Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-08

AUTHORS

Margaret T. Kasner, Rosemarie Mick, Grace R. Jeschke, Matthew Carabasi, Joanne Filicko-O’Hara, Neal Flomenberg, Noelle V. Frey, Elizabeth O. Hexner, Selina M. Luger, Alison W. Loren, James K. Mangan, John L. Wagner, Mark Weiss, Martin Carroll, Alexander E. Perl

ABSTRACT

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML. More... »

PAGES

657-666

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10637-018-0585-x

DOI

http://dx.doi.org/10.1007/s10637-018-0585-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1101900079

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29607465


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/2008/1112", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Oncology and Carcinogenesis", 
        "type": "DefinedTerm"
      }, 
      {
        "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"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Antineoplastic Combined Chemotherapy Protocols", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Cytarabine", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Etoposide", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Female", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Humans", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Leukemia, Myeloid, Acute", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Male", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mechanistic Target of Rapamycin Complex 1", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Middle Aged", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mitoxantrone", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Phosphorylation", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Pilot Projects", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Remission Induction", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Signal Transduction", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Sirolimus", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "alternateName": "Thomas Jefferson University", 
          "id": "https://www.grid.ac/institutes/grid.265008.9", 
          "name": [
            "Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Kasner", 
        "givenName": "Margaret T.", 
        "id": "sg:person.01045346007.78", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01045346007.78"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Mick", 
        "givenName": "Rosemarie", 
        "id": "sg:person.01027261122.07", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01027261122.07"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", 
            "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Jeschke", 
        "givenName": "Grace R.", 
        "id": "sg:person.01122202165.50", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01122202165.50"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Thomas Jefferson University", 
          "id": "https://www.grid.ac/institutes/grid.265008.9", 
          "name": [
            "Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Carabasi", 
        "givenName": "Matthew", 
        "id": "sg:person.01173661177.49", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01173661177.49"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Thomas Jefferson University", 
          "id": "https://www.grid.ac/institutes/grid.265008.9", 
          "name": [
            "Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Filicko-O\u2019Hara", 
        "givenName": "Joanne", 
        "id": "sg:person.01163021417.91", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01163021417.91"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Thomas Jefferson University", 
          "id": "https://www.grid.ac/institutes/grid.265008.9", 
          "name": [
            "Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Flomenberg", 
        "givenName": "Neal", 
        "id": "sg:person.01023032774.87", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01023032774.87"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", 
            "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Frey", 
        "givenName": "Noelle V.", 
        "id": "sg:person.01342471137.57", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01342471137.57"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", 
            "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Hexner", 
        "givenName": "Elizabeth O.", 
        "id": "sg:person.01157065163.51", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01157065163.51"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", 
            "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Luger", 
        "givenName": "Selina M.", 
        "id": "sg:person.012415664717.68", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.012415664717.68"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", 
            "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Loren", 
        "givenName": "Alison W.", 
        "id": "sg:person.0613365041.61", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0613365041.61"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", 
            "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Mangan", 
        "givenName": "James K.", 
        "id": "sg:person.0616503430.21", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0616503430.21"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Thomas Jefferson University", 
          "id": "https://www.grid.ac/institutes/grid.265008.9", 
          "name": [
            "Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Wagner", 
        "givenName": "John L.", 
        "id": "sg:person.014112016227.37", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.014112016227.37"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Thomas Jefferson University", 
