DeCure for Non-functional pancreatic neuroendocrine tumor
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for non-functional pancreatic neuroendocrine tumor — screening already-approved drugs against its 49-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNon-functional pancreatic neuroendocrine tumor maps to a 49-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedSunitinibApproved drug
Structures already discussed alongside non-functional pancreatic neuroendocrine tumor in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
KIT kinase domain — Sunitinib has a real, experimentally solved structure in complex with this target (PDB 3G0E, 1.6 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet b49drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3G0E · 1.6 Å · ligand Sunitinib (B49). Experimental structure, not a prediction.
What the evidence adds up to
Non-functional pancreatic neuroendocrine tumours (NF-PNETs) account for the majority of PNET cases, and most patients already have metastatic disease at diagnosis. A 2016 review notes that aggressive surgical management is associated with prolonged survival, but the available data are limited by selection bias and the frequent combination of PNETs with carcinoid tumours in reported series. Few patients with metastatic disease will be cured, though a multidisciplinary approach can lead to prolonged survival.
The tumours are rare, comprising 1% to 3% of all new pancreatic cancers per year. Poorly differentiated tumours can behave aggressively, with 5-year survival ranging from 31% to 48% according to a 2012 review. That same review reports that recent data have shown a doubling of progression-free survival in unresectable PNETs with treatments targeting molecular changes expressed in this tumour group. A 2019 consensus paper from the North American Neuroendocrine Tumor Society reviews surgical management questions but does not provide new efficacy data.
Whole-genome sequencing has increased understanding of the molecular biology of PNETs, and a 2019 review outlines current knowledge of signalling pathways involved in tumourigenesis as well as preclinical and clinical studies targeting those pathways. A separate 2019 study in a mouse model found that loss of the transcriptional repressor REST increases neuroendocrine-like properties in the pancreas and leads to greater injury and pre-neoplastic lesions during chronic pancreatitis. In human pancreatic cancer tissue microarrays, patients negative for REST had lower overall survival than patients positive for REST. The authors hypothesise that REST plays a protective effect against pancreatic damage and cancer development, but this work is in mice and early-stage human tissue analysis, not in patients with NF-PNETs.
What is still missing are prospective trials specifically for NF-PNETs that separate them from functional tumours and carcinoid tumours, which have historically been lumped together in analyses. The molecular targets identified by sequencing have not yet translated into a therapy proven to extend survival in a dedicated NF-PNET trial. Patient stratification by REST status or other biomarkers remains experimental, and funding for such stratified trials is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Pancreas · 2019 · 389 citations · open access
The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors
AbstractThis manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.
Annals of Pancreatic Cancer · 2019 · 30 citations · open access
Insights into the biology and treatment strategies of pancreatic neuroendocrine tumors
AbstractPancreatic neuroendocrine tumors (PNETs) are the second most common primary pancreatic neoplasms after pancreatic ductal adenocarcinoma. PNETs present with widely various clinical manifestation and unfavorable survival rate. The recent advances in next generation sequencing have significantly increased our understanding of the molecular landscape of PNETs and help guide the development of targeted therapies. This review intends to outline a holistic picture of the tumors by discussing current understanding of clinical presentations, up-to-date treatment strategies, novel mouse models, and molecular biology of PNETs. Furthermore, we will provide insight into the future development of more effective targeted therapies that are necessary to manage PNETs.
The Molecular and Clinical Landscape of Pancreatic Neuroendocrine Tumors
AbstractPancreatic neuroendocrine tumors are rare tumors of the pancreas originating from the islets of the Langerhans. These tumors comprise 1% to 3% of all newly diagnosed pancreatic cancers every year and have a unique heterogeneity in clinical presentation. Whole-genome sequencing has led to an increased understanding of the molecular biology of these tumors. In this review, we will summarize the current knowledge of the signaling pathways involved in the tumorigenesis of pancreatic neuroendocrine tumors as well as the major studies targeting these pathways at preclinical and clinical levels.
