools that may accelerate HSA basic research toward developing novel therapeutics. We also briefly summarize AS to help researchers comprehend HSA from the perspective of comparative pathology.
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Affiliation(s)
- Tamami Suzuki
- Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Michael James Henshaw
- English Education Section, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Teruki Yanagi
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Keisuke Aoshima
- Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan; Cancer Research Unit, One Health Research Center, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan.
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22
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Ueda S, Tanaka T, Hirosuna K, Miyamoto S, Murakami H, Nishie R, Tsuchihashi H, Toji A, Morita N, Hashida S, Daimon A, Terada S, Maruoka H, Kogata Y, Taniguchi K, Komura K, Ohmichi M. Consistency between Primary Uterine Corpus Malignancies and Their Corresponding Patient-Derived Xenograft Models. Int J Mol Sci 2024; 25:1486. [PMID: 38338763 PMCID: PMC10855170 DOI: 10.3390/ijms25031486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/23/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Patient-derived xenograft (PDX) models retain the characteristics of tumors and are useful tools for personalized therapy and translational research. In this study, we aimed to establish PDX models for uterine corpus malignancies (UC-PDX) and analyze their similarities. Tissue fragments obtained from 92 patients with uterine corpus malignancies were transplanted subcutaneously into immunodeficient mice. Histological and immunohistochemical analyses were performed to compare tumors of patients with PDX tumors. DNA and RNA sequencing were performed to validate the genetic profile. Furthermore, the RNA in extracellular vesicles (EVs) extracted from primary and PDX tumors was analyzed. Among the 92 cases, 52 UC-PDX models were established, with a success rate of 56.5%. The success rate depended on tumor histology and staging. The pathological and immunohistochemical features of primary and PDX tumors were similar. DNA sequencing revealed similarities in gene mutations between the primary and PDX tumors. RNA sequencing showed similarities in gene expressions between primary and PDX tumors. Furthermore, the RNA profiles of the EVs obtained from primary and PDX tumors were similar. As UC-PDX retained the pathological and immunohistochemical features and gene profiles of primary tumors, they may provide a platform for developing personalized medicine and translational research.
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Affiliation(s)
- Shoko Ueda
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Tomohito Tanaka
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
- Center for Medical Research & Development, Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (K.T.); (K.K.)
| | - Kensuke Hirosuna
- Department of Regenerative Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatachou, Kita-ku, Okayama 700-8558, Okayama, Japan;
| | - Shunsuke Miyamoto
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
- Center for Medical Research & Development, Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (K.T.); (K.K.)
| | - Hikaru Murakami
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Ruri Nishie
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Hiromitsu Tsuchihashi
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Akihiko Toji
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Natsuko Morita
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Sousuke Hashida
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Atsushi Daimon
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Shinichi Terada
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Hiroshi Maruoka
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Yuhei Kogata
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
| | - Kohei Taniguchi
- Center for Medical Research & Development, Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (K.T.); (K.K.)
| | - Kazumasa Komura
- Center for Medical Research & Development, Division of Translational Research, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (K.T.); (K.K.)
| | - Masahide Ohmichi
- Department of Obstetrics and Gynecology, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan; (S.U.); (S.M.); (H.M.); (R.N.); (H.T.); (A.T.); (N.M.); (S.H.); (A.D.); (S.T.); (H.M.); (Y.K.); (M.O.)
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23
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Alotaibi F, Alshammari K, Alotaibi BA, Alsaab H. Destabilizing the genome as a therapeutic strategy to enhance response to immune checkpoint blockade: a systematic review of clinical trials evidence from solid and hematological tumors. Front Pharmacol 2024; 14:1280591. [PMID: 38264532 PMCID: PMC10803447 DOI: 10.3389/fphar.2023.1280591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/11/2023] [Indexed: 01/25/2024] Open
Abstract
Background: Genomic instability is increased alterations in the genome during cell division and is common among most cancer cells. Genome instability enhances the risk of initial carcinogenic transformation, generating new clones of tumor cells, and increases tumor heterogeneity. Although genome instability contributes to malignancy, it is also an "Achilles' heel" that constitutes a therapeutically-exploitable weakness-when sufficiently advanced, it can intrinsically reduce tumor cell survival by creating DNA damage and mutation events that overwhelm the capacity of cancer cells to repair those lesions. Furthermore, it can contribute to extrinsic survival-reducing events by generating mutations that encode new immunogenic antigens capable of being recognized by the immune system, particularly when anti-tumor immunity is boosted by immunotherapy drugs. Here, we describe how genome-destabilization can induce immune activation in cancer patients and systematically review the induction of genome instability exploited clinically, in combination with immune checkpoint blockade. Methods: We performed a systematic review of clinical trials that exploited the combination approach to successfully treat cancers patients. We systematically searched PubMed, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and publication from the reference list of related articles. The most relevant inclusion criteria were peer-reviewed clinical trials published in English. Results: We identified 1,490 studies, among those 164 were clinical trials. A total of 37 clinical trials satisfied the inclusion criteria and were included in the study. The main outcome measurements were overall survival and progression-free survival. The majority of the clinical trials (30 out of 37) showed a significant improvement in patient outcome. Conclusion: The majority of the included clinical trials reported the efficacy of the concept of targeting DNA repair pathway, in combination with immune checkpoint inhibitors, to create a "ring of synergy" to treat cancer with rational combinations.
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Affiliation(s)
- Faizah Alotaibi
- College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Alahsa, Saudi Arabia
- King Abdullah International Medical Research Center, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Kanaan Alshammari
- King Abdullah International Medical Research Center, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- Oncology Department, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Badi A. Alotaibi
- King Abdullah International Medical Research Center, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Hashem Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
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24
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Rassomakhina NV, Ryazanova AY, Likhov AR, Bruskin SA, Maloshenok LG, Zherdeva VV. Tumor Organoids: The Era of Personalized Medicine. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:S127-S147. [PMID: 38621748 DOI: 10.1134/s0006297924140086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/01/2023] [Accepted: 11/09/2023] [Indexed: 04/17/2024]
Abstract
The strategies of future medicine are aimed to modernize and integrate quality approaches including early molecular-genetic profiling, identification of new therapeutic targets and adapting design for clinical trials, personalized drug screening (PDS) to help predict and individualize patient treatment regimens. In the past decade, organoid models have emerged as an innovative in vitro platform with the potential to realize the concept of patient-centered medicine. Organoids are spatially restricted three-dimensional clusters of cells ex vivo that self-organize into complex functional structures through genetically programmed determination, which is crucial for reconstructing the architecture of the primary tissue and organs. Currently, there are several strategies to create three-dimensional (3D) tumor systems using (i) surgically resected patient tissue (PDTOs, patient-derived tumor organoids) or (ii) single tumor cells circulating in the patient's blood. Successful application of 3D tumor models obtained by co-culturing autologous tumor organoids (PDTOs) and peripheral blood lymphocytes have been demonstrated in a number of studies. Such models simulate a 3D tumor architecture in vivo and contain all cell types characteristic of this tissue, including immune system cells and stem cells. Components of the tumor microenvironment, such as fibroblasts and immune system cells, affect tumor growth and its drug resistance. In this review, we analyzed the evolution of tumor models from two-dimensional (2D) cell cultures and laboratory animals to 3D tissue-specific tumor organoids, their significance in identifying mechanisms of antitumor response and drug resistance, and use of these models in drug screening and development of precision methods in cancer treatment.
