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      Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer

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          Abstract

          Development of novel multimodality radiotherapy treatments in metastatic breast cancer, especially in the most aggressive triple negative (TNBC) subtype, is of significant clinical interest. Here we show that a novel inhibitor of Polo-Like Kinase 4 (PLK4), CFI-400945, in combination with radiation, exhibits a synergistic anti-cancer effect in TNBC cell lines and patient-derived organoids in vitro and leads to a significant increase in survival to tumor endpoint in xenograft models in vivo, compared to control or single-agent treatment. Further preclinical and proof-of-concept clinical studies are warranted to characterize molecular mechanisms of action of this combination and its potential applications in clinical practice.

          Highlights

          • •

            PLK4 inhibitor CFI-400945, combined with radiation, shows synergistic antiproliferative activity in immortalized breast cancer cell lines.

          • •

            CFI-400945 in combination with radiation shows synergistic antiproliferative activity in breast cancer patient-derived organoids.

          • •

            In MDA-MB-231 xenograft mice, CFI-400945 sensitizes to radiation and significantly improves survival to the tumour endpoint.

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          A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity

          Norman Sachs, Joep de Ligt, Oded Kopper … (2018)
          Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene-expression-based classification groups and allowed in vitro drug screens that were consistent with in vivo xeno-transplantations and patient response. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion.
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            Clonogenic assay of cells in vitro.

            Nicolaas Franken, Hans Rodermond, Jan Stap … (2006)
            Clonogenic assay or colony formation assay is an in vitro cell survival assay based on the ability of a single cell to grow into a colony. The colony is defined to consist of at least 50 cells. The assay essentially tests every cell in the population for its ability to undergo "unlimited" division. Clonogenic assay is the method of choice to determine cell reproductive death after treatment with ionizing radiation, but can also be used to determine the effectiveness of other cytotoxic agents. Only a fraction of seeded cells retains the capacity to produce colonies. Before or after treatment, cells are seeded out in appropriate dilutions to form colonies in 1-3 weeks. Colonies are fixed with glutaraldehyde (6.0% v/v), stained with crystal violet (0.5% w/v) and counted using a stereomicroscope. A method for the analysis of radiation dose-survival curves is included.
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              Patient-Derived Organoids Predict Chemoradiation Responses of Locally Advanced Rectal Cancer

              Ye Yao, Xiaoya Xu, Lifeng Yang … (2019)
              Accumulating evidence indicates that patient-derived organoids (PDOs) can predict drug responses in the clinic, but the ability of PDOs to predict responses to chemoradiation in cancer patients remains an open question. Here we generate a living organoid biobank from patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NACR) enrolled in a phase III clinical trial. Our co-clinical trial data confirm that rectal cancer organoids (RCOs) closely recapitulate the pathophysiology and genetic changes of corresponding tumors. Chemoradiation responses in patients are highly matched to RCO responses, with 84.43% accuracy, 78.01% sensitivity, and 91.97% specificity. These data imply that PDOs predict LARC patient responses in the clinic and may represent a companion diagnostic tool in rectal cancer treatment.
              Article 0 comments Cited 283 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Armen Parsyan
                Journal
                Journal ID (nlm-ta): Breast
                Journal ID (iso-abbrev): Breast
                Title: The Breast : Official Journal of the European Society of Mastology
                Publisher: Elsevier
                ISSN (Print): 0960-9776
                ISSN (Electronic): 1532-3080
                Publication date PMC-release: 01 April 2021
                Publication date Collection: August 2021
                Publication date (Electronic): 01 April 2021
                Volume: 58
                Pages: 6-9
                Affiliations
                [a ]Department of Surgery, St Joseph’s Health Care and London Health Sciences Centre, Western University, London, Ontario, N6A 4V2, Canada
                [b ]Department of Oncology, Western University, London, Ontario, N6A 5W9, Canada
                [c ]London Regional Cancer Program, London Health Sciences Centre, Western University, London, Ontario, N6A 5W9, Canada
                [d ]Department of Anatomy and Cell Biology, London Regional Cancer Program, Western University, London, Ontario, N6A 5C1, Canada
                [e ]Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
                [f ]Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
                Author notes
                [∗ ]Corresponding author. 268 Grosvenor St, D1-204, London, Ontario, N6A 4V2, Canada. aparsyan@ 123456uwo.ca
                Article
                Publisher Item ID: S0960-9776(21)00350-7
                DOI: 10.1016/j.breast.2021.03.011
                PMC ID: 8079282
                PubMed ID: 33866248
                SO-VID: f4fc3671-8009-478e-ba4e-ef213df4bcf9
                Copyright © © 2021 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 26 December 2020
                Date revision received : 7 March 2021
                Date accepted : 29 March 2021
                Categories
                Subject: Short Communication

                ScienceOpen disciplines: Obstetrics & Gynecology
                Keywords: triple-negative breast cancer,radiotherapy,polo-like kinase 4,cfi-400945,radiosensitization,patient-derived organoids
                Data availability:
                ScienceOpen disciplines: Obstetrics & Gynecology
                Keywords: triple-negative breast cancer, radiotherapy, polo-like kinase 4, cfi-400945, radiosensitization, patient-derived organoids

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