          "id": "https://www.grid.ac/institutes/grid.265008.9", 
          "name": [
            "Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Weiss", 
        "givenName": "Mark", 
        "id": "sg:person.016711031432.55", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.016711031432.55"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", 
            "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Carroll", 
        "givenName": "Martin", 
        "id": "sg:person.01214031071.40", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01214031071.40"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University of Pennsylvania", 
          "id": "https://www.grid.ac/institutes/grid.25879.31", 
          "name": [
            "Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", 
            "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Perl", 
        "givenName": "Alexander E.", 
        "id": "sg:person.0661500241.33", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0661500241.33"
        ], 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "https://doi.org/10.1182/blood-2010-10-316224", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1005081622"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1200/jco.2004.07.048", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1011824596"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1056/nejmoa1516192", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1016166624"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1182/blood-2004-06-2494", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1020382829"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/1078-0432.ccr-06-0764", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1022831125"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/1078-0432.ccr-11-2346", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1025188614"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1056/nejmoa1301689", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1025463655"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1182/blood-2004-11-4468", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1027202407"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.exphem.2006.05.002", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1029614617"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/1078-0432.ccr-09-0842", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1030837144"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1200/jco.2013.52.8562", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033952429"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1371/journal.pone.0053292", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1035175984"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/leu.2013.17", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1035660563", 
          "https://doi.org/10.1038/leu.2013.17"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1111/j.1365-2141.2011.08940.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1042113352"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1097/00000421-198212000-00014", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1045278392"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1097/00000421-198212000-00014", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1045278392"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/0197-2456(96)00075-x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1047730164"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1200/jco.2003.04.036", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1064203515"
        ], 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2018-08", 
    "datePublishedReg": "2018-08-01", 
    "description": "Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p\u00a0=\u20090.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.", 
    "genre": "research_article", 
    "id": "sg:pub.10.1007/s10637-018-0585-x", 
    "inLanguage": [
      "en"
    ], 
    "isAccessibleForFree": false, 
    "isFundedItemOf": [
      {
        "id": "sg:grant.2438824", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2418478", 
        "type": "MonetaryGrant"
      }
    ], 
    "isPartOf": [
      {
        "id": "sg:journal.1094201", 
        "issn": [
          "0167-6997", 
          "1573-0646"
        ], 
        "name": "Investigational New Drugs", 
        "type": "Periodical"
      }, 
      {
        "issueNumber": "4", 
        "type": "PublicationIssue"
      }, 
      {
        "type": "PublicationVolume", 
        "volumeNumber": "36"
      }
    ], 
    "name": "Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition", 
    "pagination": "657-666", 
    "productId": [
      {
        "name": "readcube_id", 
        "type": "PropertyValue", 
        "value": [
          "e065485be84788b39a5909036c9ad34e7d036a06324bac418935c13acdb4d6f0"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "29607465"
        ]
      }, 
      {
        "name": "nlm_unique_id", 
        "type": "PropertyValue", 
        "value": [
          "8309330"
        ]
      }, 
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1007/s10637-018-0585-x"
        ]
      }, 
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1101900079"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1007/s10637-018-0585-x", 
      "https://app.dimensions.ai/details/publication/pub.1101900079"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2019-04-11T13:56", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000371_0000000371/records_130814_00000005.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "https://link.springer.com/10.1007%2Fs10637-018-0585-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.10.1007/s10637-018-0585-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.10.1007/s10637-018-0585-x'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1007/s10637-018-0585-x'

