Radium-223 mechanism of action: implications for use in treatment combinations View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-11-11

AUTHORS

Michael J. Morris, Eva Corey, Theresa A. Guise, James L. Gulley, William Kevin Kelly, David I. Quinn, Arne Scholz, George Sgouros

ABSTRACT

The targeted alpha therapy radium-223 (223Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases. Preclinical studies demonstrate that 223Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. 223Ra might also modulate immune responses within the bone. The clinical utility of 223Ra has encouraged the development of other anticancer targeted alpha therapies. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of 223Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease. More... »

PAGES

745-756

References to SciGraph publications

  • 2014-11-26. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients in NATURE
  • 2017-03-02. 213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer in EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
  • 2015-05-05. Targeting bone metastases in prostate cancer: improving clinical outcome in NATURE REVIEWS UROLOGY
  • 2017-08-11. Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials in JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
  • 2015-11-25. STING: infection, inflammation and cancer in NATURE REVIEWS IMMUNOLOGY
  • 1977-04. High-LET radiations induce a large proportion of non-rejoining DNA breaks in NATURE
  • 2007-02. The concurrent chemoradiation paradigm—general principles in NATURE REVIEWS CLINICAL ONCOLOGY
  • 2015-08-13. Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting 223Ra-dichloride in EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
  • 2009-07-11. Assessment of long-term radiotoxicity after treatment with the low-dose-rate alpha-particle-emitting radioimmunoconjugate 227Th-rituximab in EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
  • 2005-01. Osteoblasts in prostate cancer metastasis to bone in NATURE REVIEWS CANCER
  • 2013-02-12. Proposed mechanisms of action for prostate cancer vaccines in NATURE REVIEWS UROLOGY
  • 2019-01-12. Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice in EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
  • 2003-08. The mechanism of action of docetaxel (Taxotere®) in xenograft models is not limited to bcl-2 phosphorylation in INVESTIGATIONAL NEW DRUGS
  • 2012-11-13. Healthcare utilization and costs associated with skeletal-related events in prostate cancer patients with bone metastases in PROSTATE CANCER AND PROSTATIC DISEASES
  • 2018-05-16. Translational models of prostate cancer bone metastasis in NATURE REVIEWS UROLOGY
  • 2007-03. Exploitable mechanisms for combining drugs with radiation: concepts, achievements and future directions in NATURE REVIEWS CLINICAL ONCOLOGY
  • 2017-03-17. Alteration of osteoblast arrangement via direct attack by cancer cells: New insights into bone metastasis in SCIENTIFIC REPORTS
  • 2014-04-13. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease in BREAST CANCER RESEARCH AND TREATMENT
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41585-019-0251-x

    DOI

    http://dx.doi.org/10.1038/s41585-019-0251-x

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1122478263

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31712765


    Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
    Incoming Citations Browse incoming citations for this publication using opencitations.net

    JSON-LD is the canonical representation for SciGraph data.

    TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

    [
      {
        "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
        "about": [
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Medical and Health Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1103", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Clinical Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1112", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Oncology and Carcinogenesis", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Animals", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Bone Neoplasms", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Combined Modality Therapy", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Disease Models, Animal", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Humans", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Male", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Prostatic Neoplasms, Castration-Resistant", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Radium", 
            "type": "DefinedTerm"
          }
        ], 
        "author": [
          {
            "affiliation": {
              "alternateName": "Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA", 
              "id": "http://www.grid.ac/institutes/grid.5386.8", 
              "name": [
                "Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Morris", 
            "givenName": "Michael J.", 
            "id": "sg:person.010060764532.40", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010060764532.40"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Department of Urology, University of Washington, School of Medicine, Seattle, WA, USA", 
              "id": "http://www.grid.ac/institutes/grid.34477.33", 
              "name": [
                "Department of Urology, University of Washington, School of Medicine, Seattle, WA, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Corey", 
            "givenName": "Eva", 
            "id": "sg:person.01173507156.42", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01173507156.42"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Indiana University, School of Medicine, Indianapolis, IN, USA", 
              "id": "http://www.grid.ac/institutes/grid.257413.6", 
              "name": [
                "Indiana University, School of Medicine, Indianapolis, IN, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Guise", 
            "givenName": "Theresa A.", 
            "id": "sg:person.011414615457.17", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.011414615457.17"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Genitourinary Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, USA", 
              "id": "http://www.grid.ac/institutes/grid.48336.3a", 
              "name": [
                "Genitourinary Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Gulley", 
            "givenName": "James L.", 
            "id": "sg:person.01346275763.14", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01346275763.14"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA", 
              "id": "http://www.grid.ac/institutes/grid.265008.9", 
              "name": [
                "Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Kevin Kelly", 
            "givenName": "William", 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Keck School of Medicine of University of Southern California, Los Angeles, CA, USA", 
              "id": "http://www.grid.ac/institutes/grid.42505.36", 
              "name": [
                "Norris Comprehensive Cancer Center, Los Angeles, CA, USA", 
                "Keck School of Medicine of University of Southern California, Los Angeles, CA, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Quinn", 
            "givenName": "David I.", 
            "id": "sg:person.01013134010.15", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01013134010.15"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Bayer AG, Drug Discovery, Pharmaceuticals, Berlin, Germany", 
              "id": "http://www.grid.ac/institutes/grid.420044.6", 
              "name": [
                "Bayer AG, Drug Discovery, Pharmaceuticals, Berlin, Germany"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Scholz", 
            "givenName": "Arne", 
            "id": "sg:person.0577220400.41", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0577220400.41"
            ], 
            "type": "Person"
          }, 
          {
            "affiliation": {
              "alternateName": "Johns Hopkins University, School of Medicine, Baltimore, MD, USA", 
              "id": "http://www.grid.ac/institutes/grid.21107.35", 
              "name": [
                "Johns Hopkins University, School of Medicine, Baltimore, MD, USA"
              ], 
              "type": "Organization"
            }, 
            "familyName": "Sgouros", 
            "givenName": "George", 
            "id": "sg:person.01357566757.11", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01357566757.11"
            ], 
            "type": "Person"
          }
        ], 
        "citation": [
          {
            "id": "sg:pub.10.1038/nrurol.2013.8", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1038959030", 
              "https://doi.org/10.1038/nrurol.2013.8"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1186/s13046-017-0578-1", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1091167128", 
              "https://doi.org/10.1186/s13046-017-0578-1"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nri3921", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1042641626", 
              "https://doi.org/10.1038/nri3921"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s10549-014-2939-1", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1032408554", 
              "https://doi.org/10.1007/s10549-014-2939-1"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ncponc0714", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1004880954", 
              "https://doi.org/10.1038/ncponc0714"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/s41585-018-0020-2", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1104009811", 
              "https://doi.org/10.1038/s41585-018-0020-2"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/266653a0", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1011020406", 
              "https://doi.org/10.1038/266653a0"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00259-019-4261-y", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1111389931", 
              "https://doi.org/10.1007/s00259-019-4261-y"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1023/a:1025436307913", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1007000237", 
              "https://doi.org/10.1023/a:1025436307913"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrurol.2015.90", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001338966", 
