Poster Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

In vitro antineoplastic effects of the kinase inhibitor CLM24 in aggressive dedifferentiated thyroid cancer (128705)

Silvia Martina Ferrari 1 , Francesca Ragusa 1 , Giusy Elia 1 , Valeria Mazzi 1 , Eugenia Balestri 1 , Chiara Botrini 1 , Licia Rugani 1 , Simona Piaggi 2 , Concettina La Motta 3 , Giulia Antonelli 1 , Salvatore Ulisse 4 , Camilla Virili 5 , Gilda Varricchi 6 7 8 , Giulia Cantini 9 10 11 , Oriana Fabrazzo 1 , Elena Catania Romizi 1 , Maria Giorgia Martino 1 , Michaela Luconi 9 10 11 , Gabriele Materazzi 1 , Alessandro Antonelli 1 , Poupak Fallahi 2
  1. Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
  2. Department of Translational Research & New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
  3. Department of Pharmacy, University of Pisa, Pisa, Italy
  4. Department of Surgery, “Sapienza” University of Rome, Rome, Italy
  5. Department of Medico-Surgical Sciences and Biotechnologies, Endocrinology Section, “Sapienza” University of Rome, Latina, Italy
  6. Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
  7. World Allergy Organization (WAO) Center of Excellence, Naples, Italy
  8. Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, Naples, Italy
  9. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
  10. European Network for the Study of Adrenal Tumors (ENS@T) Center of Excellence, Florence, Italy
  11. Centro Di Ricerca E Innovazione Sulle Patologie Surrenaliche, AOU Careggi, Florence, Italy

Aims Thyroid cancer is the most frequently diagnosed cancer among endocrine tumors. Surgery is the standard therapeutic strategy for patients with differentiated thyroid carcinomas (DTC). After thyroidectomy radioactive iodine (RAI) treatment is used to ablate residual thyroidal tissues. When DTC progresses, cells can develop refractoriness to RAI, impacting negatively the prognosis. The available therapeutical strategies (i.e., surgery, chemotherapy and external beam radiation therapy) can cause significant side effects with no prolongation of survival. Thus, it may be worthy to delineate an effective systemic therapy in patients with dedifferentiated DTC (De-DTC) to ameliorate their quality of life. In the next future, the success of treatments may be increased by novel and more effective antineoplastic compounds. Testing the sensitivity of human primary DeDTC cells obtained from each subject, to different drugs, could determinate an increase in the effectiveness of the treatment avoiding the administration of inactive therapeutics.

 

Methods In this study we planned to evaluate in vitro the antineoplastic effects of CLM24, a compound with pyrazolo[3,4-d]pyrimidine nucleus, in human primary De-DTC cell cultures and in the AF cell line, derived from primary anaplastic TC cells.

Results CLM24 demonstrated a significant antiproliferative action on the AF cell line (with BRAF V600E mutation), and a significant pro-apoptotic effect. In primary De-DTC cells with/without V600EBRAF mutation, CLM24 reduced significantly the proliferation (vs. control), while did not in primary normal thyroid follicular cells. In De-DTC cells with/without V600EBRAF mutation, the ratio of apoptotic cells increased in a dose dependent manner after treatment with CLM24, which also significantly inhibited cell migration and invasion.

Conclusion The pyrazolo[3,4-d]pyrimidine derivative CLM24 demonstrated a potent antineoplastic effect in vitro in primary De-DTC cells, and this effect did not depend on the presence/absence of the V600EBRAF mutation. These promising results make CLM24 worthy of further investigation for a possible clinical trial.