pasireotide and Thyroid-Neoplasms

Acromegaly is a chronic disease with high morbidity and enhanced mortality if left untreated. Treatment options include surgery, medical therapy (somatostatin analogues (SA), dopamine agonists (DA) and growth hormone receptor antagonists) and radiotherapy. Despite these treatment options, "real-life" studies have shown that approximately 50% of patients are not controlled. In this scenario, a next-generation SA, pasireotide, has recently been approved for the treatment of acromegaly.. 1) pasireotide's pharmacokinetics and pharmacodynamics; 2) pasireotide's anti-secretory and anti-proliferative effects, from preclinical studies up to phase III clinical trials; and 3) the adverse effects of pasireotide, focusing on hyperglycemia; 4) biomarkers of response to SA treatment.. surgery is the primary treatment for most patients with acromegaly; however, approximately half of them will need adjuvant therapy. At present, the decision of this adjuvant treatment is made on a "trial-and-error" fashion. Nevertheless, in recent years, efforts have been made to establish biomarkers for the response to drugs involved in the treatment of acromegaly, which will change the treatment of acromegaly towards a more personalized therapeutic decision-making process. In the near future, the establishment of pasireotide response biomarkers will allow us to identify good candidates for first-line medical monotherapy with pasireotide.

Topics: Acromegaly; Animals; Antineoplastic Agents; Clinical Trials as Topic; Colonic Neoplasms; Humans; Somatostatin; Thyroid Neoplasms

Topics: Apoptosis; Calcitonin; Carcinoma, Neuroendocrine; Cell Movement; Cell Proliferation; Humans; Mutation; Neoplasm Invasiveness; Octreotide; Proto-Oncogene Proteins c-ret; Somatostatin; Thyroid Neoplasms; Tumor Cells, Cultured

Certain human carcinomas have demonstrated a distinct expression of somatostatin receptors. Data on somatostatin receptor expression in follicular thyroid cancer and anaplastic thyroid cancer has been limited and conflicting. This study seeks to characterize somatostatin receptor expression in follicular thyroid cancer and anaplastic thyroid cancer and to assess the effects of somatostatin analogues.. Anaplastic thyroid cancer (Hth7 and 8505C) and follicular thyroid cancer (FTC-236) (Sigma-Aldrich, St. Louis, MO) cells were cultured. Capillary immunoblotting and reverse transcription polymerase chain reaction (RT-PCR) were used to determine the basal expression of protein and mRNA of SSTR1-SSTR5. Cells were treated with the somatostatin analogues octreotide, pasireotride (SOM230), and KE-108 for 48h. IC. Immunoblotting analysis demonstrated that most cell lines expressed SSTR1-SSTR3 and SSTR5 in varying degrees. Reverse transcription polymerase chain reaction analysis showed that mRNA expression for SSTR2 and SSTR3 correlated with protein expression. MTT assays showed that KE-108 and SOM230 were able to inhibit cell proliferation. Tissue microarray (TMA) showed that SSTR2 was highly expressed in human tissues of aggressive thyroid carcinomas.. Follicular thyroid cancer and anaplastic thyroid cancer express SSTR1-3 and SSTR5 in distinct fashions both at a message and protein level. Our results suggest that somatostatin receptors are still a relevant and promising drug target against non-medullary thyroid cancers.

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents, Hormonal; Cell Proliferation; Humans; Immunoblotting; Immunohistochemistry; Octreotide; Peptides, Cyclic; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Cells, Cultured

Signaling through mTOR and somatostatin pathway is implicated in thyroid cancer development.. We evaluated everolimus, an mTOR inhibitor and pasireotide, a multi receptor somatostatin analogue as potential therapy of thyroid cancer focusing on the in vitro and in vivo efficacy, as well as possible mechanism to explain any observed interaction.. Both everolimus and pasireotide inhibit the growth of thyroid cancer cell lines in vitro with varied efficacy that correlates with tumor origin and somatostatin receptor (SSTR) expression profile of the cell lines. In vitro activity of everolimus show positive correlation with the expression of SSTR types 1, 4 and 5 (CC: 0.9; 0.85, 0.87) while pasireotide activity show negative correlation with SSTR2 (CC: -0.87). Although there is greater modulation of pS6 when pasireotide is combined with everolimus, there is no significant abrogation of the expected feedback upregulation of AKT induced by everolimus. Also, the combination is not significantly better than each agent alone in short and long term in vitro assays. Continuous administration of everolimus at a low dose as opposed to high intermittent dosing schedule has greater antitumor efficacy against thyroid cancer xenografts in vivo. Pasireotide LAR has modest in vivo efficacy and the combination of everolimus and pasireotide LAR achieve greater tumor growth inhibition than each agent alone in TPC-1 xenograft model of thyroid cancer (p = 0.048).. Our findings provide support for the clinical evaluation of everolimus and pasireotide in thyroid cancer and other neuroendocrine tumors.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Everolimus; Female; Humans; Mice, SCID; Neuroendocrine Tumors; Proto-Oncogene Proteins c-akt; Rats, Nude; Receptors, Somatostatin; Somatostatin; Thyroid Neoplasms; TOR Serine-Threonine Kinases

