Translational medicine: a hope for patients with Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (also known as Islet cell carcinoma) or PNETs are a type of neuroendocrine tumor found in the pancreas. Only 5 percent of pancreatic tumors arise in the islet cells. The vast majority of tumors found in the pancreas are adenocarcinoma, which is more commonly referred to as pancreatic cancer.  PNETs are very uncommon though, but are very difficult to diagnose and treat. These cancers, which originate from the hormone-producing pancreatic islet cells, stand in stark contrast to another type of pancreatic cancer, pancreatic ductal adenocarcinoma, which is much more prevalent and deadly: a larger proportion of patients with PNET undergo surgical excision, and the clinical course of the disease is highly variable. Nonetheless, patients with advanced PNET who are not candidates for surgery have a terminal illness, and their tumors are difficult to manage. So for only few chemotherapeutic agents are  available to treat PNET but they have only modest activity in these patients.

Two recent translational studies published back to back in 10 Feb issue of NEJM show a ray of hope for the patients with these tumors. One study conducted by Dr. Eric Raymond concluded that Continuous daily administration of sunitinib (a multi-tyrosine kinase inhibitor) at a dose of 37.5 mg improved progression- free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors.

http://www.nejm.org/doi/full/10.1056/NEJMoa1003825#t=abstract

While other study by Yao and colleagues  demonstrated that Everolimus which acts as an oral inhibitor of mammalian target of rapamycin (mTOR),, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. Although it must be taken with pinch of salt as Yao and colleagues note that, whereas everolimus delays time to progression of the disease (progression-free survival), it seemingly does not increase overall survival rates. This trial is still ongoing, however, so the lack of effect on overall survival is not yet conclusive.

http://www.nejm.org/doi/full/10.1056/NEJMoa1009290#t=abstract

These clinical trails, however, have their own limitations and moderate success rate, can be considered as landmarks for treating PNET. The approach that led to this — a long and well designed preclinical studies to elucidate the pathways underlying the disease and mechanism of tumor progression in a representative mouse model and human clinical trials — could also be used to test the efficacy of other anticancer drugs and may well replicate this success story. This strategy from going to preclinical studies to clinical trials is certainly going to prove as model study for other similar investigations in future in which preclinical trials in genetically engineered mouse models, and in other representative animal models, could guide the development of more effective therapies for human cancers, revealing efficacy, beneficial drug combinations and mechanisms of therapeutic resistance.