Targeting BRAF for patients with melanoma

The prognosis of patients with metastatic melanoma is poor and not influenced by systemic therapy with cytotoxic drugs. New targeted agents directed against the RAS-RAF-MEK-ERK pathway show promising activity in early clinical development and particular interest is focused on selective inhibitors of mutant BRAF, which is present in one half of the cases of metastatic melanoma. The majority of patients on early trials of these drugs develop secondary resistance and subsequent disease progression and it is, therefore, critical to understand the underlying escape mechanisms leading to resistance

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

João Vinagre, Vasco Pinto and Ricardo Celestino contributed equally to the manuscript.Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the “alternative mechanism of telomere lengthening” (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and non-neoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target

Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

Background Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. Main body The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Conclusion Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.info:eu-repo/semantics/publishedVersio

Rapamycin treatment impairs the proliferation of thyroid carcinoma cells in an oncogene-dependent manner

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Molecular characterisation of cutaneous melanoma

Introduction: Cutaneous melanoma (CM) is the least frequent but deadliest kind of skin cancer, highlighting the aggressiveness of these tumors. As a result of prolonged exposure to UV radiation, CM harbors one of the highest mutation rates among all malignancies. The three most common mutations occur in BRAF and NRAS genes, both important for the mitogen-activated protein kinase pathway upregulation, and in the telomerase reverse transcriptase promoter, which is linked to a poor prognosis. Although current therapies have improved patients’ overall survival, low response rates and treatment resistance remain major challenges for melanoma treatment. Therefore, melanoma investigations have shifted their interest to microRNAs (miRNAs), like miR-125a, miR- 155, and miR- 579, noncoding RNAs that affect the hallmarks of cancer and are potential melanoma biomarkers. Project Aim: To study the molecular alterations of melanomas, to correlate them with the patients’ clinicopathological data and follow-up, and to identify possible prognostic and/or therapeutic biomarkers. Materials and Methods: The mutational status analysis was performed by the Sanger method in primary tumors, metastatic lymph nodes, and metastases collected at Hospital de Santarém and Hospital dos Capuchos. Whereas miRNA expression, from primary tumors collected at Hospital de Santarém, was analyzed by RT-PCR Results: The median age of the studied series was 65 years, where most.info:eu-repo/semantics/publishedVersio