              "https://doi.org/10.1038/nrurol.2015.90"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00259-009-1197-7", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1017449500", 
              "https://doi.org/10.1007/s00259-009-1197-7"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/srep44824", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1084132699", 
              "https://doi.org/10.1038/srep44824"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00259-015-3150-2", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1044665818", 
              "https://doi.org/10.1007/s00259-015-3150-2"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nrc1528", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1020327087", 
              "https://doi.org/10.1038/nrc1528"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature14011", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1041312915", 
              "https://doi.org/10.1038/nature14011"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1007/s00259-017-3657-9", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1084020142", 
              "https://doi.org/10.1007/s00259-017-3657-9"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/ncponc0744", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1038688180", 
              "https://doi.org/10.1038/ncponc0744"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/pcan.2012.42", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1011582718", 
              "https://doi.org/10.1038/pcan.2012.42"
            ], 
            "type": "CreativeWork"
          }
        ], 
        "datePublished": "2019-11-11", 
        "datePublishedReg": "2019-11-11", 
        "description": "The targeted alpha therapy radium-223 (223Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases. Preclinical studies demonstrate that 223Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. 223Ra might also modulate immune responses within the bone. The clinical utility of 223Ra has encouraged the development of other anticancer targeted alpha therapies. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of 223Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease.", 
        "genre": "article", 
        "id": "sg:pub.10.1038/s41585-019-0251-x", 
        "isAccessibleForFree": true, 
        "isFundedItemOf": [
          {
            "id": "sg:grant.2438805", 
            "type": "MonetaryGrant"
          }
        ], 
        "isPartOf": [
          {
            "id": "sg:journal.1034152", 
            "issn": [
              "1759-4812", 
              "1759-4820"
            ], 
            "name": "Nature Reviews Urology", 
            "publisher": "Springer Nature", 
            "type": "Periodical"
          }, 
          {
            "issueNumber": "12", 
            "type": "PublicationIssue"
          }, 
          {
            "type": "PublicationVolume", 
            "volumeNumber": "16"
          }
        ], 
        "keywords": [
          "castration-resistant prostate cancer", 
          "new combinatorial treatment strategy", 
          "tumor cells", 
          "symptomatic bone metastases", 
          "metastatic bone disease", 
          "androgen receptor axis", 
          "immune checkpoint receptors", 
          "osteoblastic metastatic lesions", 
          "abnormal bone formation", 
          "potential clinical benefit", 
          "combinatorial treatment strategies", 
          "mechanism of action", 
          "visceral metastases", 
          "bone metastases", 
          "metastatic lesions", 
          "checkpoint receptors", 
          "radium-223", 
          "clinical benefit", 
          "combination therapy", 
          "receptor axis", 
          "prostate cancer", 
          "alpha therapy", 
          "treatment strategies", 
          "preclinical studies", 
          "immune response", 
          "current mechanistic knowledge", 
          "bone disease", 
          "clinical utility", 
          "bone microenvironment", 
          "cytotoxic drugs", 
          "tumor growth", 
          "bone formation", 
          "metastasis", 
          "bone matrix", 
          "therapy", 
          "cell death", 
          "positive feedback loop", 
          "direct effect", 
          "response proteins", 
          "monotherapy", 
          "cells", 
          "patients", 
          "lesions", 
          "cancer", 
          "DNA double-strand breaks", 
          "disease", 
          "osteoclasts", 
          "receptors", 
          "drugs", 
          "death", 
          "survival", 
          "men", 
          "treatment combinations", 
          "bone", 
          "thorough understanding", 
          "microenvironment", 
          "mechanistic knowledge", 
          "action", 
          "double-strand breaks", 
          "osteoblasts", 
          "anticancer", 
          "DNA damage response proteins", 
          "agents", 
          "mechanism", 
          "disruption", 
          "response", 
          "damage response proteins", 
          "protein", 
          "study", 
          "benefits", 
          "effect", 
          "utility", 
          "use", 
          "axis", 
          "combination", 
          "high-energy alpha particles", 
          "development", 
          "strategies", 
          "knowledge", 
          "implications", 
          "growth", 
          "understanding", 
          "basis", 
          "breaks", 
          "formation", 
          "loop", 
          "design", 
          "alpha particles", 
          "matrix", 
          "particles"
        ], 
        "name": "Radium-223 mechanism of action: implications for use in treatment combinations", 
        "pagination": "745-756", 
        "productId": [
          {
            "name": "dimensions_id", 
            "type": "PropertyValue", 
            "value": [
              "pub.1122478263"
            ]
          }, 
          {
            "name": "doi", 
            "type": "PropertyValue", 
            "value": [
              "10.1038/s41585-019-0251-x"
            ]
          }, 
          {
            "name": "pubmed_id", 
            "type": "PropertyValue", 
            "value": [
              "31712765"
            ]
          }
        ], 
        "sameAs": [
          "https://doi.org/10.1038/s41585-019-0251-x", 
          "https://app.dimensions.ai/details/publication/pub.1122478263"
        ], 
        "sdDataset": "articles", 
        "sdDatePublished": "2022-11-24T21:03", 
        "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
        "sdPublisher": {
          "name": "Springer Nature - SN SciGraph project", 
          "type": "Organization"
        }, 
        "sdSource": "s3://com-springernature-scigraph/baseset/20221124/entities/gbq_results/article/article_791.jsonl", 
        "type": "ScholarlyArticle", 
        "url": "https://doi.org/10.1038/s41585-019-0251-x"
      }
    ]
     

