<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/NCT03254888</url>
  </required_header>
  <id_info>
    <org_study_id>ABC</org_study_id>
    <nct_id>NCT03254888</nct_id>
  </id_info>
  <brief_title>Autophagy Bladder Cancer</brief_title>
  <official_title>Identification of Novel Autophagy Markers in Bladder Cancer Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assiut University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assiut University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      • Bladder cancer is the most common malignancy of the urinary tract. It represents the 7th&#xD;
      most commonly diagnosed cancer in male population worldwide and drops to the 11th when both&#xD;
      genders are considered . According to the American cancer society's estimates of bladder&#xD;
      cancer in 2017, the number of the new cases of bladder cancer is 79,030, and the mortality&#xD;
      figures reached 16,870 .&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      -  In Egypt, Bladder Cancer is the most prevalent malignancy among Egyptian males (16%)&#xD;
           producing more than 7900 deaths annually . The majority of patients with bladder cancer&#xD;
           about (70-80%) present with non-muscle invasive bladder cancer .&#xD;
&#xD;
        -  Autophagy is a highly conserved catabolic process that degrades cellular organelles and&#xD;
           proteins to maintain cellular biosynthesis during stress ; cancer cells induced&#xD;
           autophagy to counteract with anticancer therapy by helping them to evade apoptotic&#xD;
           pathway .Autophagy is achieved by many autophagy-related genes .&#xD;
&#xD;
        -  Previous studies found that human bladder cancer cell lines exhibit high basal level of&#xD;
           autophagic activity that may contribute to resistance to current anticancer treatment,&#xD;
           so targeting basal autophagy may help to develop novel therapeutic strategies .&#xD;
           Autophagy is potently induced by activating transcription factor 6(Endoplasmic Reticulum&#xD;
           stress marker) , and Malondialdehyde (oxidative stress marker) .&#xD;
&#xD;
        -  Recently several studies demonstrated the role of autophagy in Bladder Cancer&#xD;
           progression as evidenced by detection of microtubule associated protein and its&#xD;
           relevance with muscle invasion beside its grade dependency . Autophagy was grade&#xD;
           dependent process . Autophagy related gene 7 is a key protein involved in autophagosomes&#xD;
           biogenesis, Knockdown of Autophagy related gene 7 induced apoptotic cell death in&#xD;
           bladder cancer cell lines measured by increased caspase 3 level, Based on these previous&#xD;
           studies autophagy plays a role in bladder cancer progression so interruption of its&#xD;
           pathway may serve a novel target for future therapies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">December 1, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">October 1, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>autophagy marker</measure>
    <time_frame>baseline</time_frame>
    <description>differences in the level of Atg7(autophagy marker) in Low Grade bladder cancer and High Grade bladder cancer groups in comparison with safety margin and healthy control group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>stress markers</measure>
    <time_frame>baseline</time_frame>
    <description>Relation between LC3A and muscle invasiveness in bladder cancer progression, and relation between levels of ATF6, activating transcription factor6 (ER stress marker) -MDA malondialdehyde (oxidative stress marker)-Caspase3 (apoptotic marker) in different study groups and bladder cancer development.</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Bladder Cancer</condition>
  <arm_group>
    <arm_group_label>Low Grade group</arm_group_label>
    <description>• 50 tumor tissue samples from patients with Low Grade Bladder Cancer undergoing either trans urethral resection of bladder tumor or Radical Cystectomy ,&#xD;
The followings markers must be estimated :&#xD;
Autophagy markers:&#xD;
( Atg7) level using (quantitative real time polymerase chain reaction).&#xD;
(LC3A)level using immunohistochemistry .&#xD;
ER-stress marker: (ATF6) level using ELISA(Enzyme Linked Immuno sorbent Assay)&#xD;
Oxidative stress Marker:(MDA)using chemical method&#xD;
Apoptotic marker:(caspase 3) using(quantitative real time polymerase chain reaction) .</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High Grade group</arm_group_label>
    <description>• 50 tumor tissue samples from patients with High Grade Bladder Cancer undergoing either trans urethral resection of bladder tumor or Radical Cystectomy,&#xD;
The followings markers must be estimated :&#xD;
Autophagy markers:&#xD;
( Atg7) level using (quantitative real time polymerase chain reaction).&#xD;
(LC3A)level using immunohistochemistry .&#xD;
ER-stress marker: (ATF6) level using ELISA(Enzyme Linked Immuno sorbent Assay)&#xD;
Oxidative stress Marker:(MDA)using chemical method&#xD;
