Oxidative Stress and Mitochondrial TERT in Papillary Thyroid Cancer.

Recruiting

• Conditions: Papillary Thyroid Cancer

• Registration Number: NCT05752669
• Lead Sponsor: Istituto Auxologico Italiano

Brief Summary

Oxidative stress (OS) could be involved in the progression of papillary thyroid cancer (PTC). Indeed, thyroid differentiation genes are silenced by a mechanism controlled by NOX4-derived OS. On the other hand, TERT contributes to mitochondrial OS protection, which could increase the resistance of cancer cells to therapeutic agents. The investigators aim to address the role of OS and mitochondrial TERT in the progression and therapeutic resistance of PTC. OS and TERT subcellular localization will be investigated in 150 PTCs and correlated to the genetic and expression profile of the tumors and to the clinical and prognostic features of the patients. Mechanisms implicated in TERT mitochondrial migration and the contribution of mitochondrial TERT to tumor progression will be investigated in cancer cell lines and primary cell cultures. This study will allow to identify OS as a marker of therapeutic resistance in PTC and will open new opportunities for the development of novel treatments targeting ROS generation/TERT nuclear export.

Detailed Description

Not available

Study Timeline

• Study Start: 2021-09-15
• Status Verified: 2023-02
• Study First Submitted: 2023-02-21
• Study First Submitted QC: 2023-02-21
• Last Update Submitted: 2023-03-02
• Study First Posted: 2023-03-03
• Last Update Posted: 2023-03-06
• Primary Completion: 2023-12-01
• Study Completion: 2024-05-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Patients with papillary thyroid cancer
• Patients whose tumor and contralateral healthy tissues can be collected for the analyses

Exclusion Criteria

• patients who did not provide consent
• patients lost at follow-up
• tissues not adequate for the analyses

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
TERT mitochondrial localization (TERT/VDAC) in papillary thyroid tumors.	months 13-30	TERT mitochondrial localization will be investigated by Western blot of mitochondrial fractions and normalized to VDAC protein expression.
Proliferation in cells lines treated with Src kinase inhibitors.	months 25-36	Proliferation will be measured by a colorimetric assay.
Apoptosis in cells lines treated with Src kinase inhibitors.	months 25-36	Apoptosis will be measured by a luminometric assay.
Mitochondrial oxidative stress generation in cells lines treated with Src kinase inhibitors.	months 25-36	Mitochondrial oxidative stress will be measured by immunofluorescence.
H202 generation (nmol/mg tissue) in papillary thyroid cancer and in corresponding normal tissues.	months 1-24
Effect of exogenous oxidative stress (H2O2) and therapeutic agents (BRAF, MEK and Src kinase inhibitors) on TERT nuclear to mitochondrial translocation in thyroid cancer cell lines.	month 19-30	TERT mitochondrial translocation will be measured by immunofluorescence.
Migration in cells lines treated with Src kinase inhibitors.	months 25-36	Migration will be measured by wound healing assays.

Secondary Outcome Measures

Name	Time	Method
Expression profile of tumor tissues.	months 1-24	The expression level of 16 thyroid function genes will be investigated by a custom RNA sequencing panel.
Genetic characterization of tumor tissues.	months 1-24	Point mutations and fusions will be investigated in DNA and RNA, respectively,

Trial Locations

Locations (1)

Istituto Auxologico Italiano; 🇮🇹 Milan, Italy