Endocrine Abstracts

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular thyroid C cells that produce calcitonin, accounting for 5%-10% of thyroid cancers. In all inherited cases of MTC, and in about 40% of sporadic cases, activating mutations of the receptor tyrosine kinase proto-oncogene RET are found. Signaling pathways involved in cell proliferation, survival and motility are triggered by constitutively active RET, but the mechanisms underlying mali...

Somatic mutations in splicing factor 3 subunit B1 (SF3B1) were found in about 20% of PRL-secreting PitNETs. SF3B1 is involved in pre-mRNA splicing and required for assembly of the U2 complex, which is critical for branch site recognition and the early stages of spliceosome assembly. Patients with mutant prolactinomas showed higher PRL levels and shorter progression-free survival compared to wild-type patients. Aims of the present study were: 1) to characterize the genetic prof...

Dopamine receptor type 2 (DRD2) agonists (DA) are the first-choice treatment for prolactin (PRL)-secreting pituitary tumors, but poorly effective in non-functioning (NF)-PitNETs. Along with G protein-dependent signaling, DRD2 also mediates non-canonical beta-arrestin-dependent pathways, where reduction of AKT phosphorylation plays a leading role for the antiproliferative effect of DRD2 in pituitary tumors. Through UNC9994 and MLS1547, a beta-arrestin 2-biased and a G protein-b...

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...

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...

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...

The mTOR inhibitor everolimus has been shown to display antimitotic effects on diverse neoplasms, including pituitary neuroendocrine tumors (PitNETs); however, its effect is reduced by an escape mechanism that increases AKT phosphorylation (P-AKT) leading to survival pathway activation. Dopamine receptor type 2 (DRD2) reduces p-AKT in some non-functioning PitNETs (NF-PitNETs) and in lactotrophs MMQ cells, through a α-arrestin 2-dependent mechanism. This study aim...

The main target of pharmacological therapy for growth hormone (GH)-secreting pituitary tumors (GH-PitNET) is the somatostatin receptor type 2 (SST2). However, approximately half of patients treated with octreotide, an SST2 agonist, show a low response rate or are octreotide-resistant. Here we present mechanistic data that shows co-treatment with simufilam, a novel oral therapeutic candidate, enhances sensitivity to octreotide. We previously showed that the cytoskeleton protein...