Apoptotic marker:(caspase 3) using (quantitative real time polymerase chain reaction) .</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Safety margin group</arm_group_label>
    <description>• 50 normal bladder urothelial tissue samples from the safety margin around the tumor(0.5cm to the tumor),&#xD;
The followings markers must be estimated :&#xD;
Autophagy markers:&#xD;
( Atg7) level using (quantitative real time polymerase chain reaction).&#xD;
(LC3A)level using immunohistochemistry .&#xD;
ER-stress marker: (ATF6) level using ELISA(Enzyme Linked Immuno sorbent Assay)&#xD;
Oxidative stress Marker:(MDA)using chemical method&#xD;
Apoptotic marker:(caspase 3) using (quantitative real time polymerase chain reaction).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <description>• 50 (age and sex matched )control&#xD;
The followings markers must be estimated :&#xD;
Autophagy markers:&#xD;
( Atg7) level using (quantitative real time polymerase chain reaction).&#xD;
(LC3A)level using immunohistochemistry .&#xD;
ER-stress marker: (ATF6) level using ELISA(Enzyme Linked Immuno sorbent Assay)&#xD;
Oxidative stress Marker:(MDA)using chemical method&#xD;
Apoptotic marker:(caspase 3) using (quantitative real time polymerase chain reaction)..</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        patients with confirmed bladder cancer (histopathologically) having LGBC(Low Grade bladder&#xD;
        cancer) undergoing either TUR(transurethral resection of Bladder Tumour) or Radical&#xD;
        Cystectomy and patients having HGBC(High Grade bladder cancer) undergoing either&#xD;
        TUR(transurethral resection of Bladder Tumour) or Radical cystectomy. Healthy controls[age&#xD;
        and gender matched](with no previous history of gross hematuria, urolithiasis, or active&#xD;
        urinary tract infection)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1)patients confirmed histopathologically to have bladder cancer. 2) Both sexes. 3)&#xD;
             Patients who will accept to participate in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with past history of Bladder Cancer with previous chemotherapy or any other&#xD;
             types of cancer in the last 5 years.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shaimaa Shakhoun</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assiut</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>MahaAli Essam-Eldeen Mohamed, lecturer</last_name>
    <phone>00201091570963</phone>
    <email>mahabadari@hotmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Shaimaa Shakhoun</last_name>
    <phone>00201001143867</phone>
    <email>atashaimaa8@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Assiut</name>
      <address>
        <city>Assiut</city>
        <zip>71111</zip>
        <country>Egypt</country>
      </address>
    </facility>
    <contact>
      <last_name>Shaimaa Shakhoun</last_name>
      <phone>00201001143867</phone>
      <email>atashaimaa8@gmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <results_reference>
    <citation>Woldu SL, Bagrodia A, Lotan Y. Guideline of guidelines: non-muscle-invasive bladder cancer. BJU Int. 2017 Mar;119(3):371-380. doi: 10.1111/bju.13760. Epub 2017 Jan 24.</citation>
    <PMID>28058776</PMID>
  </results_reference>
  <results_reference>
    <citation>Mathew R, Karantza-Wadsworth V, White E. Assessing metabolic stress and autophagy status in epithelial tumors. Methods Enzymol. 2009;453:53-81. doi: 10.1016/S0076-6879(08)04004-4.</citation>
    <PMID>19216902</PMID>
  </results_reference>
  <results_reference>
    <citation>Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005 Sep;5(9):726-34. doi: 10.1038/nrc1692.</citation>
    <PMID>16148885</PMID>
  </results_reference>
  <results_reference>
    <citation>Mizushima N. Autophagy: process and function. Genes Dev. 2007 Nov 15;21(22):2861-73. doi: 10.1101/gad.1599207.</citation>
    <PMID>18006683</PMID>
  </results_reference>
  <results_reference>
    <citation>Lin YC, Lin JF, Wen SI, Yang SC, Tsai TF, Chen HE, Chou KY, Hwang TI. Inhibition of High Basal Level of Autophagy Induces Apoptosis in Human Bladder Cancer Cells. J Urol. 2016 Apr;195(4 Pt 1):1126-35. doi: 10.1016/j.juro.2015.10.128. Epub 2015 Oct 28.</citation>
    <PMID>26519656</PMID>
  </results_reference>
  <results_reference>
    <citation>Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52. doi: 10.1038/nrm2239.</citation>
    <PMID>17717517</PMID>
  </results_reference>
  <results_reference>
    <citation>Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011 Sep;10(9):1533-41. doi: 10.1158/1535-7163.MCT-11-0047. Epub 2011 Aug 30.</citation>
    <PMID>21878654</PMID>
  </results_reference>
  <results_reference>
    <citation>Sivridis E, Koukourakis MI, Mendrinos SE, Touloupidis S, Giatromanolaki A. Patterns of autophagy in urothelial cell carcinomas--the significance of &quot;stone-like&quot; structures (SLS) in transurethral resection biopsies. Urol Oncol. 2013 Oct;31(7):1254-60. doi: 10.1016/j.urolonc.2011.12.016. Epub 2012 Jan 24.</citation>
    <PMID>22281431</PMID>
  </results_reference>
  <results_reference>