    Download the RDF metadata as:  json-ld nt turtle xml License info

    HOW TO GET THIS DATA PROGRAMMATICALLY:

    JSON-LD is a popular format for linked data which is fully compatible with JSON.

    curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/s41585-019-0251-x'

    N-Triples is a line-based linked data format ideal for batch operations.

    curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/s41585-019-0251-x'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/s41585-019-0251-x'

    RDF/XML is a standard XML format for linked data.

    curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41585-019-0251-x'


     

    This table displays all metadata directly associated to this object as RDF triples.

    331 TRIPLES      21 PREDICATES      142 URIs      115 LITERALS      15 BLANK NODES

    Subject Predicate Object
    1 sg:pub.10.1038/s41585-019-0251-x schema:about N03f880aefeb14c16908d76040b6a0288
    2 N046b7933b1ea4160a6bb7d5189f862bc
    3 N0ea833fee0494d178575deed635e3bd5
    4 N2fee65d94f464042bccd80c60e104915
    5 N693adb62b7c845e0b912e80abc0adad2
    6 Nb67eae5b440b49d9987c1d126a08cf28
    7 Nc09b86f043f3484c9d8fd2e7a612df10
    8 Nc57aa28d2d9c45668c7fd39ed0a4eb6e
    9 anzsrc-for:11
    10 anzsrc-for:1103
    11 anzsrc-for:1112
    12 schema:author Ndac45a687dd943918dab6dfd5d420f47
    13 schema:citation sg:pub.10.1007/s00259-009-1197-7
    14 sg:pub.10.1007/s00259-015-3150-2
    15 sg:pub.10.1007/s00259-017-3657-9
    16 sg:pub.10.1007/s00259-019-4261-y
    17 sg:pub.10.1007/s10549-014-2939-1
    18 sg:pub.10.1023/a:1025436307913
    19 sg:pub.10.1038/266653a0
    20 sg:pub.10.1038/nature14011
    21 sg:pub.10.1038/ncponc0714
    22 sg:pub.10.1038/ncponc0744
    23 sg:pub.10.1038/nrc1528
    24 sg:pub.10.1038/nri3921
    25 sg:pub.10.1038/nrurol.2013.8
    26 sg:pub.10.1038/nrurol.2015.90
    27 sg:pub.10.1038/pcan.2012.42
    28 sg:pub.10.1038/s41585-018-0020-2
    29 sg:pub.10.1038/srep44824
    30 sg:pub.10.1186/s13046-017-0578-1
    31 schema:datePublished 2019-11-11
    32 schema:datePublishedReg 2019-11-11
    33 schema:description The targeted alpha therapy radium-223 (223Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases. Preclinical studies demonstrate that 223Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. 223Ra might also modulate immune responses within the bone. The clinical utility of 223Ra has encouraged the development of other anticancer targeted alpha therapies. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of 223Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease.
    34 schema:genre article
    35 schema:isAccessibleForFree true
    36 schema:isPartOf Nafca9e56176b46f896dde9af23631d27
    37 Nf953a678c62742adb93e45bc0dc4c59e
    38 sg:journal.1034152
    39 schema:keywords DNA damage response proteins
    40 DNA double-strand breaks
    41 abnormal bone formation
    42 action
    43 agents
    44 alpha particles
    45 alpha therapy
    46 androgen receptor axis
    47 anticancer
    48 axis
    49 basis
    50 benefits
    51 bone
    52 bone disease
    53 bone formation
    54 bone matrix
    55 bone metastases
    56 bone microenvironment
    57 breaks
    58 cancer
    59 castration-resistant prostate cancer
    60 cell death
    61 cells
    62 checkpoint receptors
    63 clinical benefit
    64 clinical utility
    65 combination
    66 combination therapy
    67 combinatorial treatment strategies
    68 current mechanistic knowledge
    69 cytotoxic drugs
    70 damage response proteins
    71 death
    72 design
    73 development
    74 direct effect
    75 disease
    76 disruption
    77 double-strand breaks
    78 drugs
    79 effect
    80 formation
    81 growth
    82 high-energy alpha particles
    83 immune checkpoint receptors
    84 immune response
    85 implications
    86 knowledge
    87 lesions
    88 loop
    89 matrix
    90 mechanism
    91 mechanism of action
    92 mechanistic knowledge
    93 men
    94 metastasis
    95 metastatic bone disease
    96 metastatic lesions
    97 microenvironment
    98 monotherapy
    99 new combinatorial treatment strategy
    100 osteoblastic metastatic lesions
    101 osteoblasts
    102 osteoclasts
