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Signaling Pathways Targeting Colorectal Cancer in Egypt

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ClinicalTrials.gov Identifier: NCT03467308
Recruitment Status : Not yet recruiting
First Posted : March 16, 2018
Last Update Posted : March 16, 2018
Sponsor:
Information provided by (Responsible Party):
Asmaa Alaaeldeen Kamal Thabet, Assiut University

Brief Summary:
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide. In Egypt, CRC constitutes 4.2% of all cancers with median age is 50 years old.

Condition or disease Intervention/treatment
Colorectal Cancer Genetic: Markers in tissue samples: (TIGAR , TRIM59, P53, AKT, GSH)

Detailed Description:

The TP53-induced glycolysis and apoptosis regulator (TIGAR) is a transcriptional target of p53. TIGAR functions as a fructose-2,6-bisphosphatase, decreasing the flux through the main glycolytic pathway. Consequently, glucose metabolism diverted into the pentose phosphate pathway (PPP). This results in TIGAR-mediated increase in cellular NADPH production, which contributes to the scavenging of ROS by reduced glutathione and thus a lower sensitivity of cells to oxidative stress-associated apoptosis. PPP also produce ribose phosphate for DNA synthesis and repair that play a role in tumor development and cell survival in tumor microenvironment. A high expression level of TIGAR was observed in cancers such as breast cancer, hepatocellular carcinoma, intestinal cancer, and glioblastoma. These studies suggested that TIGAR may act as an oncogene that support cancer progression.

The tripartite motif containing 59 (TRIM) proteins have been implicated in many biological processes including cell differentiation, apoptosis, transcriptional regulation, and signaling pathways.

It is related to several cancers. The oncogenic effect of TRIM59 on tumor proliferation and migration has been studied in various cancers, including gastric cancer, osteosarcoma, lung and CRC. The biological activity of TRIM59 has been observed to be closely associated with the regulation of P53. TRIM59 interacts with P53, leading to P53 ubiquitination and degradation, and consequently promotes tumor growth and migration. TRIM59 functions as an oncogene in CRC progression. It also activates the PI3K/AKT pathway. Increased activity of this pathway is often associated with tumor progression and resistance to cancer therapies. AKT can control TIGAR protein translation by activation of mTOR.

Targeting TRIM59 inhibition will inhibit PI3K-Akt pathway downregulate TIGAR protein translation. This is in turn downregulates GSH levels, increases ROS production, leading to cell death and blocks the cellular proliferation and survival of cancer cells leading to tumor regression. Therefore, TRIM59 protein can serve as a new potential therapeutic target for CRC.


Study Type : Observational
Estimated Enrollment : 70 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Identification of New Signaling Pathways Targeting Colorectal Cancer in Egyptian Patients
Estimated Study Start Date : April 1, 2018
Estimated Primary Completion Date : March 1, 2019
Estimated Study Completion Date : March 1, 2020

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Colorectal cancer patients
50 Patients confirmed histopathologically to have early stages of colorectal cancer.
Genetic: Markers in tissue samples: (TIGAR , TRIM59, P53, AKT, GSH)

The followings markers will be investigated in tissue samples:

  1. TIGAR expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry.
  2. TRIM59 expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry.

P53 expression using immunohistochemistry. P53 nuclear localization is essential for its normal function in growth inhibition or induction of apoptosis.

  • Akt expression using western blot.
  • GSH using chemical methods.

Risky group
20 risky patients (those with ulcerative colitis, chron's disease, familial adenomatous polyposis).
Genetic: Markers in tissue samples: (TIGAR , TRIM59, P53, AKT, GSH)

The followings markers will be investigated in tissue samples:

  1. TIGAR expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry.
  2. TRIM59 expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry.

P53 expression using immunohistochemistry. P53 nuclear localization is essential for its normal function in growth inhibition or induction of apoptosis.

  • Akt expression using western blot.
  • GSH using chemical methods.




Primary Outcome Measures :
  1. Measure TIGAR in the study groups. [ Time Frame: 1 YEAR ]
    Measure TIGAR expression in colorectal cancer patients and risky group patients.

  2. Measure TRIM59 in the study groups. [ Time Frame: 1Year ]
    Measure TRIM59 expression in colorectal cancer patients and risky group patients.


Secondary Outcome Measures :
  1. Targeting new prognostic and therapeutic markers for colorectal cancer. [ Time Frame: 1 year ]
    Finding a relationship between TIGAR and TRIM 59 expression and PI3K/AKT pathway as a major signaling mechanism in tumorigenesis for targeting new prognostic and therapeutic markers for colorectal cancer.


Biospecimen Retention:   Samples With DNA
tumor tissue samples and normal intestinal tissue samples from the safety margin around the tumor


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
  • All Patients confirmed histopathologically to have early stages of colorectal cancer admitted to General Surgery Department -Assiut University Hospital for CRC resection.
  • Risky group patients (including those with ulcerative colitis, chron's disease, familial adenomatous polyposis) undergoing diagnostic colonoscopy.
Criteria

Inclusion Criteria:

  • All Patients confirmed histopathologically to have early stages of colorectal cancer.
  • Risky group patients (including those with ulcerative colitis, chron's disease, familial adenomatous polyposis).

Exclusion Criteria:

  • Patients with previous history of CRC treated with chemotherapy or presence of other types of cancer.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03467308


Contacts
Contact: Ragaa Hamdy Salama, Professor (MD) 00201063492008 ragaa_2002@yahoo.com
Contact: Maha Ali Essam al-Din, lecturer (MD) 00201091570963 mahabadari@hotmail.com

Locations
Egypt
Assiut University- faculty of medicine -Medical biochemistry department Not yet recruiting
Assiut, Egypt, 71111
Contact: Ragaa Hamdy Salama, MD    00201063492008    ragaa_2002@yahoo.com   
Contact: Maha Ali Essam al-Din, MD    00201091570963    mahabadari@hotmail.com   
Sponsors and Collaborators
Assiut University
Investigators
Principal Investigator: Asmaa Alaaeldeen Kamal, MD (PhD student) Assiut University
Study Director: Ragaa Hamdy Salama, Professor (MD) Assiut University
Study Director: Maha Ali Essam al-Din, lecturer (MD) Assiut University
Study Director: Marwa AbdelHafiz Abdel Hassan, lecturer (MD) Assiut University
Study Director: Ahmed Ali Abdel Motelb, lecturer (MD) Assiut University

Publications:

Responsible Party: Asmaa Alaaeldeen Kamal Thabet, Principal Investigator, Assiut University
ClinicalTrials.gov Identifier: NCT03467308     History of Changes
Other Study ID Numbers: CRC18
First Posted: March 16, 2018    Key Record Dates
Last Update Posted: March 16, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Asmaa Alaaeldeen Kamal Thabet, Assiut University:
colorectal cancer
TIGAR
TRIM59

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases