Signaling pathways as specific pharmacologic targets for neuroendocrine tumor therapy: RET, PI3K, MEK, growth factors, and Notch

Abstract

Neuroendocrine tumors are rare tumors with a common progenitor - the neural crest cell. Included in this category are pulmonary and gastrointestinal tract carcinoid tumors and medullary thyroid cancer. The majority of these tumors are sporadic in nature, however they can be hereditary. Medullary thyroid cancers can present sporadically, with other endocrine tumors, as in the complex of multiple endocrine neoplasias 1, 2A, or 2B, or as familial medullary thyroid cancer. These tumors can become evident at later stages, with metastases already present at the time of diagnosis. Despite the small size and rare incidence of gastrointestinal neuroendocrine (carcinoid) tumors, they can be debilitating when present. Their natural history presents as early lymph node and distant metastases, as well as symptoms of the carcinoid syndrome, which result from the overproduction and secretion of serotonin and somatostatin. As a consequence of their metastases, surgical resection is non-curative and hence there is a need for novel treatment strategies to address tumor burden and symptom control. There are multiple intracellular pathways which can be targeted, either individually or in combination, to address these tumors. Here, we review some of the intracellular pathways, and identify some specific targets, which are vital to the generation and propagation of neuroendocrine tumorigenesis, and thus, can be the foci of novel drug therapies. We also elaborate on present pharmacological strategies and clinical trials involving these intracellular pathways.