    103 particles
    104 patients
    105 positive feedback loop
    106 potential clinical benefit
    107 preclinical studies
    108 prostate cancer
    109 protein
    110 radium-223
    111 receptor axis
    112 receptors
    113 response
    114 response proteins
    115 strategies
    116 study
    117 survival
    118 symptomatic bone metastases
    119 therapy
    120 thorough understanding
    121 treatment combinations
    122 treatment strategies
    123 tumor cells
    124 tumor growth
    125 understanding
    126 use
    127 utility
    128 visceral metastases
    129 schema:name Radium-223 mechanism of action: implications for use in treatment combinations
    130 schema:pagination 745-756
    131 schema:productId N50df858deec44dee9b2d16b0dda96a50
    132 N9a7d0e771dbb4a72ada5a3846d9c152c
    133 Ndae8319053e94b7fbaca936db3619fdc
    134 schema:sameAs https://app.dimensions.ai/details/publication/pub.1122478263
    135 https://doi.org/10.1038/s41585-019-0251-x
    136 schema:sdDatePublished 2022-11-24T21:03
    137 schema:sdLicense https://scigraph.springernature.com/explorer/license/
    138 schema:sdPublisher N9167ef26c5eb49e5985ff2be86feeb32
    139 schema:url https://doi.org/10.1038/s41585-019-0251-x
    140 sgo:license sg:explorer/license/
    141 sgo:sdDataset articles
    142 rdf:type schema:ScholarlyArticle
    143 N027dcbb32a2e446097d307a0306bb44c rdf:first sg:person.01357566757.11
    144 rdf:rest rdf:nil
    145 N03f880aefeb14c16908d76040b6a0288 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    146 schema:name Male
    147 rdf:type schema:DefinedTerm
    148 N046b7933b1ea4160a6bb7d5189f862bc schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    149 schema:name Animals
    150 rdf:type schema:DefinedTerm
    151 N0ea833fee0494d178575deed635e3bd5 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    152 schema:name Humans
    153 rdf:type schema:DefinedTerm
    154 N2ddbe5f55698409e90d59051267c49b6 rdf:first sg:person.011414615457.17
    155 rdf:rest N356800110e9348fb9d154a5cef4fb77c
    156 N2fee65d94f464042bccd80c60e104915 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    157 schema:name Disease Models, Animal
    158 rdf:type schema:DefinedTerm
    159 N356800110e9348fb9d154a5cef4fb77c rdf:first sg:person.01346275763.14
    160 rdf:rest N3b55075c8b6640ee8fffa00bf0d0a2bc
    161 N3b55075c8b6640ee8fffa00bf0d0a2bc rdf:first Ne975ba6bf5624cabb526992cc638eccc
    162 rdf:rest N9f5e41950b8b4e188d3b767f0f62c61a
    163 N50df858deec44dee9b2d16b0dda96a50 schema:name dimensions_id
    164 schema:value pub.1122478263
    165 rdf:type schema:PropertyValue
    166 N693adb62b7c845e0b912e80abc0adad2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    167 schema:name Radium
    168 rdf:type schema:DefinedTerm
    169 N9167ef26c5eb49e5985ff2be86feeb32 schema:name Springer Nature - SN SciGraph project
    170 rdf:type schema:Organization
    171 N9a7d0e771dbb4a72ada5a3846d9c152c schema:name pubmed_id
    172 schema:value 31712765
    173 rdf:type schema:PropertyValue
    174 N9f5e41950b8b4e188d3b767f0f62c61a rdf:first sg:person.01013134010.15
    175 rdf:rest Nc0503206bd7146a7a7b57f96ca7c78ce
    176 Nafca9e56176b46f896dde9af23631d27 schema:volumeNumber 16
    177 rdf:type schema:PublicationVolume
    178 Nb67eae5b440b49d9987c1d126a08cf28 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    179 schema:name Combined Modality Therapy
    180 rdf:type schema:DefinedTerm
    181 Nc0503206bd7146a7a7b57f96ca7c78ce rdf:first sg:person.0577220400.41
    182 rdf:rest N027dcbb32a2e446097d307a0306bb44c
    183 Nc09b86f043f3484c9d8fd2e7a612df10 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    184 schema:name Prostatic Neoplasms, Castration-Resistant
    185 rdf:type schema:DefinedTerm
    186 Nc57aa28d2d9c45668c7fd39ed0a4eb6e schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    187 schema:name Bone Neoplasms
    188 rdf:type schema:DefinedTerm
    189 Nd63144a155d44983b753e3c73cb8a2aa rdf:first sg:person.01173507156.42
    190 rdf:rest N2ddbe5f55698409e90d59051267c49b6
    191 Ndac45a687dd943918dab6dfd5d420f47 rdf:first sg:person.010060764532.40
    192 rdf:rest Nd63144a155d44983b753e3c73cb8a2aa