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Affiliation(s)
- Natalia V Rassomakhina
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia
| | - Alexandra Yu Ryazanova
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia
| | - Astemir R Likhov
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia
| | - Sergey A Bruskin
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia
| | - Liliya G Maloshenok
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia
| | - Victoria V Zherdeva
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia.
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25
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Weng T, Jenkins BJ, Saad MI. Patient-Derived Xenografts: A Valuable Preclinical Model for Drug Development and Biomarker Discovery. Methods Mol Biol 2024; 2806:19-30. [PMID: 38676793 DOI: 10.1007/978-1-0716-3858-3_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2024]
Abstract
Patient-derived xenografts (PDXs), established by implanting patient tumor cells into immunodeficient mice, offer a platform for faithfully replicating human tumors. They closely mimic the histopathology, genomics, and drug sensitivity of patient tumors. This chapter highlights the versatile applications of PDXs, including studying tumor biology, metastasis, and chemoresistance, as well as their use in biomarker identification, drug screening, and personalized medicine. It also addresses challenges in using PDXs in cancer research, including variations in metastatic potential, lengthy establishment timelines, stromal changes, and limitations in immunocompromised models. Despite these challenges, PDXs remain invaluable tools guiding patient treatment and advancing preclinical drug development.
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Affiliation(s)
- Teresa Weng
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
- South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, SA, Australia
| | - Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
- South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, SA, Australia.
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26
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Thompson J, Saad MI. Patient-Derived Xenografts: Historical Evolution, Immunocompromised Host Models, and Translational Significance. Methods Mol Biol 2024; 2806:1-8. [PMID: 38676791 DOI: 10.1007/978-1-0716-3858-3_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2024]
Abstract
Patient-derived xenografts (PDXs) represent a critical advancement in preclinical cancer research, wherein human tumor samples are implanted into animal models for evaluation of therapeutic responses. PDXs have emerged as indispensable tools in translational cancer research, facilitating investigation into tumor microenvironments and personalized medicine. This chapter elucidates the historical evolution of PDXs, from early attempts in the eighteenth century to contemporary immunocompromised host models that enhance engraftment success.
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Affiliation(s)
- James Thompson
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
- South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, SA, Australia.
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27
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Hirst TC, Wilson E, Browne D, Sena ES. A machine learning-assisted systematic review of preclinical glioma modeling: Is practice changing with the times? Neurooncol Adv 2024; 6:vdae193. [PMID: 39734809 PMCID: PMC11680884 DOI: 10.1093/noajnl/vdae193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2024] Open
Abstract
Background Despite improvements in our understanding of glioblastoma pathophysiology, there have been no major improvements in treatment in recent years. Animal models are a vital tool for investigating cancer biology and its treatment, but have known limitations. There have been advances in glioblastoma modeling techniques in this century although it is unclear to what extent they have been adopted. Methods We searched Pubmed and EMBASE using terms designed to identify all publications reporting an animal glioma experiment, using a machine learning algorithm to assist with screening. We reviewed the full text of a sample of 1000 articles and then used the findings to inform a screen of all included abstracts to appraise the modeling applications across the entire dataset. Results The search identified 26 201 publications of which 13 783 were included at screening. The automated screening had high sensitivity but limited specificity. We observed a dominance of traditional cell line paradigms and the emergence of advanced tumor model systems eclipsed by a large increase in the volume of cell line experiments. Few studies used more than 1 model in vivo and most publications did not verify critical genetic features. Conclusions Advanced models have clear advantages in terms of tumor and disease recapitulation and have largely not replaced traditional cell lines which have a number of critical deficiencies that limit their viability in modern animal research. The judicious use of advanced models or more relevant cell lines might improve the translational relevance of future animal glioblastoma experimentation.
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Affiliation(s)
- Theodore C Hirst
- Department of Neurosurgery, Royal Victoria Hospital, Belfast, UK
- Patrick G Johnson Centre for Cancer Research, Queens University Belfast, Belfast, UK
| | - Emma Wilson
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Declan Browne
- Department of Neurosurgery, Royal Victoria Hospital, Belfast, UK
| | - Emily S Sena
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
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28
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Rago V, Perri A, Di Agostino S. New Therapeutic Perspectives in Prostate Cancer: Patient-Derived Organoids and Patient-Derived Xenograft Models in Precision Medicine. Biomedicines 2023; 11:2743. [PMID: 37893116 PMCID: PMC10604340 DOI: 10.3390/biomedicines11102743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/06/2023] [Accepted: 10/08/2023] [Indexed: 10/29/2023] Open
Abstract
One of the major goals in the advancement of basic cancer research focuses on the development of new anticancer therapies. To understand the molecular mechanisms of cancer progression, acquired drug resistance, and the metastatic process, the use of preclinical in vitro models that faithfully summarize the properties of the tumor in patients is still a necessity. The tumor is represented by a diverse group of cell clones, and in recent years, to reproduce in vitro preclinical tumor models, monolayer cell cultures have been supplanted by patient-derived xenograft (PDX) models and cultured organoids derived from the patient (PDO). These models have proved indispensable for the study of the tumor microenvironment (TME) and its interaction with tumor cells. Prostate cancer (PCa) is the most common neoplasia in men in the world. It is characterized by genomic instability and resistance to conventional therapies. Despite recent advances in diagnosis and treatment, PCa remains a leading cause of cancer death. Here, we review the studies of the last 10 years as the number of papers is growing very fast in the field. We also discuss the discovered limitations and the new challenges in using the organoid culture system and in using PDXs in studying the prostate cancer phenotype, performing drug testing, and developing anticancer molecular therapies.
