Endocrine Abstracts

Adrenocortical carcinomas (ACCs) are rare endocrine tumors with poor prognosis. They overexpress the insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR. The majority of studies focused on IGF1R as mediator of IGF2 biological effects, but recently a high expression of IR, in particular of the isoform A, was observed in most ACCs, suggesting a potential role of this receptor in modulating IGF2 effects in adrenocortical tumo...

Neuroendocrine tumors (NETs) and carcinomas (NECs) are a heterogeneous group of malignances whose incidence is increasing worldwide. First-line approach is represented by surgery, whereas an effective pharmacological treatment for disseminated and relapsing disease is still needed. Somatostatin (SS) receptors (SSTs) constitute the main suitable pharmacological targets for NETs therapy with SS analogs (SSAs). Nevertheless, a large proportion of NETs and most NECs, are unrespons...

Dopamine receptor type 2 (DRD2) agonists (DAs) are the first-choice treatment for PRL-secreting pituitary tumors due to their efficacy in reducing tumor size and hormonal secretion. However, DAs are poorly effective in non-functioning pituitary tumors (NFPTs), despite most of them express DRD2. No correlation between DAs clinical responsiveness and DRD2 expression was found, suggesting post-receptor alterations underlying resistance. DRD2 signaling pathways that control cell p...

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor of the parafollicular thyroid C cells. Although somatostatin (SS) receptors (SSTs) are expressed by MTCs, treatment with octreotide, specific for SST2, has shown poor efficacy in reducing MTC proliferation, whereas pasireotide, a multi-receptor SS analogue with preferential binding to SST5, has recently demonstrated antiproliferative effects in persistent postoperative MTCs. In vitro data in human MTC ce...

Cushing’s Disease (CD) is a rare condition mostly caused by an ACTH-secreting pituitary tumor resulting in excess of cortisol release by the adrenal glands. Although pasireotide is the only pituitary-targeted drug approved to treat adult patients, many side effects are encountered during the clinical practice and a curative therapy for CD is still challenging. Recently, the discover of somatic mutations in the deubiquitinase USP8 gene in a subset of patients has ...

Cushing’s Disease (CD) is a rare condition characterized by an overproduction of ACTH by an ACTH-secreting pituitary tumor resulting in excess of cortisol release by the adrenal glands. Somatic mutations in the deubiquitinases USP8 and USP48, and in BRAF genes, have been reported in a subset of patients affected by CD. Aim of this study was to characterize the genetic profile of a cohort of 66 patients with ACTH-secreting tumors, searching for somatic mutations in USP8, U...

Alternative splicing is a crucial mechanism of gene regulation and this process can be dysregulated in cancer. In pituitary tumors (PitNETs), alteration in the serine/arginine-rich splicing factors (SRSFs) has been reported. Newly synthetized SRSFs are phosphorylated by serine-arginine protein kinase 1 (SRPK1) to facilitate their nuclear import. In response to extracellular stimuli SRPK1 may translocate to the nucleus as well to hyperphosphorylate SRSFs and favor their interac...

Pheochromocytomas and paragangliomas (PPGL) are commonly benign catecholamine-producing neuroendocrine tumors (NETs); however, up to 25 % of patients develop distant metastases or aggressive behavior. The current classification of PPGL comprises pseudohypoxia-profile, MAPK-pathway alteration, and Wnt-pathway dysregulation clusters according to their genomic characterization. However, to date, there are no biomarkers to help stratify patients based on their prognosis. Alternati...

Lung neuroendocrine neoplasms (LungNENs) are highly heterogeneous tumors, which are classified by the WHO according to their histological grade into low grade: Typical Carcinoids (TC) and intermediate grade Atypical Carcinoids (AC), and high-grade: Large Cell Neuroendocrine Carcinoma (LCNEC) and Small Cell Lung Cancer (SCLC). Recently, a number of studies have tried to untangle the molecular features that define each subtype by applying different approaches, including genomic,...

Somatic mutations in the ubiquitin specific peptidase 8 (USP8) gene have been associated with higher levels of somatostatin (SS) receptor subtype 5 (SSTR5) in adrenocorticotroph hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs). However, a correlation between the USP8 mutational status and favorable responses to pasireotide, the somatostatin multi-receptor ligand acting especially on SSTR5, has not been investigated yet. Here, we studied the impact of USP8 mut...