    193 Ndae8319053e94b7fbaca936db3619fdc schema:name doi
    194 schema:value 10.1038/s41585-019-0251-x
    195 rdf:type schema:PropertyValue
    196 Ne975ba6bf5624cabb526992cc638eccc schema:affiliation grid-institutes:grid.265008.9
    197 schema:familyName Kevin Kelly
    198 schema:givenName William
    199 rdf:type schema:Person
    200 Nf953a678c62742adb93e45bc0dc4c59e schema:issueNumber 12
    201 rdf:type schema:PublicationIssue
    202 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
    203 schema:name Medical and Health Sciences
    204 rdf:type schema:DefinedTerm
    205 anzsrc-for:1103 schema:inDefinedTermSet anzsrc-for:
    206 schema:name Clinical Sciences
    207 rdf:type schema:DefinedTerm
    208 anzsrc-for:1112 schema:inDefinedTermSet anzsrc-for:
    209 schema:name Oncology and Carcinogenesis
    210 rdf:type schema:DefinedTerm
    211 sg:grant.2438805 http://pending.schema.org/fundedItem sg:pub.10.1038/s41585-019-0251-x
    212 rdf:type schema:MonetaryGrant
    213 sg:journal.1034152 schema:issn 1759-4812
    214 1759-4820
    215 schema:name Nature Reviews Urology
    216 schema:publisher Springer Nature
    217 rdf:type schema:Periodical
    218 sg:person.010060764532.40 schema:affiliation grid-institutes:grid.5386.8
    219 schema:familyName Morris
    220 schema:givenName Michael J.
    221 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010060764532.40
    222 rdf:type schema:Person
    223 sg:person.01013134010.15 schema:affiliation grid-institutes:grid.42505.36
    224 schema:familyName Quinn
    225 schema:givenName David I.
    226 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01013134010.15
    227 rdf:type schema:Person
    228 sg:person.011414615457.17 schema:affiliation grid-institutes:grid.257413.6
    229 schema:familyName Guise
    230 schema:givenName Theresa A.
    231 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.011414615457.17
    232 rdf:type schema:Person
    233 sg:person.01173507156.42 schema:affiliation grid-institutes:grid.34477.33
    234 schema:familyName Corey
    235 schema:givenName Eva
    236 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01173507156.42
    237 rdf:type schema:Person
    238 sg:person.01346275763.14 schema:affiliation grid-institutes:grid.48336.3a
    239 schema:familyName Gulley
    240 schema:givenName James L.
    241 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01346275763.14
    242 rdf:type schema:Person
    243 sg:person.01357566757.11 schema:affiliation grid-institutes:grid.21107.35
    244 schema:familyName Sgouros
    245 schema:givenName George
    246 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01357566757.11
    247 rdf:type schema:Person
    248 sg:person.0577220400.41 schema:affiliation grid-institutes:grid.420044.6
    249 schema:familyName Scholz
    250 schema:givenName Arne
    251 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0577220400.41
    252 rdf:type schema:Person
    253 sg:pub.10.1007/s00259-009-1197-7 schema:sameAs https://app.dimensions.ai/details/publication/pub.1017449500
    254 https://doi.org/10.1007/s00259-009-1197-7
    255 rdf:type schema:CreativeWork
    256 sg:pub.10.1007/s00259-015-3150-2 schema:sameAs https://app.dimensions.ai/details/publication/pub.1044665818
    257 https://doi.org/10.1007/s00259-015-3150-2
    258 rdf:type schema:CreativeWork
    259 sg:pub.10.1007/s00259-017-3657-9 schema:sameAs https://app.dimensions.ai/details/publication/pub.1084020142
    260 https://doi.org/10.1007/s00259-017-3657-9
    261 rdf:type schema:CreativeWork
    262 sg:pub.10.1007/s00259-019-4261-y schema:sameAs https://app.dimensions.ai/details/publication/pub.1111389931
    263 https://doi.org/10.1007/s00259-019-4261-y
    264 rdf:type schema:CreativeWork
    265 sg:pub.10.1007/s10549-014-2939-1 schema:sameAs https://app.dimensions.ai/details/publication/pub.1032408554
    266 https://doi.org/10.1007/s10549-014-2939-1
    267 rdf:type schema:CreativeWork
    268 sg:pub.10.1023/a:1025436307913 schema:sameAs https://app.dimensions.ai/details/publication/pub.1007000237
    269 https://doi.org/10.1023/a:1025436307913
    270 rdf:type schema:CreativeWork
    271 sg:pub.10.1038/266653a0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011020406