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Affiliation(s)
- Vittoria Rago
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Anna Perri
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy;
| | - Silvia Di Agostino
- Department of Health Sciences, Magna Græcia University of Catanzaro, 88100 Catanzaro, Italy
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29
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Blanco-Fernandez B, Ibañez-Fonseca A, Orbanic D, Ximenes-Carballo C, Perez-Amodio S, Rodríguez-Cabello JC, Engel E. Elastin-like Recombinamer Hydrogels as Platforms for Breast Cancer Modeling. Biomacromolecules 2023; 24:4408-4418. [PMID: 36597885 PMCID: PMC10565832 DOI: 10.1021/acs.biomac.2c01080] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 12/07/2022] [Indexed: 01/05/2023]
Abstract
The involvement of the extracellular matrix (ECM) in tumor progression has motivated the development of biomaterials mimicking the tumor ECM to develop more predictive cancer models. Particularly, polypeptides based on elastin could be an interesting approach to mimic the ECM due to their tunable properties. Here, we demonstrated that elastin-like recombinamer (ELR) hydrogels can be suitable biomaterials to develop breast cancer models. This hydrogel was formed by two ELR polypeptides, one containing sequences biodegradable by matrix metalloproteinase and cyclooctyne and the other carrying arginylglycylaspartic acid and azide groups to allow cell adhesion, biodegradability, and suitable stiffness through "click-chemistry" cross-linking. Our findings show that breast cancer or nontumorigenic breast cells showed high viability and cell proliferation for up to 7 days. MCF7 and MCF10A formed spheroids whereas MDA-MB-231 formed cell networks, with the expression of ECM and high drug resistance in all cases, evidencing that ELR hydrogels are a promising biomaterial for breast cancer modeling.
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Affiliation(s)
- Barbara Blanco-Fernandez
- Institute
for Bioengineering of Catalonia (IBEC), The Barcelona Institute of
Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
- CIBER
en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid 28029, Spain
| | - Arturo Ibañez-Fonseca
- BIOFORGE
Lab, CIBER-BBN, University of Valladolid, Paseo de Belén 19, 47011 Valladolid, Spain
| | - Doriana Orbanic
- BIOFORGE
Lab, CIBER-BBN, University of Valladolid, Paseo de Belén 19, 47011 Valladolid, Spain
| | - Celia Ximenes-Carballo
- Institute
for Bioengineering of Catalonia (IBEC), The Barcelona Institute of
Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
| | - Soledad Perez-Amodio
- Institute
for Bioengineering of Catalonia (IBEC), The Barcelona Institute of
Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
| | | | - Elisabeth Engel
- Institute
for Bioengineering of Catalonia (IBEC), The Barcelona Institute of
Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
- CIBER
en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid 28029, Spain
- IMEM-BRT
Group, Department of Materials Science and Engineering, EEBE, Technical University of Catalonia (UPC), Barcelona 08019, Spain
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30
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Mahmoudian RA, Farshchian M, Golyan FF, Mahmoudian P, Alasti A, Moghimi V, Maftooh M, Khazaei M, Hassanian SM, Ferns GA, Mahaki H, Shahidsales S, Avan A. Preclinical tumor mouse models for studying esophageal cancer. Crit Rev Oncol Hematol 2023; 189:104068. [PMID: 37468084 DOI: 10.1016/j.critrevonc.2023.104068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/21/2023] Open
Abstract
Preclinical models are extensively employed in cancer research because they can be manipulated in terms of their environment, genome, molecular biology, organ systems, and physical activity to mimic human behavior and conditions. The progress made in in vivo cancer research has resulted in significant advancements, enabling the creation of spontaneous, metastatic, and humanized mouse models. Most recently, the remarkable and extensive developments in genetic engineering, particularly the utilization of CRISPR/Cas9, transposable elements, epigenome modifications, and liquid biopsies, have further facilitated the design and development of numerous mouse models for studying cancer. In this review, we have elucidated the production and usage of current mouse models, such as xenografts, chemical-induced models, and genetically engineered mouse models (GEMMs), for studying esophageal cancer. Additionally, we have briefly discussed various gene-editing tools that could potentially be employed in the future to create mouse models specifically for esophageal cancer research.
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Affiliation(s)
- Reihaneh Alsadat Mahmoudian
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Moein Farshchian
- Division of Oncology, Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Fatemeh Fardi Golyan
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Mahmoudian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Alasti
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Moghimi
- Department of Biology, Faculty of Science, Hakim Sabzevari University, Sabzevar, Iran
| | - Mina Maftooh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Hanie Mahaki
- Vascular & Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq; Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.
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31
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Tardito S, MacKay C. Rethinking our approach to cancer metabolism to deliver patient benefit. Br J Cancer 2023; 129:406-415. [PMID: 37340094 PMCID: PMC10403540 DOI: 10.1038/s41416-023-02324-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/25/2023] [Accepted: 06/12/2023] [Indexed: 06/22/2023] Open
Abstract
Altered cellular metabolism is a major mechanism by which tumours support nutrient consumption associated with increased cellular proliferation. Selective dependency on specific metabolic pathways provides a therapeutic vulnerability that can be targeted in cancer therapy. Anti-metabolites have been used clinically since the 1940s and several agents targeting nucleotide metabolism are now well established as standard of care treatment in a range of indications. However, despite great progress in our understanding of the metabolic requirements of cancer and non-cancer cells within the tumour microenvironment, there has been limited clinical success for novel agents targeting pathways outside of nucleotide metabolism. We believe that there is significant therapeutic potential in targeting metabolic processes within cancer that is yet to be fully realised. However, current approaches to identify novel targets, test novel therapies and select patient populations most likely to benefit are sub-optimal. We highlight recent advances in technologies and understanding that will support the identification and validation of novel targets, re-evaluation of existing targets and design of optimal clinical positioning strategies to deliver patient benefit.
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Affiliation(s)
- Saverio Tardito
- The Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Craig MacKay
- Cancer Research Horizons, The Cancer Research UK Beatson Institute, Glasgow, UK.
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Pieper AA, Spiegelman DV, Felder MAR, Feils AS, Tsarovsky NW, Zaborek J, Morris ZS, Erbe AK, Rakhmilevich AL, Sondel PM. Factors impacting the efficacy of the in-situ vaccine with CpG and OX40 agonist. Cancer Immunol Immunother 2023; 72:2459-2471. [PMID: 37016127 PMCID: PMC10264285 DOI: 10.1007/s00262-023-03433-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 03/22/2023] [Indexed: 04/06/2023]
Abstract
BACKGROUND The in-situ vaccine using CpG oligodeoxynucleotide combined with OX40 agonist antibody (CpG + OX40) has been shown to be an effective therapy activating an anti-tumor T cell response in certain settings. The roles of tumor volume, tumor model, and the addition of checkpoint blockade in the efficacy of CpG + OX40 in-situ vaccination remains unknown. METHODS Mice bearing flank tumors (B78 melanoma or A20 lymphoma) were treated with combinations of CpG, OX40, and anti-CTLA-4. Tumor growth and survival were monitored. In vivo T cell depletion, tumor cell phenotype, and tumor infiltrating lymphocyte (TIL) studies were performed. Tumor cell sensitivity to CpG and macrophages were evaluated in vitro. RESULTS As tumor volumes increased in the B78 (one-tumor) and A20 (one-tumor or two-tumor) models, the anti-tumor efficacy of the in-situ vaccine decreased. In vitro, CpG had a direct effect on A20 proliferation and phenotype and an indirect effect on B78 proliferation via macrophage activation. As A20 tumors progressed in vivo, tumor cell phenotype changed, and T cells became more involved in the local CpG + OX40 mediated anti-tumor response. In mice with larger tumors that were poorly responsive to CpG + OX40, the addition of anti-CTLA-4 enhanced the anti-tumor efficacy in the A20 but not B78 models. CONCLUSIONS Increased tumor volume negatively impacts the anti-tumor capability of CpG + OX40 in-situ vaccine. The addition of checkpoint blockade augmented the efficacy of CpG + OX40 in the A20 but not B78 model. These results highlight the importance of considering multiple preclinical model conditions when assessing the efficacy of cancer immunotherapy regimens and their translation to clinical testing.