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

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1007/s10637-018-0585-x'


 

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

288 TRIPLES      21 PREDICATES      61 URIs      36 LITERALS      24 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1007/s10637-018-0585-x schema:about N0c1f4ec5a37f45af96e15606cd23d456
2 N23dd037c6dca41d5b42dd05eacfeaa92
3 N398fad99381b4cb8aba95d525d9ba4cc
4 N4bfaf751a0e74687ac2057a1c4c8937d
5 N6a072d6f0fa7418f90a5248db26f596c
6 N9b99ff13b16b4cd1b323c225ed7e70ca
7 Na836701b7de54665b2722e9f30f1bfbe
8 Nad2daea2d988485da2143f632700c8bc
9 Nad3d4ef9b3ae4b009d2a381725f21c3c
10 Nbfa81fa923994a0e844f193f4009ac2d
11 Nd3a9e324612547a8ba86d693846ceca9
12 Nd4be4f873139484795ff4d2ec85986bc
13 Ndf28d6ceeec549f8b4eb31bc9d5d86a1
14 Ne1f45443eb9d44b78531431b807d0f5f
15 Nf6a249310e984f9d89f79ab28db368fa
16 anzsrc-for:11
17 anzsrc-for:1112
18 schema:author Ndc5f02ac68d14cf9a356dca28f209838
19 schema:citation sg:pub.10.1038/leu.2013.17
20 https://doi.org/10.1016/0197-2456(96)00075-x
21 https://doi.org/10.1016/j.exphem.2006.05.002
22 https://doi.org/10.1056/nejmoa1301689
23 https://doi.org/10.1056/nejmoa1516192
24 https://doi.org/10.1097/00000421-198212000-00014
25 https://doi.org/10.1111/j.1365-2141.2011.08940.x
26 https://doi.org/10.1158/1078-0432.ccr-06-0764
27 https://doi.org/10.1158/1078-0432.ccr-09-0842
28 https://doi.org/10.1158/1078-0432.ccr-11-2346
29 https://doi.org/10.1182/blood-2004-06-2494
30 https://doi.org/10.1182/blood-2004-11-4468
31 https://doi.org/10.1182/blood-2010-10-316224
32 https://doi.org/10.1200/jco.2003.04.036
33 https://doi.org/10.1200/jco.2004.07.048
34 https://doi.org/10.1200/jco.2013.52.8562
35 https://doi.org/10.1371/journal.pone.0053292
36 schema:datePublished 2018-08
37 schema:datePublishedReg 2018-08-01
38 schema:description Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.
39 schema:genre research_article
40 schema:inLanguage en
41 schema:isAccessibleForFree false
42 schema:isPartOf N6fcb2f33dcd6422a99686e1a15acfc41
43 N936c0d08a5b545628dadc57e7dedf9e2
44 sg:journal.1094201
45 schema:name Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition
46 schema:pagination 657-666
47 schema:productId N44a57d36edf44cfe84e580dcae10c574
48 N471f295ca36d49ab85ceebc2019fb789
49 N6a768d07291e4713b1e6d101c768224a
50 Nc9fef3e9afb9466bb16b9173ee9455da
51 Nfd1958f9fe094096b8705c952862f1c8
52 schema:sameAs https://app.dimensions.ai/details/publication/pub.1101900079
53 https://doi.org/10.1007/s10637-018-0585-x
54 schema:sdDatePublished 2019-04-11T13:56
55 schema:sdLicense https://scigraph.springernature.com/explorer/license/
56 schema:sdPublisher N6851168f93d44227affa4b05c31446c2
57 schema:url https://link.springer.com/10.1007%2Fs10637-018-0585-x
58 sgo:license sg:explorer/license/
59 sgo:sdDataset articles
60 rdf:type schema:ScholarlyArticle
61 N0c1f4ec5a37f45af96e15606cd23d456 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
62 schema:name Male
63 rdf:type schema:DefinedTerm
64 N0e8fb6c19e83407282d61a62b457487c rdf:first sg:person.01173661177.49
65 rdf:rest N4de05e2dc73b46e08e5cecd406d645a0
66 N0f7fe8a936cb4a2cbfca1981e9896bc1 rdf:first sg:person.0613365041.61
67 rdf:rest Nc20c7718fd6a450383f3841274593f1f
68 N23dd037c6dca41d5b42dd05eacfeaa92 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
69 schema:name Pilot Projects
70 rdf:type schema:DefinedTerm
71 N288e02c7606d4527b0f87802198b8a36 rdf:first sg:person.012415664717.68
72 rdf:rest N0f7fe8a936cb4a2cbfca1981e9896bc1
73 N310ee117d6d64c18b0a25c4ddcb29c6c rdf:first sg:person.01214031071.40
74 rdf:rest Na1491a4141554b97870d9267fa399aab
75 N398fad99381b4cb8aba95d525d9ba4cc schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
76 schema:name Female
77 rdf:type schema:DefinedTerm
78 N44a57d36edf44cfe84e580dcae10c574 schema:name nlm_unique_id
79 schema:value 8309330
