Signaling Pathways Targeting Colorectal Cancer in Egypt

Colorectal Cancer Clinical Trial

Official title:

Identification of New Signaling Pathways Targeting Colorectal Cancer in Egyptian Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03467308
• Other study ID #: CRC18
• Status: Completed
• Start date: March 1, 2018
• Est. completion date: April 1, 2020

Study information

• Verified date: May 2020
• Source: Assiut University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 180
• Est. completion date: April 1, 2020
• Est. primary completion date: January 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

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.

Locations

Country	Name	City	State
Egypt	Assiut University- faculty of medicine -Medical biochemistry department	Assiut

Sponsors (1)

Lead Sponsor	Collaborator
Assiut University

Country where clinical trial is conducted

Egypt, 

References & Publications (9)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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-?B pathway modulation. Int J Oncol. 2016 Feb;48(2):756-64. doi: 10.3892/ijo.2015.3297. Epub 2015 Dec 17. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measure TIGAR in the study groups.	Measure TIGAR expression in colorectal cancer patients and risky group patients.	1 YEAR
Primary	Measure TRIM59 in the study groups.	Measure TRIM59 expression in colorectal cancer patients and risky group patients.	1Year
Secondary	Targeting new prognostic and therapeutic markers for colorectal cancer.	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.	1 year