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Affiliation(s)
- Alexander A Pieper
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Dan V Spiegelman
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Mildred A R Felder
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Arika S Feils
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Noah W Tsarovsky
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Jen Zaborek
- Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Zachary S Morris
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Amy K Erbe
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Alexander L Rakhmilevich
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Paul M Sondel
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
- 4159 MACC Fund UW Childhood Cancer Research Wing, Wisconsin Institute for Medical Research, University of Wisconsin, 1111 Highland Avenue, Madison, WI, 53705-2275, USA.
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Daneshdoust D, Yin M, Luo M, Sundi D, Dang Y, Lee C, Li J, Liu X. Conditional Reprogramming Modeling of Bladder Cancer for Clinical Translation. Cells 2023; 12:1714. [PMID: 37443748 PMCID: PMC10341071 DOI: 10.3390/cells12131714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
The use of advanced preclinical models has become increasingly important in drug development. This is particularly relevant in bladder cancer, where the global burden of disease is quite high based on prevalence and a relatively high rate of lethality. Predictive tools to select patients who will be responsive to invasive or morbid therapies (chemotherapy, radiotherapy, immunotherapy, and/or surgery) are largely absent. Patient-derived and clinically relevant models including patient-derived xenografts (PDX), organoids, and conditional reprogramming (CR) of cell cultures efficiently generate numerous models and are being used in both basic and translational cancer biology. These CR cells (CRCs) can be reprogrammed to maintain a highly proliferative state and reproduce the genomic and histological characteristics of the parental tissue. Therefore, CR technology may be a clinically relevant model to test and predict drug sensitivity, conduct gene profile analysis and xenograft research, and undertake personalized medicine. This review discusses studies that have utilized CR technology to conduct bladder cancer research.
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Affiliation(s)
- Danyal Daneshdoust
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Ming Yin
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Medicine, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Mingjue Luo
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Debasish Sundi
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Urology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Yongjun Dang
- Center for Novel Target and Therapeutic Intervention, Chongqing Medical University, Chongqing 400016, China
| | - Cheryl Lee
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Urology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Jenny Li
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Xuefeng Liu
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Departments of Pathology, Urology and Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
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Chen A, Neuwirth I, Herndler-Brandstetter D. Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice. Cancers (Basel) 2023; 15:2989. [PMID: 37296949 PMCID: PMC10251926 DOI: 10.3390/cancers15112989] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/10/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023] Open
Abstract
Cancer immunotherapy has brought significant clinical benefits to numerous patients with malignant disease. However, only a fraction of patients experiences complete and durable responses to currently available immunotherapies. This highlights the need for more effective immunotherapies, combination treatments and predictive biomarkers. The molecular properties of a tumor, intratumor heterogeneity and the tumor immune microenvironment decisively shape tumor evolution, metastasis and therapy resistance and are therefore key targets for precision cancer medicine. Humanized mice that support the engraftment of patient-derived tumors and recapitulate the human tumor immune microenvironment of patients represent a promising preclinical model to address fundamental questions in precision immuno-oncology and cancer immunotherapy. In this review, we provide an overview of next-generation humanized mouse models suitable for the establishment and study of patient-derived tumors. Furthermore, we discuss the opportunities and challenges of modeling the tumor immune microenvironment and testing a variety of immunotherapeutic approaches using human immune system mouse models.
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Affiliation(s)
| | | | - Dietmar Herndler-Brandstetter
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090 Vienna, Austria; (A.C.); (I.N.)
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35
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Jannoo R, Walker W, Kanamarlapudi V. Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide. Cancers (Basel) 2023; 15:2772. [PMID: 37345109 PMCID: PMC10216279 DOI: 10.3390/cancers15102772] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/04/2023] [Accepted: 05/14/2023] [Indexed: 06/23/2023] Open
Abstract
Highly metastatic breast cancers, such as triple-negative subtypes (TNBC), require the most effective treatments. Since interleukin-13 receptor (IL-13R)α2 is reportedly over-expressed in some cancers, we investigated here its expression and the feasibility of therapeutically targeting this receptor in breast cancer using a novel hybrid cytolytic peptide (Pep-1-Phor21) consisting of IL-13Rα2-binding (Pep-1) and cytolytic (Phor21) domains. This study demonstrates that particularly TNBC tissues and cells display the prominent expression of IL-13Rα2. Furthermore, Pep-1-Phor21 induced the rapid necrosis of tumor cells expressing cell-surface IL-13Rα2. Notably, IL-13Rα2 expression was found to be epigenetically regulated in breast cancer cells in that the inhibition of histone deacetylase (HDAC) or DNA methyltransferase (DNMT) upregulated IL-13Rα2 expression, thereby sensitizing them to Pep-1-Phor21. IL-13Rα2-negative non-malignant cells were refractory to these epigenetic effects. Consistent with its cytolytic activity, Pep-1-Phor21 readily destroyed IL-13Rα2-expressing breast cancer spheroids with HDAC or DNMT inhibition, further enhancing cytolytic activity. Therefore, the Pep-1-Phor21-mediated targeting of IL-13Rα2 is a potentially novel therapeutic strategy for TNBC. Given that tumor cells can be selectively sensitized to Pep-1-Phor21 via the epigenetic up-regulation of IL-13Rα2, a combined adjuvant approach involving Pep-1-Phor21 and epigenetic inhibitors may be an effective strategy.
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Affiliation(s)
- Riaz Jannoo
- UCL ECMC GCLP Facility, UCL Cancer Institute, University College London, London WC1E 6DD, UK;
| | - William Walker
- Institute of Life Science, School of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK;
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36
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Liu Y, Wu W, Cai C, Zhang H, Shen H, Han Y. Patient-derived xenograft models in cancer therapy: technologies and applications. Signal Transduct Target Ther 2023; 8:160. [PMID: 37045827 PMCID: PMC10097874 DOI: 10.1038/s41392-023-01419-2] [Citation(s) in RCA: 134] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority in recapitulating the characteristics of cancer, such as the spatial structure of cancer and the intratumor heterogeneity of cancer. Moreover, PDX models retain the genomic features of patients across different stages, subtypes, and diversified treatment backgrounds. Optimized PDX engraftment procedures and modern technologies such as multi-omics and deep learning have enabled a more comprehensive depiction of the PDX molecular landscape and boosted the utilization of PDX models. These irreplaceable advantages make PDX models an ideal choice in cancer treatment studies, such as preclinical trials of novel drugs, validating novel drug combinations, screening drug-sensitive patients, and exploring drug resistance mechanisms. In this review, we gave an overview of the history of PDX models and the process of PDX model establishment. Subsequently, the review presents the strengths and weaknesses of PDX models and highlights the integration of novel technologies in PDX model research. Finally, we delineated the broad application of PDX models in chemotherapy, targeted therapy, immunotherapy, and other novel therapies.
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Affiliation(s)
- Yihan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Wantao Wu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Changjing Cai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China.
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China.
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37
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Nair L, Mukherjee S, Kaur K, Murphy CM, Ravichandiran V, Roy S, Singh M. Multi compartmental 3D breast cancer disease model–recapitulating tumor complexity in in-vitro. Biochim Biophys Acta Gen Subj 2023; 1867:130361. [PMID: 37019341 DOI: 10.1016/j.bbagen.2023.130361] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/26/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023]
Abstract
Breast cancer is the most common ailment among women. In 2020, it had the highest incidence of any type of cancer. Many Phase II and III anti-cancer drugs fail due to efficacy, durability, and side effects. Thus, accelerated drug screening models must be accurate. In-vivo models have been used for a long time, but delays, inconsistent results, and a greater sense of responsibility among scientists toward wildlife have led to the search for in-vitro alternatives. Stromal components support breast cancer growth and survival. Multi-compartment Transwell models may be handy instruments. Co-culturing breast cancer cells with endothelium and fibroblasts improves modelling. The extracellular matrix (ECM) supports native 3D hydrogels in natural and polymeric forms. 3D Transwell cultured tumor spheroids mimicked in-vivo pathological conditions. Tumor invasion, migration, Trans-endothelial migration, angiogenesis, and spread are studied using comprehensive models. Transwell models can create a cancer niche and conduct high-throughput drug screening, promising future applications. Our comprehensive shows how 3D in-vitro multi compartmental models may be useful in producing breast cancer stroma in Transwell culture.
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Affiliation(s)
- Lakshmi Nair
- Department of Pharmaceutical Sciences, Assam Central University, Silchar, Assam 788011, India
| | - Souvik Mukherjee
- Department of Pharmaceutical Sciences, Guru Ghasidas University, Koni, Bilaspur,(C.G 495009, India
| | - Kulwinder Kaur
- Tissue Engineering Research Group, Department of Anatomy & Regenerative Medicine, Royal College of Surgeons (RCSI), Dublin D02YN77, Ireland
| | - Ciara M Murphy
- Tissue Engineering Research Group, Department of Anatomy & Regenerative Medicine, Royal College of Surgeons (RCSI), Dublin D02YN77, Ireland; Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), Dublin D02YN77, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin, Ireland
| | - Velayutham Ravichandiran
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal 700054, India
| | - Subhadeep Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal 700054, India.
| | - Manjari Singh
- Department of Pharmaceutical Sciences, Assam Central University, Silchar, Assam 788011, India.
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Tosca EM, Ronchi D, Facciolo D, Magni P. Replacement, Reduction, and Refinement of Animal Experiments in Anticancer Drug Development: The Contribution of 3D In Vitro Cancer Models in the Drug Efficacy Assessment. Biomedicines 2023; 11:biomedicines11041058. [PMID: 37189676 DOI: 10.3390/biomedicines11041058] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/26/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
In the last decades three-dimensional (3D) in vitro cancer models have been proposed as a bridge between bidimensional (2D) cell cultures and in vivo animal models, the gold standards in the preclinical assessment of anticancer drug efficacy. 3D in vitro cancer models can be generated through a multitude of techniques, from both immortalized cancer cell lines and primary patient-derived tumor tissue. Among them, spheroids and organoids represent the most versatile and promising models, as they faithfully recapitulate the complexity and heterogeneity of human cancers. Although their recent applications include drug screening programs and personalized medicine, 3D in vitro cancer models have not yet been established as preclinical tools for studying anticancer drug efficacy and supporting preclinical-to-clinical translation, which remains mainly based on animal experimentation. In this review, we describe the state-of-the-art of 3D in vitro cancer models for the efficacy evaluation of anticancer agents, focusing on their potential contribution to replace, reduce and refine animal experimentations, highlighting their strength and weakness, and discussing possible perspectives to overcome current challenges.
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Sinenko IL, Turnell-Ritson RC, Munier FL, Dyson PJ. The predictive capacity of in vitro preclinical models to evaluate drugs for the treatment of retinoblastoma. Exp Eye Res 2023; 230:109447. [PMID: 36940901 DOI: 10.1016/j.exer.2023.109447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 02/22/2023] [Accepted: 03/16/2023] [Indexed: 03/23/2023]
Abstract
Retinoblastoma is a rare childhood cancer of the eye. Of the small number of drugs are used to treat retinoblastoma, all have been repurposed from drugs developed for other conditions. In order to find drugs or drug combinations better suited to the improved treatment of retinoblastoma, reliable predictive models are required, which facilitate the challenging transition from in vitro studies to clinical trials. In this review, the research performed to date on the development of 2D and 3D in vitro models for retinoblastoma is presented. Most of this research was undertaken with a view to better biological understanding of retinoblastoma, and we discuss the potential for these models to be applied to drug screening. Future research directions for streamlined drug discovery are considered and evaluated, and many promising avenues identified.
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Affiliation(s)
- Irina L Sinenko
- Institute of Chemical Sciences and Engineering, École Polytechnique Fedérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland; Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, CH-1004, Lausanne, Switzerland
| | - Roland C Turnell-Ritson
- Institute of Chemical Sciences and Engineering, École Polytechnique Fedérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland
| | - Francis L Munier
- Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, CH-1004, Lausanne, Switzerland.
| | - Paul J Dyson
- Institute of Chemical Sciences and Engineering, École Polytechnique Fedérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland
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40
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Zhang J, Hong Z, Lu W, Fang T, Ren Y, Yin S, Xuan Q, Li D, Xi JJ, Yao B. Assessment of Drug Susceptibility for Patient-Derived Tumor Models through Lactate Biosensing and Machine Learning. ACS Sens 2023; 8:803-810. [PMID: 36787531 DOI: 10.1021/acssensors.2c02381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
A patient-derived tumor model (PDM) is a practical tool to rapidly screen chemotherapeutics for individual patients. The evaluation method of cell viability directly determines the application of PDMs for drug susceptibility testing. As one of the metabolites of "glycosis", the lactate content was used to evaluate cell viability, but these assays were not specific for tumor cells. Based on the "Warburg effect", wherein tumor cells preferentially rely on "aerobic glycolysis" to produce lactate instead of pyruvate in "anaerobic glycolysis" of normal cells, we reported a gold lactate sensor (GLS) to estimate the cell viability of PDMs in drug susceptibility testing. It demonstrated high consistency between the GLS and commercial cell viability assay. Unlike either imaging or cell viability assay, the GLS characterizes the cell viability, enables dynamic monitoring, and distinguishes tumor cells from other cells. Moreover, machine learning (ML) was employed to perform a multi-index assessment for drug susceptibility of PDMs, which proved to be accurate and practical for clinical application. Therefore, the GLS provides an ideal drug susceptibility testing tool for individualized medicine.
