WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

Abstract

Neuroendocrine tumors (NETs) are a group of heterogenous neoplasms. Evidencebased treatment options for antiproliferative therapy include somatostatin analogues, the mTOR inhibitor everolimus, the multiple tyrosine kinase inhibitor sunitinib and peptide receptor radionuclide therapy with 177-Lu-octreotate. In the absence of definite predictive markers, therapeutic decision making follows clinical and pathological criteria. As objective response rates with targeted drugs are rather low, and response duration is limited in most patients, numerous combination therapies targeting multiple pathways have been explored in the field. Upfront combination of drugs, however, is associated with increasing toxicity and has shown little benefit. Major advancements in the molecular understanding of NET based on genomic, epigenomic and transcriptomic analysis have been achieved with prognostic and therapeutic impact. New insight into molecular alterations has paved the way to biomarker-driven clinical trials and may facilitate treatment stratification toward personalized medicine in the near future. However, an improved understanding of the complexity of pathway interactions is required for successful treatment. A systems biology approach is one of the tools that may help to achieve this endeavor.

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

“…CNV) and oncogenic pathway activation. Mutational signatures detected by targeted sequencing were similar to previously reported alterations in PanNENs16,42,43 , and identified two subgroups within α-like samples: one group is characterized by MEN1, and DAXX or ATRX mutations, the second group is devoid of any PanNEN-specific mutations detected by this approach. In contrast to these two α-like mutation signatures, β-like samples had few and variable mutations and MEN1/DAXX/ATRX alterations were completely absent (Figure 3).A strong indicator of different tumorigenic mechanisms both within α-like PanNEN subgroups and between α-and β-like PanNENs became apparent within the CNV signatures.…”

“…This observation, nevertheless, indicates a distinct mTOR phenotype in α-like PanNENs, which is largely independent of mutations. MTOR pathway activation can occur in PanNENs via deletions and mutations in PTEN and TSC2 genes, respectively, yet these are rather low frequency events12,16,42,43 . Based on these observations, the mTOR inhibitor Everolimus has been approved for well-differentiatedPanNENs and has shown efficacy in several clinical trials 45 .…”

GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors

“…5-FU, a standard chemotherapy in combination with streptozotocin or temozolomide for pancreatic NETs according to current guidelines [67], also showed significant synergistic effects in combination with AR-A014418 in QGP1 and additive effects in BON1 and H727 cells. Hence, treatment with AR-A014418 displayed promising chemosensitizing properties in NET cell lines.…”

The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours

“…Cabozantanib, a multi-tyrosine kinase inhibitor targeting VEGF and c-MET, has shown responses in early-phase trials, though final results are currently awaited (Chan et al 2017). The CDK4/6 inhibitors, palbociclib and ribociclib, commonly used in breast cancer, are currently being trialled in PanNETs due to the observed overexpression of CDKs (Tang et al 2012, Pavel & Sers 2016.…”