    <citation>Ojha R, Singh SK, Bhattacharyya S, Dhanda RS, Rakha A, Mandal AK, Jha V. Inhibition of grade dependent autophagy in urothelial carcinoma increases cell death under nutritional limiting condition and potentiates the cytotoxicity of chemotherapeutic agent. J Urol. 2014 Jun;191(6):1889-98. doi: 10.1016/j.juro.2014.01.006. Epub 2014 Jan 15.</citation>
    <PMID>24440234</PMID>
  </results_reference>
  <results_reference>
    <citation>Mukhopadhyay S, Sinha N, Das DN, Panda PK, Naik PP, Bhutia SK. Clinical relevance of autophagic therapy in cancer: Investigating the current trends, challenges, and future prospects. Crit Rev Clin Lab Sci. 2016 Aug;53(4):228-52. doi: 10.3109/10408363.2015.1135103. Epub 2016 Feb 16.</citation>
    <PMID>26743568</PMID>
  </results_reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>August 17, 2017</study_first_submitted>
  <study_first_submitted_qc>August 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 21, 2017</study_first_posted>
  <last_update_submitted>July 7, 2020</last_update_submitted>
  <last_update_submitted_qc>July 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Assiut University</investigator_affiliation>
    <investigator_full_name>Shaimaa Ramadan</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
  </condition_browse>
  <!-- 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/NCT03254888
org study id: ABC
nct id: NCT03254888
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
• Bladder cancer is the most common malignancy of the urinary tract. It represents the 7th
      most commonly diagnosed cancer in male population worldwide and drops to the 11th when both
      genders are considered . According to the American cancer society's estimates of bladder
      cancer in 2017, the number of the new cases of bladder cancer is 79,030, and the mortality
      figures reached 16,870 .
-  In Egypt, Bladder Cancer is the most prevalent malignancy among Egyptian males (16%)
           producing more than 7900 deaths annually . The majority of patients with bladder cancer
           about (70-80%) present with non-muscle invasive bladder cancer .

        -  Autophagy is a highly conserved catabolic process that degrades cellular organelles and
           proteins to maintain cellular biosynthesis during stress ; cancer cells induced
           autophagy to counteract with anticancer therapy by helping them to evade apoptotic
           pathway .Autophagy is achieved by many autophagy-related genes .

        -  Previous studies found that human bladder cancer cell lines exhibit high basal level of
           autophagic activity that may contribute to resistance to current anticancer treatment,
           so targeting basal autophagy may help to develop novel therapeutic strategies .
           Autophagy is potently induced by activating transcription factor 6(Endoplasmic Reticulum
           stress marker) , and Malondialdehyde (oxidative stress marker) .

        -  Recently several studies demonstrated the role of autophagy in Bladder Cancer
           progression as evidenced by detection of microtubule associated protein and its
           relevance with muscle invasion beside its grade dependency . Autophagy was grade
           dependent process . Autophagy related gene 7 is a key protein involved in autophagosomes
           biogenesis, Knockdown of Autophagy related gene 7 induced apoptotic cell death in
           bladder cancer cell lines measured by increased caspase 3 level, Based on these previous
           studies autophagy plays a role in bladder cancer progression so interruption of its
           pathway may serve a novel target for future therapies.
observational model: Case-Control
time perspective: Retrospective
measure: autophagy marker
time frame: baseline
description: differences in the level of Atg7(autophagy marker) in Low Grade bladder cancer and High Grade bladder cancer groups in comparison with safety margin and healthy control group.
measure: stress markers
time frame: baseline
description: Relation between LC3A and muscle invasiveness in bladder cancer progression, and relation between levels of ATF6, activating transcription factor6 (ER stress marker) -MDA malondialdehyde (oxidative stress marker)-Caspase3 (apoptotic marker) in different study groups and bladder cancer development.
arm group label: Low Grade group
description: • 50 tumor tissue samples from patients with Low Grade Bladder Cancer undergoing either trans urethral resection of bladder tumor or Radical Cystectomy ,
The followings markers must be estimated :
Autophagy markers:
( Atg7) level using (quantitative real time polymerase chain reaction).
(LC3A)level using immunohistochemistry .
ER-stress marker: (ATF6) level using ELISA(Enzyme Linked Immuno sorbent Assay)
Oxidative stress Marker:(MDA)using chemical method
Apoptotic marker:(caspase 3) using(quantitative real time polymerase chain reaction) .
arm group label: High Grade group
description: • 50 tumor tissue samples from patients with High Grade Bladder Cancer undergoing either trans urethral resection of bladder tumor or Radical Cystectomy,
The followings markers must be estimated :
Autophagy markers:
( Atg7) level using (quantitative real time polymerase chain reaction).