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Affiliation(s)
- Jingfeng Zhang
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Zichen Hong
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Wei Lu
- GeneX (Zhejiang) Precision Medicine Co., Ltd., Hangzhou 311100, China
| | - Tianyuan Fang
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Yongan Ren
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Shenyi Yin
- College of Future Technology, Peking University, Beijing 100871, China
| | - Qijia Xuan
- Department of Oncology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China
| | - Dezhi Li
- Department of Oncology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China
| | - Jianzhong Jeff Xi
- College of Future Technology, Peking University, Beijing 100871, China
| | - Bo Yao
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
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41
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Lowenthal R, Taylor M, Gidden JA, Heflin B, Lay JO, Avaritt N, Tackett AJ, Urbaniak A. The mycelium of the Trametes versicolor synn. Coriolus versicolor (Turkey tail mushroom) exhibit anti-melanoma activity in vitro. Biomed Pharmacother 2023; 161:114424. [PMID: 36827712 PMCID: PMC10147383 DOI: 10.1016/j.biopha.2023.114424] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/16/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Melanoma is one of the most aggressive forms of skin cancer and is characterized by high metastatic potential. Despite improvements in early diagnosis and treatment, the mortality rate among metastatic melanoma patients continues to represent a significant clinical challenge. Therefore, it is imperative that we search for new forms of treatment. Trametes versicolor is a mushroom commonly used in Chinese traditional medicine due to its numerous beneficial properties. In the present work, we demonstrate T. versicolor fruiting body and mycelium ethanol extracts exhibit potent cytotoxic activity towards A375 (IC50 = 663.3 and 114.5 µg/mL respectively) and SK-MEL-5 (IC50 = 358.4 and 88.6 µg/mL respectively) human melanoma cell lines. Further studies revealed that T. versicolor mycelium extract induced apoptotic cell death and poly (ADP-ribose) polymerase cleavage, upregulated the expression of autophagy-associated marker LC3-II, increased the presentation of major histocompatibility complex II and expression of programmed death-ligand receptor, and inhibited cell migration in SK-MEL-5 cells. Therefore, our present findings highlight the therapeutic potential of T. versicolor mycelium extract for the treatment of melanoma and merit further study.
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Affiliation(s)
- Rocky Lowenthal
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Megan Taylor
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Jennifer A Gidden
- Arkansas Statewide MS Facility, University of Arkansas, Fayetteville 72701, AR, United States
| | - Billie Heflin
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Jackson O Lay
- Arkansas Statewide MS Facility, University of Arkansas, Fayetteville 72701, AR, United States; Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville 72701, AR, United States
| | - Nathan Avaritt
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Alan J Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
| | - Alicja Urbaniak
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
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Preclinical models in head and neck squamous cell carcinoma. Br J Cancer 2023; 128:1819-1827. [PMID: 36765175 PMCID: PMC10147614 DOI: 10.1038/s41416-023-02186-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/19/2023] [Accepted: 01/25/2023] [Indexed: 02/12/2023] Open
Abstract
Head and neck cancer is the sixth most frequent cancer type. Drug resistance and toxicity are common challenges of the existing therapies, making the development of reliable preclinical models essential for the study of the involved molecular mechanisms as well as for eventual intervention approaches that improve the clinical outcome. Preclinical models of head and neck squamous cell carcinoma have been traditionally based on cell lines and murine models. In this review, we will go over the most frequently used preclinical models, from immortalised-cell and primary tumour cultures in monolayer or 3D, to the currently available animal models. We will scrutinise their efficiency in mimicking the molecular and cellular complexity of head and neck squamous cell carcinoma. Finally, the challenges and the opportunities of other envisaged putative approaches, as well as the potential of the preclinical models to further develop personalised therapies will be discussed.
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Harada Y, Sato A, Nakamura H, Kai K, Kitamura S, Nakamura T, Kurihara Y, Ikeda S, Sueoka E, Kimura S, Sueoka-Aragane N. Anti-cancer effect of afatinib, dual inhibitor of HER2 and EGFR, on novel mutation HER2 E401G in models of patient-derived cancer. BMC Cancer 2023; 23:77. [PMID: 36690964 PMCID: PMC9872313 DOI: 10.1186/s12885-022-10428-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 12/08/2022] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. METHODS We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient's cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug's efficacies against HER2 E401G. RESULTS We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. CONCLUSIONS Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.
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Affiliation(s)
- Yohei Harada
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
- Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Akemi Sato
- Department of Clinical Laboratory Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Hideaki Nakamura
- Department of Transfusion Medicine, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Keita Kai
- Department of Pathology, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Sho Kitamura
- Department of Pathology, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Tomomi Nakamura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Yuki Kurihara
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Sadakatsu Ikeda
- Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Eisaburo Sueoka
- Department of Clinical Laboratory Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Shinya Kimura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Naoko Sueoka-Aragane
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
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Aaltonen K, Radke K, Adamska A, Seger A, Mañas A, Bexell D. Patient-derived models: Advanced tools for precision medicine in neuroblastoma. Front Oncol 2023; 12:1085270. [PMID: 36776363 PMCID: PMC9910084 DOI: 10.3389/fonc.2022.1085270] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/21/2022] [Indexed: 01/27/2023] Open
Abstract
Neuroblastoma is a childhood cancer derived from the sympathetic nervous system. High-risk neuroblastoma patients have a poor overall survival and account for ~15% of childhood cancer deaths. There is thus a need for clinically relevant and authentic models of neuroblastoma that closely resemble the human disease to further interrogate underlying mechanisms and to develop novel therapeutic strategies. Here we review recent developments in patient-derived neuroblastoma xenograft models and in vitro cultures. These models can be used to decipher mechanisms of metastasis and treatment resistance, for drug screening, and preclinical drug testing. Patient-derived neuroblastoma models may also provide useful information about clonal evolution, phenotypic plasticity, and cell states in relation to neuroblastoma progression. We summarize current opportunities for, but also barriers to, future model development and application. Integration of patient-derived models with patient data holds promise for the development of precision medicine treatment strategies for children with high-risk neuroblastoma.
