Signaling Pathways Targeting Colorectal Cancer in Egypt

Overview

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.

Full Title of Study: “Identification of New Signaling Pathways Targeting Colorectal Cancer in Egyptian Patients”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: January 1, 2020

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.

Interventions

  • Genetic: Markers in tissue samples: (TIGAR , TRIM59, P53, AKT, GSH)
    • The followings markers will be investigated in tissue samples: TIGAR expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry. 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.

Arms, Groups and Cohorts

  • Colorectal cancer patients
    • 50 Patients confirmed histopathologically to have early stages of colorectal cancer.
  • Risky group
    • 20 risky patients (those with ulcerative colitis, chron’s disease, familial adenomatous polyposis).

Clinical Trial Outcome Measures

Primary Measures

  • Measure TIGAR in the study groups.
    • Time Frame: 1 YEAR
    • Measure TIGAR expression in colorectal cancer patients and risky group patients.
  • Measure TRIM59 in the study groups.
    • Time Frame: 1Year
    • Measure TRIM59 expression in colorectal cancer patients and risky group patients.

Secondary Measures

  • 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.

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Assiut University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Asmaa Alaaeldeen Kamal Thabet, Principal Investigator – Assiut University
  • Overall Official(s)
    • Asmaa Alaaeldeen Kamal, MD (PhD student), Principal Investigator, Assiut University
    • Ragaa Hamdy Salama, Professor (MD), Study Director, Assiut University
    • Maha Ali Essam al-Din, lecturer (MD), Study Director, Assiut University
    • Marwa AbdelHafiz Abdel Hassan, lecturer (MD), Study Director, Assiut University
    • Ahmed Ali Abdel Motelb, lecturer (MD), Study Director, Assiut University

References

Yang J, Wen J, Tian T, Lu Z, Wang Y, Wang Z, Wang X, Yang Y. GLUT-1 overexpression as an unfavorable prognostic biomarker in patients with colorectal cancer. Oncotarget. 2017 Feb 14;8(7):11788-11796. doi: 10.18632/oncotarget.14352.

Cheung EC, Athineos D, Lee P, Ridgway RA, Lambie W, Nixon C, Strathdee D, Blyth K, Sansom OJ, Vousden KH. TIGAR is required for efficient intestinal regeneration and tumorigenesis. Dev Cell. 2013 Jun 10;25(5):463-77. doi: 10.1016/j.devcel.2013.05.001. Epub 2013 May 30.

Won KY, Lim SJ, Kim GY, Kim YW, Han SA, Song JY, Lee DK. Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer. Hum Pathol. 2012 Feb;43(2):221-8. doi: 10.1016/j.humpath.2011.04.021. Epub 2011 Aug 4.

Zhao M, Fan J, Liu Y, Yu Y, Xu J, Wen Q, Zhang J, Fu S, Wang B, Xiang L, Feng J, Wu J, Yang L. Oncogenic role of the TP53-induced glycolysis and apoptosis regulator in nasopharyngeal carcinoma through NF-kappaB pathway modulation. Int J Oncol. 2016 Feb;48(2):756-64. doi: 10.3892/ijo.2015.3297. Epub 2015 Dec 17.

Zhou Z, Ji Z, Wang Y, Li J, Cao H, Zhu HH, Gao WQ. TRIM59 is up-regulated in gastric tumors, promoting ubiquitination and degradation of p53. Gastroenterology. 2014 Nov;147(5):1043-54. doi: 10.1053/j.gastro.2014.07.021. Epub 2014 Jul 18.

Liang J, Xing D, Li Z, Shen J, Zhao H, Li S. TRIM59 is upregulated and promotes cell proliferation and migration in human osteosarcoma. Mol Med Rep. 2016 Jun;13(6):5200-6. doi: 10.3892/mmr.2016.5183. Epub 2016 Apr 25.

Zhan W, Han T, Zhang C, Xie C, Gan M, Deng K, Fu M, Wang JB. TRIM59 Promotes the Proliferation and Migration of Non-Small Cell Lung Cancer Cells by Upregulating Cell Cycle Related Proteins. PLoS One. 2015 Nov 24;10(11):e0142596. doi: 10.1371/journal.pone.0142596. eCollection 2015.

Sun Y, Ji B, Feng Y, Zhang Y, Ji D, Zhu C, Wang S, Zhang C, Zhang D, Sun Y. TRIM59 facilitates the proliferation of colorectal cancer and promotes metastasis via the PI3K/AKT pathway. Oncol Rep. 2017 Jul;38(1):43-52. doi: 10.3892/or.2017.5654. Epub 2017 May 22.

Ahmad R, Alam M, Hasegawa M, Uchida Y, Al-Obaid O, Kharbanda S, Kufe D. Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer. Mol Cancer. 2017 Feb 2;16(1):33. doi: 10.1186/s12943-017-0608-9.

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.