From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

Abstract

Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.

Neutrophil-lymphocyte ratio predicts survival in pancreatic neuroendocrine tumors

“…Unlike functioning neoplasms, non-functioning PNETs are often detected at an advanced stage due to the lack of specific symptoms (6). PNETs are highly heterogeneous neoplasms presenting a spectrum of biologic behavior (7,8). Aggressive progression can even be observed in incidentally detected and small tumors (9).…”

An uncommon cause of Cushing's syndrome in a 70-year-old man

“…12 Although P-NETs are relatively radioresistant, recently developed peptide receptor radiotherapy employing radionuclidetargeted somatostatin receptor agonists for internal cytotoxic radiotherapy in somatostatin receptorexpressing NETs seem promising. 12 Systemic therapies for unresectable tumours include sunitinib malate, a potent tyrosine kinase inhibitor with antiangiogenic effects, and everolimus, an inhibitor of mammalian target of rapamycin. 12,13 After surgical resection of malignant P-NETs, Ki-67 >5% of tumour cells is a predictor of recurrence.…”

“…12 Systemic therapies for unresectable tumours include sunitinib malate, a potent tyrosine kinase inhibitor with antiangiogenic effects, and everolimus, an inhibitor of mammalian target of rapamycin. 12,13 After surgical resection of malignant P-NETs, Ki-67 >5% of tumour cells is a predictor of recurrence. 5 Since our patient had a Ki-67 of approximately 15%, oncological treatment will be needed, hence, the referral.…”

Nowotwory neuroendokrynne trzustki — zasady postępowania (rekomendowane przez Polską Sieć Guzów Neuroendokrynnych)

“…Sunitinib is indicated in the case of well-differentiated neoplasms (NENG1), and indications for everolimus comprise well-and moderately-differentiated neoplasms (NENG1 and NENG2) [136,137]. These medications -everolimus (a serine/ /threonine kinase -mTOR -inhibitor) and sunitinib (a tyrosine-kinase inhibitor) [138] significantly extend progression-free survival (PFS) by approximately 5.5-6 months. Adding everolimus to octreotide (the RADIANT-3 trial) extended progression-free survival by approximately five months (16.4 v. 11.3) compared to monotherapy with SST analogue.…”