Oxidative Stress and Mitochondrial TERT in Papillary Thyroid Cancer.

Papillary Thyroid Cancer Clinical Trial

— TEMPEST  

Official title:

The Role of Oxidative Stress and Mitochondrial TERT in the Progression and Therapeutic Resistance of Papillary Thyroid Cancer.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05752669
• Other study ID #: 05M902
• Status: Recruiting
• Start date: September 15, 2021
• Est. completion date: May 31, 2024

Study information

• Verified date: February 2023
• Source: Istituto Auxologico Italiano
• Contact: Marina Muzza, PhD
• Phone: +390261911
• Email: m.muzza[@]auxologico.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: May 31, 2024
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Papillary Thyroid Cancer
• Thyroid Cancer, Papillary
• Thyroid Diseases
• Thyroid Neoplasms

Locations

Country	Name	City	State
Italy	Istituto Auxologico Italiano	Milan

Sponsors (1)

Lead Sponsor	Collaborator
Istituto Auxologico Italiano

Country where clinical trial is conducted

Italy, 

References & Publications (5)

Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014 Oct 23;159(3):676-90. doi: 10.1016/j.cell.2014.09.050. — View Citation

Coperchini F, Croce L, Denegri M, Awwad O, Ngnitejeu ST, Muzza M, Capelli V, Latrofa F, Persani L, Chiovato L, Rotondi M. The BRAF-inhibitor PLX4720 inhibits CXCL8 secretion in BRAFV600E mutated and normal thyroid cells: a further anti-cancer effect of BRAF-inhibitors. Sci Rep. 2019 Mar 13;9(1):4390. doi: 10.1038/s41598-019-40818-w. — View Citation

Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan;26(1):1-133. doi: 10.1089/thy.2015.0020. — View Citation

Muzza M, Colombo C, Cirello V, Perrino M, Vicentini L, Fugazzola L. Oxidative stress and the subcellular localization of the telomerase reverse transcriptase (TERT) in papillary thyroid cancer. Mol Cell Endocrinol. 2016 Aug 15;431:54-61. doi: 10.1016/j.mce.2016.05.005. Epub 2016 May 7. — View Citation

Pesenti C, Muzza M, Colombo C, Proverbio MC, Fare C, Ferrero S, Miozzo M, Fugazzola L, Tabano S. MassARRAY-based simultaneous detection of hotspot somatic mutations and recurrent fusion genes in papillary thyroid carcinoma: the PTC-MA assay. Endocrine. 2018 Jul;61(1):36-41. doi: 10.1007/s12020-017-1483-2. Epub 2017 Dec 6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	H202 generation (nmol/mg tissue) in papillary thyroid cancer and in corresponding normal tissues.		months 1-24
Primary	TERT mitochondrial localization (TERT/VDAC) in papillary thyroid tumors.	TERT mitochondrial localization will be investigated by Western blot of mitochondrial fractions and normalized to VDAC protein expression.	months 13-30
Primary	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.	TERT mitochondrial translocation will be measured by immunofluorescence.	month 19-30
Primary	Mitochondrial oxidative stress generation in cells lines treated with Src kinase inhibitors.	Mitochondrial oxidative stress will be measured by immunofluorescence.	months 25-36
Primary	Proliferation in cells lines treated with Src kinase inhibitors.	Proliferation will be measured by a colorimetric assay.	months 25-36
Primary	Apoptosis in cells lines treated with Src kinase inhibitors.	Apoptosis will be measured by a luminometric assay.	months 25-36
Primary	Migration in cells lines treated with Src kinase inhibitors.	Migration will be measured by wound healing assays.	months 25-36
Secondary	Genetic characterization of tumor tissues.	Point mutations and fusions will be investigated in DNA and RNA, respectively,	months 1-24
Secondary	Expression profile of tumor tissues.	The expression level of 16 thyroid function genes will be investigated by a custom RNA sequencing panel.	months 1-24

External Links

•   PubMed ID: 25417114
•   PubMed ID: 26462967
•   PubMed ID: 27164443
•   PubMed ID: 29214440
•   PubMed ID: 30867499