80 rdf:type schema:PropertyValue
81 N471f295ca36d49ab85ceebc2019fb789 schema:name pubmed_id
82 schema:value 29607465
83 rdf:type schema:PropertyValue
84 N4bfaf751a0e74687ac2057a1c4c8937d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
85 schema:name Phosphorylation
86 rdf:type schema:DefinedTerm
87 N4de05e2dc73b46e08e5cecd406d645a0 rdf:first sg:person.01163021417.91
88 rdf:rest Ne1fb9d95f46a4819a6574bd662dda0f1
89 N582dd1b9aa0d458a8406bea7a5a1e630 rdf:first sg:person.016711031432.55
90 rdf:rest N310ee117d6d64c18b0a25c4ddcb29c6c
91 N65ca2a69f757409890207abaa896c1dc rdf:first sg:person.01157065163.51
92 rdf:rest N288e02c7606d4527b0f87802198b8a36
93 N6765d6eafa6744afa4cb056d66afe61c rdf:first sg:person.014112016227.37
94 rdf:rest N582dd1b9aa0d458a8406bea7a5a1e630
95 N6851168f93d44227affa4b05c31446c2 schema:name Springer Nature - SN SciGraph project
96 rdf:type schema:Organization
97 N6a072d6f0fa7418f90a5248db26f596c schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
98 schema:name Antineoplastic Combined Chemotherapy Protocols
99 rdf:type schema:DefinedTerm
100 N6a768d07291e4713b1e6d101c768224a schema:name doi
101 schema:value 10.1007/s10637-018-0585-x
102 rdf:type schema:PropertyValue
103 N6fcb2f33dcd6422a99686e1a15acfc41 schema:issueNumber 4
104 rdf:type schema:PublicationIssue
105 N8984f44bf42c41479228267a3fd2e1f4 rdf:first sg:person.01027261122.07
106 rdf:rest Nc26f59bdf5764ea3a55475d7f5802de8
107 N936c0d08a5b545628dadc57e7dedf9e2 schema:volumeNumber 36
108 rdf:type schema:PublicationVolume
109 N9b99ff13b16b4cd1b323c225ed7e70ca schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
110 schema:name Cytarabine
111 rdf:type schema:DefinedTerm
112 Na1491a4141554b97870d9267fa399aab rdf:first sg:person.0661500241.33
113 rdf:rest rdf:nil
114 Na836701b7de54665b2722e9f30f1bfbe schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
115 schema:name Sirolimus
116 rdf:type schema:DefinedTerm
117 Nad2daea2d988485da2143f632700c8bc schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
118 schema:name Remission Induction
119 rdf:type schema:DefinedTerm
120 Nad3d4ef9b3ae4b009d2a381725f21c3c schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
121 schema:name Signal Transduction
122 rdf:type schema:DefinedTerm
123 Nbfa81fa923994a0e844f193f4009ac2d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
124 schema:name Middle Aged
125 rdf:type schema:DefinedTerm
126 Nc20c7718fd6a450383f3841274593f1f rdf:first sg:person.0616503430.21
127 rdf:rest N6765d6eafa6744afa4cb056d66afe61c
128 Nc26f59bdf5764ea3a55475d7f5802de8 rdf:first sg:person.01122202165.50
129 rdf:rest N0e8fb6c19e83407282d61a62b457487c
130 Nc9fef3e9afb9466bb16b9173ee9455da schema:name readcube_id
131 schema:value e065485be84788b39a5909036c9ad34e7d036a06324bac418935c13acdb4d6f0
132 rdf:type schema:PropertyValue
133 Nd3a9e324612547a8ba86d693846ceca9 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
134 schema:name Mechanistic Target of Rapamycin Complex 1
135 rdf:type schema:DefinedTerm
136 Nd4be4f873139484795ff4d2ec85986bc schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
137 schema:name Etoposide
138 rdf:type schema:DefinedTerm
139 Ndc5f02ac68d14cf9a356dca28f209838 rdf:first sg:person.01045346007.78
140 rdf:rest N8984f44bf42c41479228267a3fd2e1f4
141 Ndf28d6ceeec549f8b4eb31bc9d5d86a1 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
142 schema:name Mitoxantrone
143 rdf:type schema:DefinedTerm
144 Ne1f45443eb9d44b78531431b807d0f5f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
145 schema:name Leukemia, Myeloid, Acute
146 rdf:type schema:DefinedTerm
147 Ne1fb9d95f46a4819a6574bd662dda0f1 rdf:first sg:person.01023032774.87
148 rdf:rest Ne2bdf206cecc48f0b6978a5293d49b9b
149 Ne2bdf206cecc48f0b6978a5293d49b9b rdf:first sg:person.01342471137.57
150 rdf:rest N65ca2a69f757409890207abaa896c1dc