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Liu W, Cui Y, Zheng X, Yu K, Sun G. Application status and future prospects of the PDX model in lung cancer. Front Oncol 2023; 13:1098581. [PMID: 37035154 PMCID: PMC10080030 DOI: 10.3389/fonc.2023.1098581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/13/2023] [Indexed: 04/11/2023] Open
Abstract
Lung cancer is one of the most prevalent, fatal, and highly heterogeneous diseases that, seriously threaten human health. Lung cancer is primarily caused by the aberrant expression of multiple genes in the cells. Lung cancer treatment options include surgery, radiation, chemotherapy, targeted therapy, and immunotherapy. In recent decades, significant progress has been made in developing therapeutic agents for lung cancer as well as a biomarker for its early diagnosis. Nonetheless, the alternative applications of traditional pre-clinical models (cell line models) for diagnosis and prognosis prediction are constrained by several factors, including the lack of microenvironment components necessary to affect cancer biology and drug response, and the differences between laboratory and clinical results. The leading reason is that substantial shifts accrued to cell biological behaviors, such as cell proliferative, metastatic, invasive, and gene expression capabilities of different cancer cells after decades of growing indefinitely in vitro. Moreover, the introduction of individualized treatment has prompted the development of appropriate experimental models. In recent years, preclinical research on lung cancer has primarily relied on the patient-derived tumor xenograft (PDX) model. The PDX provides stable models with recapitulate characteristics of the parental tumor such as the histopathology and genetic blueprint. Additionally, PDXs offer valuable models for efficacy screening of new cancer drugs, thus, advancing the understanding of tumor biology. Concurrently, with the heightened interest in the PDX models, potential shortcomings have gradually emerged. This review summarizes the significant advantages of PDXs over the previous models, their benefits, potential future uses and interrogating open issues.
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Bharti V, Watkins R, Kumar A, Shattuck-Brandt RL, Mossing A, Mittra A, Shen C, Tsung A, Davies AE, Hanel W, Reneau JC, Chung C, Sizemore GM, Richmond A, Weiss VL, Vilgelm AE. BCL-xL inhibition potentiates cancer therapies by redirecting the outcome of p53 activation from senescence to apoptosis. Cell Rep 2022; 41:111826. [PMID: 36543138 PMCID: PMC10030045 DOI: 10.1016/j.celrep.2022.111826] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 10/26/2022] [Accepted: 11/21/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer therapies trigger diverse cellular responses, ranging from apoptotic death to acquisition of persistent therapy-refractory states such as senescence. Tipping the balance toward apoptosis could improve treatment outcomes regardless of therapeutic agent or malignancy. We find that inhibition of the mitochondrial protein BCL-xL increases the propensity of cancer cells to die after treatment with a broad array of oncology drugs, including mitotic inhibitors and chemotherapy. Functional precision oncology and omics analyses suggest that BCL-xL inhibition redirects the outcome of p53 transcriptional response from senescence to apoptosis, which likely occurs via caspase-dependent down-modulation of p21 and downstream cytostatic proteins. Consequently, addition of a BCL-2/xL inhibitor strongly improves melanoma response to the senescence-inducing drug targeting mitotic kinase Aurora kinase A (AURKA) in mice and patient-derived organoids. This study shows a crosstalk between the mitochondrial apoptotic pathway and cell cycle regulation that can be targeted to augment therapeutic efficacy in cancers with wild-type p53.
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Affiliation(s)
- Vijaya Bharti
- Department of Pathology, The Ohio State University, 460 W. 12th Avenue, Office 496, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Reese Watkins
- Department of Pathology, The Ohio State University, 460 W. 12th Avenue, Office 496, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Amrendra Kumar
- Department of Pathology, The Ohio State University, 460 W. 12th Avenue, Office 496, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Rebecca L Shattuck-Brandt
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Alexis Mossing
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA
| | - Arjun Mittra
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Division of Medical Oncology, The Ohio State University, Columbus, OH, USA
| | - Chengli Shen
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Allan Tsung
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Alexander E Davies
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Walter Hanel
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - John C Reneau
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Catherine Chung
- Department of Pathology, The Ohio State University, 460 W. 12th Avenue, Office 496, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Gina M Sizemore
- The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA
| | - Ann Richmond
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Vivian L Weiss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Anna E Vilgelm
- Department of Pathology, The Ohio State University, 460 W. 12th Avenue, Office 496, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
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Huang M, Hou W, Zhang J, Li M, Zhang Z, Li X, Chen Z, Wang C, Yang L. Evaluation of AMG510 Therapy on KRAS-Mutant Non-Small Cell Lung Cancer and Colorectal Cancer Cell Using a 3D Invasive Tumor Spheroid System under Normoxia and Hypoxia. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 9:bioengineering9120792. [PMID: 36550998 PMCID: PMC9774149 DOI: 10.3390/bioengineering9120792] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022]
Abstract
A 3D tumor spheroid has been increasingly applied in pharmaceutical development for its simulation of the tumor structure and microenvironment. The embedded-culture of a tumor spheroid within a hydrogel microenvironment could help to improve the mimicking of in vivo cell growth and the development of 3D models for tumor invasiveness evaluation, which could enhance its drug efficiency prediction together with cell viability detection. NCI-H23 spheroids and CT-26 spheroids, from a non-small cell lung cancer and colorectal cancer cell line, respectively, together with extracellular matrix were generated for evaluating their sensitivity to AMG510 (a KRASG12C inhibitor) under normoxia and hypoxia conditions, which were created by an on-stage environmental chamber. Results demonstrated that NCI-H23, the KRASG12C moderate expression cell line, only mildly responded to AMG510 treatment in normal 2D and 3D cultures and could be clearly evaluated by our system in hypoxia conditions, while the negative control CT-26 (G12D-mutant) spheroid exhibited no significant response to AMG510 treatment. In summary, our system, together with a controlled microenvironment and imaging methodology, provided an easily assessable and effective methodology for 3D in vitro drug efficiency testing and screenings.
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Affiliation(s)
- Meng Huang
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Wei Hou
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- Department of Oncology, School of Medicine, Southeast University, Nanjing 210009, China
| | - Jing Zhang
- Institute of Medical Devices (Suzhou), Southeast University, Suzhou 215163, China
- Jiangsu Avatarget Biotechnology Co., Ltd., Suzhou 215163, China
| | - Menglan Li
- Jiangsu Avatarget Biotechnology Co., Ltd., Suzhou 215163, China
| | - Zilin Zhang
- Jiangsu Avatarget Biotechnology Co., Ltd., Suzhou 215163, China
| | - Xiaoran Li
- Jiangsu Avatarget Biotechnology Co., Ltd., Suzhou 215163, China
| | - Zaozao Chen
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- Institute of Medical Devices (Suzhou), Southeast University, Suzhou 215163, China
- Jiangsu Avatarget Biotechnology Co., Ltd., Suzhou 215163, China
- Correspondence: (Z.C.); (C.W.); (L.Y.)
| | - Cailian Wang
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- Department of Oncology, School of Medicine, Southeast University, Nanjing 210009, China
- Correspondence: (Z.C.); (C.W.); (L.Y.)
| | - Lihua Yang
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210009, China
- Correspondence: (Z.C.); (C.W.); (L.Y.)