(LC3A)level using immunohistochemistry .
ER-stress marker: (ATF6) level using ELISA(Enzyme Linked Immuno sorbent Assay)
Oxidative stress Marker:(MDA)using chemical method
Apoptotic marker:(caspase 3) using (quantitative real time polymerase chain reaction) .
arm group label: Safety margin group
description: • 50 normal bladder urothelial tissue samples from the safety margin around the tumor(0.5cm to the tumor),
The followings markers must be estimated :
Autophagy markers:
( Atg7) level using (quantitative real time polymerase chain reaction).
(LC3A)level using immunohistochemistry .
ER-stress marker: (ATF6) level using ELISA(Enzyme Linked Immuno sorbent Assay)
Oxidative stress Marker:(MDA)using chemical method
Apoptotic marker:(caspase 3) using (quantitative real time polymerase chain reaction).
arm group label: Control group
description: • 50 (age and sex matched )control
The followings markers must be estimated :
Autophagy markers:
( Atg7) level using (quantitative real time polymerase chain reaction).
(LC3A)level using immunohistochemistry .
ER-stress marker: (ATF6) level using ELISA(Enzyme Linked Immuno sorbent Assay)
Oxidative stress Marker:(MDA)using chemical method
Apoptotic marker:(caspase 3) using (quantitative real time polymerase chain reaction)..
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Shaimaa Shakhoun
role: Principal Investigator
affiliation: Assiut
last name: MahaAli Essam-Eldeen Mohamed, lecturer
phone: 00201091570963
email: mahabadari@hotmail.com
last name: Shaimaa Shakhoun
phone: 00201001143867
email: atashaimaa8@gmail.com
facility: 
contact: 
country: Egypt
citation: Woldu SL, Bagrodia A, Lotan Y. Guideline of guidelines: non-muscle-invasive bladder cancer. BJU Int. 2017 Mar;119(3):371-380. doi: 10.1111/bju.13760. Epub 2017 Jan 24.
PMID: 28058776
citation: Mathew R, Karantza-Wadsworth V, White E. Assessing metabolic stress and autophagy status in epithelial tumors. Methods Enzymol. 2009;453:53-81. doi: 10.1016/S0076-6879(08)04004-4.
PMID: 19216902
citation: Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005 Sep;5(9):726-34. doi: 10.1038/nrc1692.
PMID: 16148885
citation: Mizushima N. Autophagy: process and function. Genes Dev. 2007 Nov 15;21(22):2861-73. doi: 10.1101/gad.1599207.
PMID: 18006683
citation: Lin YC, Lin JF, Wen SI, Yang SC, Tsai TF, Chen HE, Chou KY, Hwang TI. Inhibition of High Basal Level of Autophagy Induces Apoptosis in Human Bladder Cancer Cells. J Urol. 2016 Apr;195(4 Pt 1):1126-35. doi: 10.1016/j.juro.2015.10.128. Epub 2015 Oct 28.
PMID: 26519656
citation: Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52. doi: 10.1038/nrm2239.
PMID: 17717517
citation: Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011 Sep;10(9):1533-41. doi: 10.1158/1535-7163.MCT-11-0047. Epub 2011 Aug 30.
PMID: 21878654
citation: Sivridis E, Koukourakis MI, Mendrinos SE, Touloupidis S, Giatromanolaki A. Patterns of autophagy in urothelial cell carcinomas--the significance of "stone-like" structures (SLS) in transurethral resection biopsies. Urol Oncol. 2013 Oct;31(7):1254-60. doi: 10.1016/j.urolonc.2011.12.016. Epub 2012 Jan 24.
PMID: 22281431
citation: Ojha R, Singh SK, Bhattacharyya S, Dhanda RS, Rakha A, Mandal AK, Jha V. Inhibition of grade dependent autophagy in urothelial carcinoma increases cell death under nutritional limiting condition and potentiates the cytotoxicity of chemotherapeutic agent. J Urol. 2014 Jun;191(6):1889-98. doi: 10.1016/j.juro.2014.01.006. Epub 2014 Jan 15.
PMID: 24440234
citation: Mukhopadhyay S, Sinha N, Das DN, Panda PK, Naik PP, Bhutia SK. Clinical relevance of autophagic therapy in cancer: Investigating the current trends, challenges, and future prospects. Crit Rev Clin Lab Sci. 2016 Aug;53(4):228-52. doi: 10.3109/10408363.2015.1135103. Epub 2016 Feb 16.
PMID: 26743568
responsible party type: Principal Investigator
investigator affiliation: Assiut University
investigator full name: Shaimaa Ramadan
investigator title: Principal investigator
mesh term: Urinary Bladder Neoplasms