151 Nf6a249310e984f9d89f79ab28db368fa schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
152 schema:name Humans
153 rdf:type schema:DefinedTerm
154 Nfd1958f9fe094096b8705c952862f1c8 schema:name dimensions_id
155 schema:value pub.1101900079
156 rdf:type schema:PropertyValue
157 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
158 schema:name Medical and Health Sciences
159 rdf:type schema:DefinedTerm
160 anzsrc-for:1112 schema:inDefinedTermSet anzsrc-for:
161 schema:name Oncology and Carcinogenesis
162 rdf:type schema:DefinedTerm
163 sg:grant.2418478 http://pending.schema.org/fundedItem sg:pub.10.1007/s10637-018-0585-x
164 rdf:type schema:MonetaryGrant
165 sg:grant.2438824 http://pending.schema.org/fundedItem sg:pub.10.1007/s10637-018-0585-x
166 rdf:type schema:MonetaryGrant
167 sg:journal.1094201 schema:issn 0167-6997
168 1573-0646
169 schema:name Investigational New Drugs
170 rdf:type schema:Periodical
171 sg:person.01023032774.87 schema:affiliation https://www.grid.ac/institutes/grid.265008.9
172 schema:familyName Flomenberg
173 schema:givenName Neal
174 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01023032774.87
175 rdf:type schema:Person
176 sg:person.01027261122.07 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
177 schema:familyName Mick
178 schema:givenName Rosemarie
179 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01027261122.07
180 rdf:type schema:Person
181 sg:person.01045346007.78 schema:affiliation https://www.grid.ac/institutes/grid.265008.9
182 schema:familyName Kasner
183 schema:givenName Margaret T.
184 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01045346007.78
185 rdf:type schema:Person
186 sg:person.01122202165.50 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
187 schema:familyName Jeschke
188 schema:givenName Grace R.
189 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01122202165.50
190 rdf:type schema:Person
191 sg:person.01157065163.51 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
192 schema:familyName Hexner
193 schema:givenName Elizabeth O.
194 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01157065163.51
195 rdf:type schema:Person
196 sg:person.01163021417.91 schema:affiliation https://www.grid.ac/institutes/grid.265008.9
197 schema:familyName Filicko-O’Hara
198 schema:givenName Joanne
199 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01163021417.91
200 rdf:type schema:Person
201 sg:person.01173661177.49 schema:affiliation https://www.grid.ac/institutes/grid.265008.9
202 schema:familyName Carabasi
203 schema:givenName Matthew
204 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01173661177.49
205 rdf:type schema:Person
206 sg:person.01214031071.40 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
207 schema:familyName Carroll
208 schema:givenName Martin
209 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01214031071.40
210 rdf:type schema:Person
211 sg:person.012415664717.68 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
212 schema:familyName Luger
213 schema:givenName Selina M.
214 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.012415664717.68
215 rdf:type schema:Person
216 sg:person.01342471137.57 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
217 schema:familyName Frey
218 schema:givenName Noelle V.
219 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01342471137.57
220 rdf:type schema:Person
221 sg:person.014112016227.37 schema:affiliation https://www.grid.ac/institutes/grid.265008.9
222 schema:familyName Wagner
223 schema:givenName John L.
224 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.014112016227.37
225 rdf:type schema:Person
226 sg:person.016711031432.55 schema:affiliation https://www.grid.ac/institutes/grid.265008.9
227 schema:familyName Weiss
228 schema:givenName Mark
229 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.016711031432.55
230 rdf:type schema:Person