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Yun KH, Park C, Ryu HJ, Ock CY, Lee YH, Baek W, Yoon HI, Han YD, Kim SK, Lee J, Kim SJ, Yang KM, Kim SH, Kim HS. Therapeutic Implications of TGF-β Pathway in Desmoid Tumor Based on Comprehensive Molecular Profiling and Clinicopathological Properties. Cancers (Basel) 2022; 14:cancers14235975. [PMID: 36497457 PMCID: PMC9737545 DOI: 10.3390/cancers14235975] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/21/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-β signaling pathway. Moreover, we selected the combination treatment comprising TGF-β inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-β inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.
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Affiliation(s)
- Kum-Hee Yun
- Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Changhee Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul 03722, Republic of Korea
| | - Hyang Joo Ryu
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Chan-Young Ock
- Bang & Ock Consulting Inc., Seoul 03722, Republic of Korea
| | - Young Han Lee
- Department of Radiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Wooyeol Baek
- Department of Plastic Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Hong In Yoon
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Yoon Dae Han
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Sang Kyum Kim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - JooHee Lee
- Department of Radiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | | | | | - Seung Hyun Kim
- Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Correspondence: (S.H.K.); (H.S.K.); Tel.: +82-2-2228-2135 (S.H.K.); +82-2-2228-8124 (H.S.K.)
| | - Hyo Song Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Correspondence: (S.H.K.); (H.S.K.); Tel.: +82-2-2228-2135 (S.H.K.); +82-2-2228-8124 (H.S.K.)
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Passeri T, Dahmani A, Masliah-Planchon J, El Botty R, Courtois L, Vacher S, Marangoni E, Nemati F, Roman-Roman S, Adle-Biassette H, Mammar H, Froelich S, Bièche I, Decaudin D. In vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in human chordoma xenografts. Front Oncol 2022; 12:960720. [PMID: 36505864 PMCID: PMC9732546 DOI: 10.3389/fonc.2022.960720] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 10/18/2022] [Indexed: 11/26/2022] Open
Abstract
Background Management of advanced chordomas remains delicate considering their insensitivity to chemotherapy. Homozygous deletion of the regulatory gene CDKN2A has been described as the most frequent genetic alteration in chordomas and may be considered as a potential theranostic marker. Here, we evaluated the tumor efficacy of the CDK4/6 inhibitor palbociclib, as well as the PLK1 inhibitor volasertib, in three chordoma patient-derived xenograft (PDX) models to validate and identify novel therapeutic approaches. Methods From our chordoma xenograft panel, we selected three models, two of them harboring a homozygous deletion of CDKN2A/2B genes, and the last one a PBRM1 pathogenic variant (as control). For each model, we tested the palbociclib and volasertib drugs with pharmacodynamic studies together with RT-PCR and RNAseq analyses. Results For palbociclib, we observed a significant tumor response for one of two models harboring the deletion of CDKN2A/2B (p = 0.02), and no significant tumor response in the PBRM1-mutated PDX; for volasertib, we did not observe any response in the three tested models. RT-PCR and RNAseq analyses showed a correlation between cell cycle markers and responses to palbociclib; finally, RNAseq analyses showed a natural enrichment of the oxidative phosphorylation genes (OxPhos) in the palbociclib-resistant PDX (p = 0.02). Conclusion CDK4/6 inhibition appears as a promising strategy to manage advanced chordomas harboring a loss of CDKN2A/2B. However, further preclinical studies are strongly requested to confirm it and to understand acquired or de novo resistance to palbociclib, in the peculiar view of a targeting of the oxidative phosphorylation genes.
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Affiliation(s)
- Thibault Passeri
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, University of Paris Saclay, Paris, France
- Department of Genetics, Institut Curie, University of Paris Saclay, Paris, France
- Department of Neurosurgery, Lariboisière Hospital, Assistance Publique des Hôpitaux de Paris, University of Paris, Paris, France
| | - Ahmed Dahmani
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, University of Paris Saclay, Paris, France
| | | | - Rania El Botty
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, University of Paris Saclay, Paris, France
| | - Laura Courtois
- Department of Genetics, Institut Curie, University of Paris Saclay, Paris, France
| | - Sophie Vacher
- Department of Genetics, Institut Curie, University of Paris Saclay, Paris, France
| | - Elisabetta Marangoni
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, University of Paris Saclay, Paris, France
| | - Fariba Nemati
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, University of Paris Saclay, Paris, France
| | - Sergio Roman-Roman
- Department of Translational Research, Institut Curie, University of Paris Saclay, Paris, France
| | - Homa Adle-Biassette
- Department of Pathology, Lariboisière Hospital, Assistance Publique des Hôpitaux de Paris, University of Paris, Paris, France
| | - Hamid Mammar
- Department of Radiotherapy - Proton Therapy Center, Institut Curie, Paris-Saclay University, Orsay, France
| | - Sébastien Froelich
- Department of Neurosurgery, Lariboisière Hospital, Assistance Publique des Hôpitaux de Paris, University of Paris, Paris, France
| | - Ivan Bièche
- Department of Genetics, Institut Curie, University of Paris Saclay, Paris, France
| | - Didier Decaudin
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, University of Paris Saclay, Paris, France
- Department of Medical Oncology, Institut Curie, Paris, France
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Devis‐Jauregui L, Vidal A, Plata‐Peña L, Santacana M, García‐Mulero S, Bonifaci N, Noguera‐Delgado E, Ruiz N, Gil M, Dorca E, Llobet FJ, Coll‐Iglesias L, Gassner K, Martinez‐Iniesta M, Rodriguez‐Barrueco R, Barahona M, Marti L, Viñals F, Ponce J, Sanz‐Pamplona R, Piulats JM, Vivancos A, Matias‐Guiu X, Villanueva A, Llobet‐Navas D. Generation and Integrated Analysis of Advanced Patient-Derived Orthoxenograft Models (PDOX) for the Rational Assessment of Targeted Therapies in Endometrial Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 10:e2204211. [PMID: 36373729 PMCID: PMC9811454 DOI: 10.1002/advs.202204211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/18/2022] [Indexed: 05/19/2023]
Abstract
Clinical management of endometrial cancer (EC) is handicapped by the limited availability of second line treatments and bona fide molecular biomarkers to predict recurrence. These limitations have hampered the treatment of these patients, whose survival rates have not improved over the last four decades. The advent of coordinated studies such as The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA_UCEC) has partially solved this issue, but the lack of proper experimental systems still represents a bottleneck that precludes translational studies from successful clinical testing in EC patients. Within this context, the first study reporting the generation of a collection of endometrioid-EC-patient-derived orthoxenograft (PDOX) mouse models is presented that is believed to overcome these experimental constraints and pave the way toward state-of-the-art precision medicine in EC. The collection of primary tumors and derived PDOXs is characterized through an integrative approach based on transcriptomics, mutational profiles, and morphological analysis; and it is demonstrated that EC tumors engrafted in the mouse uterus retain the main molecular and morphological features from analogous tumor donors. Finally, the molecular properties of these tumors are harnessed to assess the therapeutic potential of trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor with growing interest in EC, using patient-derived organotypic multicellular tumor spheroids and in vivo experiments.
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