<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03026361</url>
  </required_header>
  <id_info>
    <org_study_id>06509824642532</org_study_id>
    <nct_id>NCT03026361</nct_id>
  </id_info>
  <brief_title>Molecular Mechanisms of the Development of Precancerous and Cancerous Lesions of the Oral Cavity</brief_title>
  <official_title>Molecular Mechanisms of Precancerous and Cancerous Lesions of the Oral Cavity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Zagreb</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Rijeka</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Zagreb</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study was to examine molecular alterations on the protein level in lesions of&#xD;
      oral lichen planus (OLP), oral squamous cell carcinoma (OSCC) and healthy mucosa. Global&#xD;
      protein profiling methods based on liquid chromatography coupled to mass spectrometry were&#xD;
      used, with a special emphasis on evaluation of deregulated extracellular matrix molecules&#xD;
      expression, as well as on analyses of insulin-like growtg factor 2 (IG2F) and insulin-like&#xD;
      growth factor 2 receptor (IGFR2) expression in healthy mucosa, OLP and OSCC tissues by&#xD;
      comparative semiquantitative immunohistochemistry.&#xD;
&#xD;
      Mass spectrometry based proteomics profiling of healthy mucosa, OLP and OSCC tissues (and&#xD;
      accompanied histologically unaltered tissues, respectively) identified 55 extracellular&#xD;
      matrix proteins. Twenty among identified proteins were common to all groups of samples.&#xD;
      Statistically significant difference between final IGF2 and IGF2R IRS scores in favour to&#xD;
      IGF2R may further corroborate the IG2FR antitumor role in OLP and OSCC where it acts as a&#xD;
      negative regulator of IGF2 activity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Although OLP is categorised as a precancerous condition associated with a significantly&#xD;
      increased risk of oral cancer, molecular pathophysiology of OLP and its potential for&#xD;
      malignant transformation in OSCC are poorly understood and remain controversial. Development&#xD;
      of new analytical methods enhances research in the field of malignant disorders.&#xD;
      Identification of novel biomarkers help in the diagnostic process, pre-symptomatic&#xD;
      interventions or prediction of treatment response. Proteomics based on mass spectrometry&#xD;
      enables analysis of novel, putative biomarkers. In this study, proteomics was used to analyse&#xD;
      in more details extracellular matrix (ECM) proteins and proteins related to ECM signalization&#xD;
      which have a well-established role in malignant transformation and invasion of tumor cells.&#xD;
&#xD;
      IGF2 and IGF2R are known biomarkers in cellular metabolism,but their role in oral&#xD;
      precancerous lesions, namely oral lichen planus (OLP) as well as in oral squamous cell&#xD;
      carcinoma (OSCC) has not been explored so far. The second aim of our study was to analyse&#xD;
      IG2F and IGFR2 expression in oral lichen planus and oral squamous cell carcinoma tissues by&#xD;
      comparative semiquantitative immunohistochemistry&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2010</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">December 2014</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Global proteomic profiling of oral lichen planus and oral squamous cell carcinoma</measure>
    <time_frame>2012-2014</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>evaluation of the Insulin-like growth factor receptor 2 (IGF2R) and IGF2 role in oral lichen planus</measure>
    <time_frame>2011-2014</time_frame>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">71</enrollment>
  <condition>Oral Lichen Planus</condition>
  <condition>Oral Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>oral lichen planus (OLP)</arm_group_label>
    <description>Histopathologically confirmed samples of OLP underwent immunohistochemical analysis of IGF2 and IGF2R expression.&#xD;
Fresh-frozen samples of clinically OLP changed and adjacent healthy mucosa underwent global proteomic profiling and two proteins were subsequently validated with Western blot.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>oral squamous cell carcinoma (OSCC)</arm_group_label>
    <description>Histopathologically confirmed samples of OSCC underwent immunohistochemical analysis of IGF2 and IGF2R expression.&#xD;
Fresh-frozen samples of clinically OSCC changed and adjacent healthy mucosa underwent global proteomic profiling and two proteins were subsequently validated with Western blot.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>healthy mucosa</arm_group_label>
    <description>Archival samples of healthy oral mucosa underwent immunohistochemical analysis of IGF2 and IGF2R expression.&#xD;
Fresh-frozen samples of healthy mucosa taken during alveolotomy underwent global proteomic profiling and two proteins were subsequently validated with Western blot.</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>global proteomic profiling</intervention_name>
