The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms
Franziska Briest1, Patricia Grabowski2
1Dept. of Gastroenterology, Infectious Diseases, Rheumatology CC13, Medizinische Klinik 1, CBF, Charité - Universitätsmedizin Berlin, Germany; Dept. of Chemistry and Biochemistry, Freie Universität (FU) Berlin, Germany.
Abstract:
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous and especially the midgut tumors currently lack effective therapy options. Actionable driver mutations as therapeutic targets are rare. Subtype specific data concerning regulatory mechanisms or epigenetic aberrations are necessary for novel clinical trials. Although the p53 protein itself is rarely mutated in GEP-NENs, epigenetic and regulatory aberrations interfere with the p53 network activity and might function as s target for novel therapeutic approaches. In this review we analyze the current knowledge about the p53 network in GEP-NENs and discuss three possible strategies that include recovering p53 function, enforcing apoptosis by genotoxic stress induction and restoring silenced gene function, based on in vitro, in vivo and clinical data.
Insights
Gastroenteropancreatic neuroendocrine neoplasms, particularly midgut tumors, lack effective treatments. This review explores targeting the p53 network through epigenetic and regulatory mechanisms for novel therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a diverse group of tumors.
- Midgut GEP-NENs often lack effective therapeutic targets and actionable driver mutations.
- Understanding regulatory and epigenetic aberrations is crucial for developing new treatments.
Purpose of the Study:
- To review current knowledge of the p53 network in GEP-NENs.
- To explore the potential of targeting the p53 network for therapeutic strategies.
- To identify novel therapeutic approaches for GEP-NENs based on p53 network modulation.
Main Methods:
- Comprehensive literature review of in vitro, in vivo, and clinical data.
- Analysis of epigenetic and regulatory mechanisms affecting the p53 network in GEP-NENs.
- Discussion of therapeutic strategies targeting the p53 network.
Main Results:
- While p53 mutations are rare in GEP-NENs, the p53 network is frequently dysregulated by epigenetic and regulatory aberrations.
- These dysregulations present potential therapeutic vulnerabilities.
- Three strategies are proposed: recovering p53 function, inducing apoptosis via genotoxic stress, and restoring silenced gene function.
Conclusions:
- The p53 network is a promising target for novel therapies in GEP-NENs.
- Epigenetic and regulatory targeting of the p53 network offers potential for treating midgut GEP-NENs.
- Further research and clinical trials are warranted to validate these therapeutic strategies.
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