Molecular pathways and emerging therapeutic strategies in advanced thyroid cancer: from targeted therapy to precision oncology.

Anaplastic thyroid cancer: genomic landscape, molecular drivers and novel therapeutics.

TARGETED THERAPY AND IMMUNOTHERAPY IN COMBINED ANAPLASTIC AND PAPILLARY THYROID CARCINOMA WITH BRAF V600E MUTATION AND PD-L1 EXPRESSION: A CLINICAL CASE

Relevance: Thyroid cancer is one of the most common malignant neoplasms of the endocrine system, demonstrating a steady increase in incidence worldwide. Particular attention among thyroid malignancies is drawn to anaplastic thyroid carcinoma (ATC), a rare but extremely aggressive form of the disease. Although it accounts for less than 2% of all thyroid cancers, anaplastic thyroid carcinoma is responsible for the majority of thyroid cancer-related mortality. ATC is characterized by a fulminant clinical course, rapid local progression, early metastasis, and marked resistance to conventional treatment methods, including surgery, radiotherapy, and chemotherapy. The median survival after diagnosis usually does not exceed 6-12 months, highlighting the poor prognosis of this disease. Thus, ATC remains one of the most challenging and unresolved problems in modern oncology, requiring further investigation, improvements in early diagnostic approaches, and the development of novel therapeutic strategies.The study aimed to evaluate the effectiveness of targeted therapy and immunotherapy in a patient with anaplastic thyroid cancer with the BRAFV600E mutation and PD-L1 expression.Materials and Methods: A clinical case of a 70-year-old female patient diagnosed with T4N1M1 stage IV anaplastic thyroid carcinoma is presented.Results: After surgical treatment and two courses of polychemotherapy, disease progression was observed with enlargement of metastatic lesions in the lungs and the appearance of subcutaneous dissemination. Molecular genetic testing revealed a BRAF V600E mutation; therefore, targeted therapy with a combination of dabrafenib and trametinib was initiated. During treatment, a short-term partial response lasting approximately 3 months was achieved, accompanied by a reduction in metastatic lesion size and improvement in clinical condition. Subsequently, further disease progression was noted. Given the high PD-L1 expression (TPS 100%), pembrolizumab was administered, but no clinical benefit was observed. The patient died shortly after the initiation of treatment. Targeted therapy provided only a temporary effect in the setting of aggressive disease progression.Conclusion: Targeted therapy demonstrates temporary efficacy in anaplastic thyroid carcinoma; however, the development of resistance and the aggressive nature of the disease significantly limit long-term treatment outcomes.

Advances in FGFR Inhibition for Bladder Cancer: A Review of Molecular Targets and Therapeutic Progress

Bladder cancer (BC) ranks among the most prevalent urological malignancies globally, presenting with a wide spectrum of clinical behavior from non-muscle-invasive to deeply invasive and metastatic forms. Despite progress in surgical interventions, chemotherapy, and immunotherapy, challenges such as high recurrence rates and therapeutic resistance persist, particularly in advanced disease stages. This review provides an indepth analysis of current understanding of BC, including its epidemiology, classification, diagnostic tools, and standard treatment approaches. Special attention is given to the fibroblast growth factor receptor (FGFR) signaling pathway, a key molecular driver increasingly recognized for its role in tumor progression. Alterations in FGFR, especially FGFR3 mutations and gene fusions, are frequently observed in non-muscle-invasive and luminal subtypes and carry important prognostic and therapeutic implications. The recent clinical approval of FGFR inhibitors, such as erdafitinib, marks a promising advancement in precision oncology, offering targeted options for patients with FGFR-altered tumors. Ongoing clinical trials are exploring combinatorial therapies and resistance mechanisms to further enhance outcomes. A more thorough knowledge of FGFR-driven oncogenesis is essential for developing more refined, personalized treatment strategies. This review underscores the transformative potential of molecular profiling and FGFR-targeted therapies in the evolving management of bladder cancer.

Signaling pathways and targeted therapy in high-risk refractory thyroid cancer: From bench to bedside (Review)

Thyroid cancer is the most common endocrine malignancy worldwide, with its incidence increasing markedly over the past several decades, while mortality trends have shown complex patterns. High-risk refractory thyroid cancers (including radioactive iodine-refractory differentiated thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid carcinoma, progressive medullary thyroid carcinoma and locally advanced disease) pose major challenges in clinical management. The present review systematically reviewed recent epidemiological trends in thyroid cancer and provided an in-depth exploration of the molecular regulatory mechanisms of key signaling pathways, including MAPK, PI3K/AKT, Janus kinase/STAT, WNT/β-catenin and NF-κB, along with their roles in the pathogenesis and progression of thyroid cancer. Based on this, the latest clinical research advances in targeted therapies for high-risk, refractory thyroid cancer are elaborated on, covering multikinase inhibitors, B-Raf proto-oncogene, serine/threonine kinase/mitogen-activated protein kinase kinase inhibitors, immunotherapy combinations, innovative targeted strategies and redifferentiation approaches. Finally, future directions are discussed based on the 'total treatment' paradigm and strategies to overcome drug resistance, aiming to provide a systematic reference for basic research and clinical translation in thyroid cancer.

Current status and targeted therapies in endometrial cancer: Molecular classification-driven treatment strategies (Review)

Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. Although numerous patients are diagnosed at an early stage with favorable outcomes, advanced and metastatic disease remains associated with limited therapeutic options and poor prognosis. Advances in molecular characterization have reshaped the understanding of EC pathogenesis and enabled the development of classification-driven treatment strategies. The present review summarized current standard therapies, including surgery, chemotherapy and radiotherapy, and highlighted the growing role of molecularly targeted treatments. The integration of pathogenetic, histopathological and molecular classifications provides a framework for identifying actionable alterations. Key oncogenic signaling pathways, including PI3K/AKT/mTOR and RAS/RAF/MEK/ERK, were discussed in the context of therapeutic targeting and precision medicine. In addition, emerging strategies, particularly immunotherapy and combination approaches, were addressed. A deeper understanding of molecular heterogeneity may facilitate individualized treatment selection and improve clinical outcomes in patients with EC.

RET Alterations in Thyroid Cancer: Molecular Mechanisms, Targeted Therapies, and Emerging Resistance.

RET alterations, including RET fusions and RET mutations, have been identified in thyroid cancer. RET fusions are predominantly found in papillary thyroid carcinoma, whereas RET mutations are primarily associated with medullary thyroid carcinoma. Consequently, RET has emerged as an attractive therapeutic target. Previously, multikinase inhibitors, such as vandetanib and cabozantinib, were primarily used for treatment; however, their efficacy was limited due to off-target effects. Recently, selective tyrosine kinase inhibitors, including selpercatinib and pralsetinib, have been introduced, demonstrating improved selectivity and clinical efficacy. Nevertheless, challenges such as gatekeeper and solvent-front mutations have emerged, contributing to acquired drug resistance. To address this issue, next-generation RET inhibitors, including zeteletinib and SYHA1815, are currently under investigation, reflecting an expanding therapeutic landscape. This article provides an overview of the molecular mechanisms of RET alterations in thyroid cancer, targeted therapies, and emerging resistance to targeted treatment.