    <description>Global proteomic profiling was performed on OLP and OSCC samples and healthy mucosa. Obtained data was analysed in Uniprot database (http://uniprot.org) with the emphasis on extracellular matrix proteins. In total, 55 extracellular matrix proteins were found to be expressed in analysed samples with very high confidence.</description>
    <arm_group_label>healthy mucosa</arm_group_label>
    <arm_group_label>oral lichen planus (OLP)</arm_group_label>
    <arm_group_label>oral squamous cell carcinoma (OSCC)</arm_group_label>
    <other_name>immunohistochemistry</other_name>
    <other_name>Western blot</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        A study consisted of 71 consented patients, among which 27 with histologically confirmed&#xD;
        diagnosis of oral lichen planus, 23 with oral squamous cell carcinoma and 21 sample of&#xD;
        healthy oral mucosa (18 archive samples). Study included 36 male and 35 female patients.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  histopathologically confirmed oral lichen planus and oral squamous cell carcinoma&#xD;
&#xD;
          -  healthy volunteers referred for alveolotomy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  non-consent patients&#xD;
&#xD;
          -  previously treated OSCC&#xD;
&#xD;
          -  patients under immunosuppressive therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marinka Mravak-Stipetic, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>School of Dental Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>School of Dental Medicine, University of Zagreb</name>
      <address>
        <city>Zagreb</city>
        <zip>10000</zip>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Croatia</country>
  </location_countries>
  <results_reference>
    <citation>Schiller HB, Szekeres A, Binder BR, Stockinger H, Leksa V. Mannose 6-phosphate/insulin-like growth factor 2 receptor limits cell invasion by controlling alphaVbeta3 integrin expression and proteolytic processing of urokinase-type plasminogen activator receptor. Mol Biol Cell. 2009 Feb;20(3):745-56. doi: 10.1091/mbc.e08-06-0569. Epub 2008 Nov 26.</citation>
    <PMID>19037107</PMID>
  </results_reference>
  <results_reference>
    <citation>Zavras AI, Pitiphat W, Wu T, Cartsos V, Lam A, Douglass CW, Diehl SR. Insulin-like growth factor II receptor gene-167 genotype increases the risk of oral squamous cell carcinoma in humans. Cancer Res. 2003 Jan 15;63(2):296-7.</citation>
    <PMID>12543777</PMID>
  </results_reference>
  <results_reference>
    <citation>Pawar H, Kashyap MK, Sahasrabuddhe NA, Renuse S, Harsha HC, Kumar P, Sharma J, Kandasamy K, Marimuthu A, Nair B, Rajagopalan S, Maharudraiah J, Premalatha CS, Kumar KV, Vijayakumar M, Chaerkady R, Prasad TS, Kumar RV, Kumar RV, Pandey A. Quantitative tissue proteomics of esophageal squamous cell carcinoma for novel biomarker discovery. Cancer Biol Ther. 2011 Sep 15;12(6):510-22. doi: 10.4161/cbt.12.6.16833. Epub 2011 Sep 15.</citation>
    <PMID>21743296</PMID>
  </results_reference>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>January 18, 2017</study_first_submitted>
  <study_first_submitted_qc>January 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 20, 2017</study_first_posted>
  <last_update_submitted>January 18, 2017</last_update_submitted>
  <last_update_submitted_qc>January 18, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 20, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Zagreb</investigator_affiliation>
    <investigator_full_name>Marinka Mravak Stipetic</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
    <mesh_term>Lichen Planus, Oral</mesh_term>
    <mesh_term>Lichen Planus</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03026361
org study id: 06509824642532
nct id: NCT03026361
lead sponsor: 
collaborator: 
has dmc: Yes
The aim of this study was to examine molecular alterations on the protein level in lesions of
      oral lichen planus (OLP), oral squamous cell carcinoma (OSCC) and healthy mucosa. Global
      protein profiling methods based on liquid chromatography coupled to mass spectrometry were
      used, with a special emphasis on evaluation of deregulated extracellular matrix molecules
      expression, as well as on analyses of insulin-like growtg factor 2 (IG2F) and insulin-like
      growth factor 2 receptor (IGFR2) expression in healthy mucosa, OLP and OSCC tissues by
      comparative semiquantitative immunohistochemistry.

      Mass spectrometry based proteomics profiling of healthy mucosa, OLP and OSCC tissues (and
      accompanied histologically unaltered tissues, respectively) identified 55 extracellular
      matrix proteins. Twenty among identified proteins were common to all groups of samples.
      Statistically significant difference between final IGF2 and IGF2R IRS scores in favour to
      IGF2R may further corroborate the IG2FR antitumor role in OLP and OSCC where it acts as a
      negative regulator of IGF2 activity.
