Clinical trial NCT05752669: Oxidative Stress and Mitochondrial TERT in Papillary Thyroid Cancer.
Official title: The Role of Oxidative Stress and Mitochondrial TERT in the Progression and Therapeutic Resistance of Papillary Thyroid Cancer.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Papillary Thyroid Cancer
Lead sponsor: Istituto Auxologico Italiano
Sponsor class: OTHER
First posted: 2023-03-03
Enrollment: 100
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients operated for papillary thyroid cancer and followed by our Center of Excellence for the Diagnosis and Treatment of Thyroid Tumors.

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.


Eligibility criteria: 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

Primary outcomes:
measure: H202 generation (nmol/mg tissue) in papillary thyroid cancer and in corresponding normal tissues.
timeFrame: months 1-24
measure: TERT mitochondrial localization (TERT/VDAC) in papillary thyroid tumors.
timeFrame: months 13-30
measure: 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.
timeFrame: month 19-30
measure: Mitochondrial oxidative stress generation in cells lines treated with Src kinase inhibitors.
timeFrame: months 25-36
measure: Proliferation in cells lines treated with Src kinase inhibitors.
timeFrame: months 25-36
measure: Apoptosis in cells lines treated with Src kinase inhibitors.
timeFrame: months 25-36
measure: Migration in cells lines treated with Src kinase inhibitors.
timeFrame: months 25-36
Secondary outcomes:
measure: Genetic characterization of tumor tissues.
timeFrame: months 1-24
measure: Expression profile of tumor tissues.
timeFrame: months 1-24
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Istituto Auxologico Italiano
Study officials:
affiliation: Istituto Auxologico Italiano
name: Marina Muzza, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: 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.
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.
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.