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Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors
Gabriele Capurso1, Livia Archibugi1, Gianfranco Delle Fave1
1Digestive and Liver Disease Unit, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Rome, Italy.
Abstract:
Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN-1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options.
Insights
Advances in understanding pancreatic neuroendocrine tumors (PNETs) reveal molecular targets for therapy. This review explores PNET molecular pathology and its link to treatment options, including approved drugs and potential future therapies.
Area of Science:
- Oncology
- Molecular Biology
- Translational Medicine
Background:
- Significant progress has been made in understanding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs).
- Targeted agents have been investigated in clinical trials for PNETs, with some, like Everolimus and Sunitinib, gaining approval.
- Knowledge gaps exist regarding biomarkers for predicting treatment efficacy and understanding resistance mechanisms.
Purpose of the Study:
- To review the main molecular alterations in sporadic PNETs.
- To explore the link between these molecular changes and current/emerging treatment strategies.
- To identify areas needing further research, particularly concerning biomarkers and resistance mechanisms.
Main Methods:
- Literature review of molecular pathology in sporadic PNETs.
- Analysis of clinical trial data for targeted agents in PNETs.
- Discussion of potential therapeutic targets based on molecular alterations.
Main Results:
- Approved treatments like Everolimus and Sunitinib target specific pathways in PNETs.
- Other agents targeting angiogenesis, Src, Hedgehog, or PI3K pathways show potential.
- The clinical significance of mutations in MEN-1, ATRX, and DAXX genes in PNETs remains unclear.
Conclusions:
- Understanding PNET molecular pathology is crucial for developing effective targeted therapies.
- Further research is needed to identify predictive biomarkers and overcome resistance mechanisms.
- Integrating molecular insights into treatment strategies holds promise for improving patient outcomes in PNETs.