Although OLP is categorised as a precancerous condition associated with a significantly
      increased risk of oral cancer, molecular pathophysiology of OLP and its potential for
      malignant transformation in OSCC are poorly understood and remain controversial. Development
      of new analytical methods enhances research in the field of malignant disorders.
      Identification of novel biomarkers help in the diagnostic process, pre-symptomatic
      interventions or prediction of treatment response. Proteomics based on mass spectrometry
      enables analysis of novel, putative biomarkers. In this study, proteomics was used to analyse
      in more details extracellular matrix (ECM) proteins and proteins related to ECM signalization
      which have a well-established role in malignant transformation and invasion of tumor cells.

      IGF2 and IGF2R are known biomarkers in cellular metabolism,but their role in oral
      precancerous lesions, namely oral lichen planus (OLP) as well as in oral squamous cell
      carcinoma (OSCC) has not been explored so far. The second aim of our study was to analyse
      IG2F and IGFR2 expression in oral lichen planus and oral squamous cell carcinoma tissues by
      comparative semiquantitative immunohistochemistry
observational model: Cohort
time perspective: Prospective
measure: Global proteomic profiling of oral lichen planus and oral squamous cell carcinoma
time frame: 2012-2014
measure: evaluation of the Insulin-like growth factor receptor 2 (IGF2R) and IGF2 role in oral lichen planus
time frame: 2011-2014
arm group label: oral lichen planus (OLP)
description: Histopathologically confirmed samples of OLP underwent immunohistochemical analysis of IGF2 and IGF2R expression.
Fresh-frozen samples of clinically OLP changed and adjacent healthy mucosa underwent global proteomic profiling and two proteins were subsequently validated with Western blot.
arm group label: oral squamous cell carcinoma (OSCC)
description: Histopathologically confirmed samples of OSCC underwent immunohistochemical analysis of IGF2 and IGF2R expression.
Fresh-frozen samples of clinically OSCC changed and adjacent healthy mucosa underwent global proteomic profiling and two proteins were subsequently validated with Western blot.
arm group label: healthy mucosa
description: Archival samples of healthy oral mucosa underwent immunohistochemical analysis of IGF2 and IGF2R expression.
Fresh-frozen samples of healthy mucosa taken during alveolotomy underwent global proteomic profiling and two proteins were subsequently validated with Western blot.
intervention type: Genetic
intervention name: global proteomic profiling
description: Global proteomic profiling was performed on OLP and OSCC samples and healthy mucosa. Obtained data was analysed in Uniprot database (http://uniprot.org) with the emphasis on extracellular matrix proteins. In total, 55 extracellular matrix proteins were found to be expressed in analysed samples with very high confidence.
arm group label: healthy mucosa
arm group label: oral lichen planus (OLP)
arm group label: oral squamous cell carcinoma (OSCC)
other name: immunohistochemistry
other name: Western blot
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 30 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Marinka Mravak-Stipetic, Professor
role: Principal Investigator
affiliation: School of Dental Medicine
facility: 
country: Croatia
citation: Schiller HB, Szekeres A, Binder BR, Stockinger H, Leksa V. Mannose 6-phosphate/insulin-like growth factor 2 receptor limits cell invasion by controlling alphaVbeta3 integrin expression and proteolytic processing of urokinase-type plasminogen activator receptor. Mol Biol Cell. 2009 Feb;20(3):745-56. doi: 10.1091/mbc.e08-06-0569. Epub 2008 Nov 26.
PMID: 19037107
citation: Zavras AI, Pitiphat W, Wu T, Cartsos V, Lam A, Douglass CW, Diehl SR. Insulin-like growth factor II receptor gene-167 genotype increases the risk of oral squamous cell carcinoma in humans. Cancer Res. 2003 Jan 15;63(2):296-7.
PMID: 12543777
citation: Pawar H, Kashyap MK, Sahasrabuddhe NA, Renuse S, Harsha HC, Kumar P, Sharma J, Kandasamy K, Marimuthu A, Nair B, Rajagopalan S, Maharudraiah J, Premalatha CS, Kumar KV, Vijayakumar M, Chaerkady R, Prasad TS, Kumar RV, Kumar RV, Pandey A. Quantitative tissue proteomics of esophageal squamous cell carcinoma for novel biomarker discovery. Cancer Biol Ther. 2011 Sep 15;12(6):510-22. doi: 10.4161/cbt.12.6.16833. Epub 2011 Sep 15.
PMID: 21743296
responsible party type: Principal Investigator
investigator affiliation: University of Zagreb
investigator full name: Marinka Mravak Stipetic
investigator title: Professor
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Lichen Planus, Oral
mesh term: Lichen Planus
sharing ipd: No