    272 https://doi.org/10.1038/266653a0
    273 rdf:type schema:CreativeWork
    274 sg:pub.10.1038/nature14011 schema:sameAs https://app.dimensions.ai/details/publication/pub.1041312915
    275 https://doi.org/10.1038/nature14011
    276 rdf:type schema:CreativeWork
    277 sg:pub.10.1038/ncponc0714 schema:sameAs https://app.dimensions.ai/details/publication/pub.1004880954
    278 https://doi.org/10.1038/ncponc0714
    279 rdf:type schema:CreativeWork
    280 sg:pub.10.1038/ncponc0744 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038688180
    281 https://doi.org/10.1038/ncponc0744
    282 rdf:type schema:CreativeWork
    283 sg:pub.10.1038/nrc1528 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020327087
    284 https://doi.org/10.1038/nrc1528
    285 rdf:type schema:CreativeWork
    286 sg:pub.10.1038/nri3921 schema:sameAs https://app.dimensions.ai/details/publication/pub.1042641626
    287 https://doi.org/10.1038/nri3921
    288 rdf:type schema:CreativeWork
    289 sg:pub.10.1038/nrurol.2013.8 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038959030
    290 https://doi.org/10.1038/nrurol.2013.8
    291 rdf:type schema:CreativeWork
    292 sg:pub.10.1038/nrurol.2015.90 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001338966
    293 https://doi.org/10.1038/nrurol.2015.90
    294 rdf:type schema:CreativeWork
    295 sg:pub.10.1038/pcan.2012.42 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011582718
    296 https://doi.org/10.1038/pcan.2012.42
    297 rdf:type schema:CreativeWork
    298 sg:pub.10.1038/s41585-018-0020-2 schema:sameAs https://app.dimensions.ai/details/publication/pub.1104009811
    299 https://doi.org/10.1038/s41585-018-0020-2
    300 rdf:type schema:CreativeWork
    301 sg:pub.10.1038/srep44824 schema:sameAs https://app.dimensions.ai/details/publication/pub.1084132699
    302 https://doi.org/10.1038/srep44824
    303 rdf:type schema:CreativeWork
    304 sg:pub.10.1186/s13046-017-0578-1 schema:sameAs https://app.dimensions.ai/details/publication/pub.1091167128
    305 https://doi.org/10.1186/s13046-017-0578-1
    306 rdf:type schema:CreativeWork
    307 grid-institutes:grid.21107.35 schema:alternateName Johns Hopkins University, School of Medicine, Baltimore, MD, USA
    308 schema:name Johns Hopkins University, School of Medicine, Baltimore, MD, USA
    309 rdf:type schema:Organization
    310 grid-institutes:grid.257413.6 schema:alternateName Indiana University, School of Medicine, Indianapolis, IN, USA
    311 schema:name Indiana University, School of Medicine, Indianapolis, IN, USA
    312 rdf:type schema:Organization
    313 grid-institutes:grid.265008.9 schema:alternateName Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
    314 schema:name Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
    315 rdf:type schema:Organization
    316 grid-institutes:grid.34477.33 schema:alternateName Department of Urology, University of Washington, School of Medicine, Seattle, WA, USA
    317 schema:name Department of Urology, University of Washington, School of Medicine, Seattle, WA, USA
    318 rdf:type schema:Organization
    319 grid-institutes:grid.420044.6 schema:alternateName Bayer AG, Drug Discovery, Pharmaceuticals, Berlin, Germany
    320 schema:name Bayer AG, Drug Discovery, Pharmaceuticals, Berlin, Germany
    321 rdf:type schema:Organization
    322 grid-institutes:grid.42505.36 schema:alternateName Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
    323 schema:name Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
    324 Norris Comprehensive Cancer Center, Los Angeles, CA, USA
    325 rdf:type schema:Organization
    326 grid-institutes:grid.48336.3a schema:alternateName Genitourinary Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, USA
    327 schema:name Genitourinary Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, USA
    328 rdf:type schema:Organization
    329 grid-institutes:grid.5386.8 schema:alternateName Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA
    330 schema:name Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA
    331 rdf:type schema:Organization
     




    Preview window. Press ESC to close (or click here)


    ...