231 sg:person.0613365041.61 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
232 schema:familyName Loren
233 schema:givenName Alison W.
234 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0613365041.61
235 rdf:type schema:Person
236 sg:person.0616503430.21 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
237 schema:familyName Mangan
238 schema:givenName James K.
239 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0616503430.21
240 rdf:type schema:Person
241 sg:person.0661500241.33 schema:affiliation https://www.grid.ac/institutes/grid.25879.31
242 schema:familyName Perl
243 schema:givenName Alexander E.
244 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0661500241.33
245 rdf:type schema:Person
246 sg:pub.10.1038/leu.2013.17 schema:sameAs https://app.dimensions.ai/details/publication/pub.1035660563
247 https://doi.org/10.1038/leu.2013.17
248 rdf:type schema:CreativeWork
249 https://doi.org/10.1016/0197-2456(96)00075-x schema:sameAs https://app.dimensions.ai/details/publication/pub.1047730164
250 rdf:type schema:CreativeWork
251 https://doi.org/10.1016/j.exphem.2006.05.002 schema:sameAs https://app.dimensions.ai/details/publication/pub.1029614617
252 rdf:type schema:CreativeWork
253 https://doi.org/10.1056/nejmoa1301689 schema:sameAs https://app.dimensions.ai/details/publication/pub.1025463655
254 rdf:type schema:CreativeWork
255 https://doi.org/10.1056/nejmoa1516192 schema:sameAs https://app.dimensions.ai/details/publication/pub.1016166624
256 rdf:type schema:CreativeWork
257 https://doi.org/10.1097/00000421-198212000-00014 schema:sameAs https://app.dimensions.ai/details/publication/pub.1045278392
258 rdf:type schema:CreativeWork
259 https://doi.org/10.1111/j.1365-2141.2011.08940.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1042113352
260 rdf:type schema:CreativeWork
261 https://doi.org/10.1158/1078-0432.ccr-06-0764 schema:sameAs https://app.dimensions.ai/details/publication/pub.1022831125
262 rdf:type schema:CreativeWork
263 https://doi.org/10.1158/1078-0432.ccr-09-0842 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030837144
264 rdf:type schema:CreativeWork
265 https://doi.org/10.1158/1078-0432.ccr-11-2346 schema:sameAs https://app.dimensions.ai/details/publication/pub.1025188614
266 rdf:type schema:CreativeWork
267 https://doi.org/10.1182/blood-2004-06-2494 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020382829
268 rdf:type schema:CreativeWork
269 https://doi.org/10.1182/blood-2004-11-4468 schema:sameAs https://app.dimensions.ai/details/publication/pub.1027202407
270 rdf:type schema:CreativeWork
271 https://doi.org/10.1182/blood-2010-10-316224 schema:sameAs https://app.dimensions.ai/details/publication/pub.1005081622
272 rdf:type schema:CreativeWork
273 https://doi.org/10.1200/jco.2003.04.036 schema:sameAs https://app.dimensions.ai/details/publication/pub.1064203515
274 rdf:type schema:CreativeWork
275 https://doi.org/10.1200/jco.2004.07.048 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011824596
276 rdf:type schema:CreativeWork
277 https://doi.org/10.1200/jco.2013.52.8562 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033952429
278 rdf:type schema:CreativeWork
279 https://doi.org/10.1371/journal.pone.0053292 schema:sameAs https://app.dimensions.ai/details/publication/pub.1035175984
280 rdf:type schema:CreativeWork
281 https://www.grid.ac/institutes/grid.25879.31 schema:alternateName University of Pennsylvania
282 schema:name Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
283 Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
284 Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
285 rdf:type schema:Organization
286 https://www.grid.ac/institutes/grid.265008.9 schema:alternateName Thomas Jefferson University
287 schema:name Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
288 rdf:type schema:Organization
 




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


...