pasireotide and Intestinal-Neoplasms

Acromegaly is a hormonal disorder that arises when the pituitary gland secretes excess growth hormone (GH), which in turn stimulates a concomitant increase in serum insulin-like growth factor 1 (IGF-1) levels. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) constitute a heterogeneous group of tumours that can secrete serotonin and a variety of peptide hormones that may cause characteristic symptoms known as carcinoid syndrome or other symptoms and hormonal hypersecretion syndromes depending on the tumour's site of origin. Current medical therapy for the treatment of acromegaly and GEP-NET involves the administration of somatostatin analogues that effectively suppress excess hormone secretion. After its discovery in 1979, octreotide became the first synthetic biologically stable somatostatin analogue with a short-acting formulation of octreotide introduced into clinical practice in the late 1980s. Lanreotide, another somatostatin analogue, became available in the mid-1990s initially as a prolonged-release formulation administered every 10 or 14 days. Long-acting release formulations of both octreotide (Sandostatin LAR and Novartis) and lanreotide (Somatuline Autogel, Ipsen), based on microparticle and nanoparticle drug-delivery technologies, respectively, were later developed, which allowed for once-monthly administration and improved convenience. First-generation somatostatin analogues remain one of the cornerstones of medical therapy in the management of pituitary and GEP-NET hormone hypersecretion, with octreotide having the longest established efficacy and safety profile of the somatostatin analogue class. More recently, pasireotide (Signifor), a next-generation multireceptor-targeted somatostatin analogue, has emerged as an alternative therapeutic option for the treatment of acromegaly. This review summarizes the development and clinical success of somatostatin analogues.

Topics: Acromegaly; Adenoma; Antineoplastic Agents; Growth Hormone-Secreting Pituitary Adenoma; Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms

Somatostatin analogs (SSAs) were initially developed as antisecretory agents used for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating evidence has also supported their role as antiproliferative agents in well or moderately differentiated NETs. The phase III PROMID trial demonstrated that octreotide long-acting repeatable (LAR) can significantly prolong time to progression among patients with metastatic midgut NETs. More recently, the randomized CLARINET trial reported a significant improvement in progression-free survival in a heterogeneous population of patients with gastroenteropancreatic (GEP)-NETs treated with depot lanreotide. Octreotide and lanreotide target somatostatin receptor subtypes in a similar fashion, and appear to be clinically interchangeable; however, comparative noninferiority trials have not been performed. Further studies are needed to evaluate the efficacy of novel SSAs such as pasireotide in the refractory setting, and the role of high-dose SSAs for symptom and tumor control.

Topics: Antineoplastic Agents, Hormonal; Disease-Free Survival; Humans; Intestinal Neoplasms; Lung Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms

Somatostatin is a peptide hormone that posses several biological functions of which inhibition of hormone secretion from endocrine cells is one. Neuroendocrine tumors usually express somatostatin receptors (SSTRs), although the subtypes and number of SSTRs expressed in a certain tumor is very variable. The primary goal of somatostatin analog treatment is to decrease hormone production and secretion, resulting in control of hormone induced symptoms, while the ability of somatostatin analogs to retard tumor growth is less well documented. All patients considered for somatostatin analog treatment should undergo SSTR scintigraphy (111In-pentetreotide) to establish SSTR status, since the expression is usually correlated to therapeutic response. By this approach, it is possible to select patients suitable for treatment. Among patients with functioning neuroendocrine tumors expressing SSTR, more than 80% respond with symptomatic relief during somatostatin analog treatment, while treatment of non-functioning tumors still remains somewhat controversial.

Topics: Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Pancreatic Neoplasms; Receptors, Somatostatin; Somatostatin; Stomach Neoplasms; Thoracic Neoplasms

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Chromogranin A; Drug Synergism; Everolimus; Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; Somatostatin; Stomach Neoplasms; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of carcinomas that remain difficult to treat with conventional cytotoxic regimens. The 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium brought us new insights into the management of gastroenteropancreatic neuroendocrine tumors. The focus of this review will serve to highlight specific Abstracts (#268 and #273) that help shed light on a novel, targeted means of treating gastroenteropancreatic neuroendocrine tumors.

Topics: Antineoplastic Agents; Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms; Treatment Outcome

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Apoptosis; Caspase 3; Caspase 7; Cell Proliferation; Cell Survival; Chromogranin A; Cyclic AMP; DNA Fragmentation; Female; Humans; Intestinal Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Receptors, Somatostatin; Somatostatin; Stomach Neoplasms; Tumor Cells, Cultured

Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of malignancies, characterized by varying degrees of biological activity and metastatic potential. A common thread between this wide mix of neoplasms has remained their sensitivity to hormonal modulation with somatostatin analogues. New analogues of somatostatin have been recently introduced and are beginning to shape a different picture of how we treat and monitor for response in patients with gastroenteropancreatic neuroendocrine tumors. Here we discuss three important abstracts presented at the annual meeting of the American Society for Clinical Oncology (ASCO) 2014 (#4107, #4108, and #4111) that highlight the changing landscape of somatostatin-based therapy.

Topics: Antineoplastic Agents; Humans; Intestinal Neoplasms; Molecular Structure; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Somatostatin; Stomach Neoplasms; Survival Analysis; Treatment Outcome