Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter.

The sodium iodide symporter (NIS) functions to transport iodide and is critical for successful radioiodide ablation of cancer cells. Approaches to bolster NIS function and diminish recurrence post-radioiodide therapy are impeded by oncogenic pathways that suppress NIS, as well as the inherent complexity of NIS regulation. Here, we utilize NIS in high-throughput drug screening and undertake rigorous evaluation of lead compounds to identify and target key processes underpinning NIS function. We find that multiple proteostasis pathways, including proteasomal degradation and autophagy, are central to the cellular processing of NIS. Utilizing inhibitors targeting distinct molecular processes, we pinpoint combinatorial drug strategies giving robust >5-fold increases in radioiodide uptake. We also reveal significant dysregulation of core proteostasis genes in human tumors, identifying a 13-gene risk score classifier as an independent predictor of recurrence in radioiodide-treated patients. We thus propose and discuss a model for targetable steps of intracellular processing of NIS function.

Update on Fundamental Mechanisms of Thyroid Cancer.

The incidence of thyroid cancer (TC) has increased worldwide over the past four decades. TC is divided into three main histological types: differentiated (papillary and follicular TC), undifferentiated (poorly differentiated and anaplastic TC), and medullary TC, arising from TC cells. This review discusses the molecular mechanisms associated to the pathogenesis of different types of TC and their clinical relevance. In the last years, progresses in the genetic characterization of TC have provided molecular markers for diagnosis, risk stratification, and treatment targets. Recently, papillary TC, the most frequent form of TC, has been reclassified into two molecular subtypes, named BRAF-like and RAS-like, associated to a different range of cancer risks. Similarly, the genetic characterization of follicular TC has been proposed to complement the new histopathological classification in order to estimate the prognosis. New analyses characterized a comprehensive molecular profile of medullary TC, raising the role of RET mutations. More recent evidences suggested that immune microenvironment associated to TC may play a critical role in tumor invasion, with potential immunotherapeutic implications in advanced and metastatic TC. Several types of ancillary approaches have been developed to improve the diagnostic value of fine needle aspiration biopsies in indeterminate thyroid nodules. Finally, liquid biopsy, as a non-invasive diagnostic tool for body fluid genotyping, brings a new prospective of disease and therapy monitoring. Despite all these novelties, much work remains to be done to fully understand the pathogenesis and biological behaviors of the different types of TC and to transfer this knowledge in clinical practice.

NEP-Score Thresholds Predict Survival of Patients With Bronchial Carcinoids.

Survival prognostic markers are extremely needed to better define therapeutic strategies in patients with bronchial carcinoids (BC). We aim to verify the applicability of the NEP-Score in a homogeneous BC cohort and identify a derivative prognostic marker, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up. Sixty-four patients (38 females, and 26 males, mean age at diagnosis 58.9 ± 1.7 years) with BC were retrospectively evaluated. NEP-Score was calculated at the end of follow-up (NEP-T). A derivative score, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up, was then assessed. Patients were subdivided according to their living status at the end of follow-up. A NEP-Score threshold was investigated to predict survival. Mean NEP-T and mean NEP-D were significantly lower in live patients at end of follow-up. A NEP-T cut-off >138 significantly predicts survival. Atypical BC relapsed more frequently than Typical BC. Male gender and previous malignancy were negative prognostic factors for survival. We confirmed NEP-Score applicability in BC and NEP-D utility, being the latter a simple, quick, and cheap prognostic score that can help clinicians in decision making. The identified NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy. In this context, a validation study is needed.

Peptides derived from the extracellular domain of the somatostatin receptor splicing variant SST5TMD4 increase malignancy in multiple cancer cell types.

Extracellular fragments derived from plasma membrane receptors can play relevant roles in the development/progression of tumor pathologies, thereby offering novel diagnostic or therapeutic opportunities. The truncated variant of somatostatin receptor subtype-5, SST5TMD4, is an aberrantly spliced receptor with 4 transmembrane domains, highly overexpressed in several tumor types, whose C-terminal tail is exposed towards the extracellular matrix, and could therefore be the substrate for proteolytic enzymes. In silico analysis implemented herein predicted 2 possible cleavage sites for metalloproteases MMP2, 9, 14, and 16 in its sequence, which could generate 3 releasable peptides. Of note, expression of those MMPs was directly correlated with SST5TMD4 in several cancer-derived cell lines (ie neuroendocrine tumors and prostate, breast, and liver cancers). Moreover, incubation with SST5TMD4-derived peptides enhanced malignancy features in all cancer cell types tested (ie proliferation, migration, etc.) and blunted the antiproliferative response to somatostatin in QGP-1 cells, acting probably through PI3K/AKT and/or MEK/ERK signaling pathways and the modulation of key cancer-associated genes (eg MMPs, MKI67, ACTR2/3, CD24/44). These results suggest that SST5TMD4-derived peptides could contribute to the strong oncogenic role of SST5TMD4 observed in multiple tumor pathologies, and, therefore, represent potential candidates to identify novel diagnostic, prognostic, or therapeutic targets in cancer.

Is receptor profiling useful for predicting pituitary therapy?

Medical treatment of pituitary tumours may present important challenges in the presence of resistance to first line therapy. In this setting, the availability of specific markers of responsiveness/resistance could be helpful to provide tailored patients' treatment. Pituitary receptor profiling has emerged as a potentially useful tool for predicting the response to specific pituitary-directed medical therapy, mainly somatostatin analogues and dopamine agonists. However, its utility is not always straightforward. In fact, agonist-receptor coupling to the consequent biological response is complex and sometimes jeopardizes the understanding of the molecular basis of pharmacological resistance. Defective expression of pituitary receptors, genetic alterations, truncated variants, impaired signal transduction or involvement of other proteins, such as cytoskeleton proteins or the Aryl hydrocarbon receptor interacting protein amongst others, have been linked to differential tumour phenotype or treatment responsiveness with conflicting results, keeping the debate on the utility of pituitary receptor profiling open. Why does this occur? How can we overcome the difficulties? Is there a true role for pituitary receptor profiling in the near future? All authors of this debate article agree on the need of prospective studies using standardized methods in order to assess the efficacy of receptor profiling as a reliable clinical predictive factor.