Medullary thyroid cancer (MTC) is a neuroendocrine tumour of the thyroid C cells. Pasireotide, a multi-receptor targeted somatostatin analogue, and everolimus, an inhibitor of mTOR, showed antitumour properties in neuroendocrine tumours. Aim of this study was to evaluate pasireotide alone and in combination with everolimus in patients with MTC.. Patients with progressive metastatic or persistent postoperative MTC received pasireotide LAR 60 mg/m for at least 6 months. Patients exhibiting progressive disease received everolimus 10 mg/d as combination therapy. Primary endpoint was progression free survival (PFS). Secondary endpoints included, overall survival, objective response rates, change in circulating markers, safety. Study registration no. NCT01625520.. Nineteen consecutive patients were enrolled. Median follow-up was 31 months. Median PFS with pasireotide was 36 months (95% CI: 19.5-52.5). Nine patients (47%) had tumour progression: seven of them started everolimus in combination with pasireotide, achieving a median PFS of 9.0 months (95% CI: 0-21.83). Five of them (71%) had further tumour progression, one objective response (14.3%), one stopped treatment because of pulmonary embolism. Pasireotide alone and with everolimus was safe and required withdrawal only in one case. Diarrhoea and hyperglycaemia were the most frequent adverse events with pasireotide (grade 3 in 5.3% each). Hyperglycaemia was the most frequent grade 3 toxicity with the combination therapy (28.6%).. Pasireotide therapy shows antiproliferative effects in persistent postoperative MTC suggesting further investigation on larger series of patients. In progressive MTC lesions, the combination pasireotide plus everolimus may be of benefit. Both schemes were safe and well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Medullary; Drug Therapy, Combination; Everolimus; Female; Humans; Male; Middle Aged; Progression-Free Survival; Somatostatin; Survival Rate; Thyroid Neoplasms; Treatment Outcome

A 51-year-old man with a history of metastatic medullary thyroid cancer (MTC) presented with high adrenocorticotropin (ACTH) and urinary free cortisol levels. The diagnosis of ectopic ACTH production, a rare MTC complication, was established in this patient. PET/CT using the somatostatin analogue DOTA-(Tyr)-octreotate labeled with gallium (Ga-DOTATATE) was performed, showing positive radionuclide uptake in multiple MTC metastases. After this therapy with the novel somatostatin analogue, pasireotide was initiated after which urinary free cortisol and ACTH levels decreased. The present case thus illustrates a potential theranostic use of Ga-DOTATATE PET/CT in MTC.

Topics: Adrenocorticotropic Hormone; Carcinoma, Neuroendocrine; Humans; Male; Middle Aged; Multimodal Imaging; Organometallic Compounds; Positron-Emission Tomography; Radiopharmaceuticals; Somatostatin; Thyroid Neoplasms; Tomography, X-Ray Computed

Recent discoveries in molecular biology offer new perspectives in the treatment of endocrine tumors. There is currently no medical therapy for Cushing's disease that targets the pituitary adenoma. Pasireotide, a new somatostatin analog, demonstrates a strong affinity for somatostatin receptors expressed by corticotroph adenomas. Some recent clinical trials showed a decrease of urinary free cortisol with pasireotide. This new treatment could be useful in case of pituitary surgery failure. Thyroid tumorigenesis involves kinase signaling cascade. Tyrosine-kinase inhibitors have now been tested in the treatment of progressive differentiated iodine refractory thyroid carcinomas or medullary carcinomas and showed modestly encouraging results.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Benzenesulfonates; Carcinoma; Carcinoma, Medullary; Clinical Trials as Topic; Endocrine Gland Neoplasms; Endocrinology; Humans; Niacinamide; Phenylurea Compounds; Pituitary ACTH Hypersecretion; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Receptors, Somatostatin; Somatostatin; Sorafenib; Thyroid Neoplasms; Treatment Outcome