World Journal of Gastroenterology · 2016 · 10 citations · open access
Multidisciplinary management of nonfunctional neuroendocrine tumor of the pancreas
AbstractPancreatic neuroendocrine tumors (PNETs) are a rare and diverse group of tumors; nonfunctional (NF) PNETs account for the majority of cases. Most patients with NF-PNETs have metastatic disease at the time of presentation. A variety of treatment modalities exist, including medical, liver directed, and surgical treatments. Aggressive surgical management is associated with prolonged survival, however available data are limited by selection bias and the frequent combination of PNETs with carcinoid tumors. Although few patients with metastatic disease will be cured, application of currently available therapies in a multidisciplinary setting can lead to excellent outcomes with prolonged patient survival.
Current Clinical Pharmacology · 2015 · 2 citations
Advances in Systemic Therapy for Gastroenteropancreatic Neuroendocrine Malignancies
AbstractNeuroendocrine tumors (NETs) are relatively uncommon. They typically arise in the gastrointestinal tract and lungs, and their incidence seems to be rising. Most patients have advanced disease at the time of diagnosis and many more will relapse after surgery. There is thus a great need for improvements in therapy for advanced neuroendocrine tumors. This article reviews the current therapy for both pancreatic NETs and non-pancreatic gastrointestinal NETs, and discusses recent advances in NET management with an emphasis on targeted therapy.
Targeted Agents in Treatment of Neuroendocrine Tumors of Pancreas
AbstractNeuroendocrine tumors (NET) of the pancreas are uncommon neoplasms that arise from the pancreatic islet cells. Surgical resections are being tested, as well as multiple chemotherapy agents. Current treatment options for nonresectable disease include somatostatin analogs and chemotherapy. New therapies focus on specific molecular targets such as sunitinib, angiogenesis inhibitor, that target vascular endothelial growth factor receptor (VEGFR) and other growth factor receptors and everolimus, an inhibitor of the mammalian target of rapamycin. Functionally based medical therapies for NET include somatostatin analogs to control symptoms. The 2014 annual meeting of American Society of Clinical Oncology (ASCO) brought us new insights into the management of pancreatic neuroendocrine tumors. The focus of this review will serve to highlight specific Abstracts (#e15160 and #e15161), that shed light on new therapeutic options that help target the unique pathways of this malignancies.
Advances in the treatment of pancreatic neuroendocrine tumours
AbstractPancreatic neuroendocrine tumours (pNETs) are relatively rare and generally felt to follow an indolent course. But poorly differentiated tumours can behave aggressively with 5-year survival ranging from 31% to 48%. Recent data suggest that patients with pNETs may derive benefit from treatment targeting the molecular changes expressed in this tumour group. This article describes advances in the treatment of unresectable pNETs that have led to a doubling of progression free survival.
Abstract 5222: Repression of neuronal genes protects the pancreas from certain injuries and aberrant plasticity
AbstractAmong the major cancer types, pancreatic ductal adenocarcinoma has one of the lowest survival rates with little improvement over the past 3 decades. To address this dire clinical need, this study explores the unique and underexploited neuronal property of the pancreas that correlates with greater injury and pancreatic cancer development. The pancreas has a remarkable innate plasticity, and a shift toward neuroendocrine transdifferentiation has been shown to correlate with poor survival and tumor progression in numerous cancers, such as lung and prostate cancers. Recent reports show a subpopulation of cells within pancreatic tumors that express neuroendocrine-related genes correlate with poor outcome and chemoresistance. We hypothesize one regulator of this ductal-neuroendocrine lineage plasticity may be REST, a transcriptional repressor most known for orchestrating neuronal development. Tissue microarray of human pancreatic cancer shows patients negative for REST had a lower overall survival than patients positive for REST. To investigate the role of REST in the pancreas, we developed a novel transgenic mouse model with REST conditionally knocked out of the pancreas. REST KO resulted in an increase of neuroendocrine markers and an increase of zymogen granules, resulting in a lighter, cloudy appearance of the pancreas. When pancreatic injury was introduced by injections of cholecystokinin analog caerulein to induce acute pancreatitis, the REST KO mice show greater serum amylase levels and higher pancreatic edema indicating greater pancreatitis. Furthermore, an increase in neuronal-related genes was observed within REST KO pancreas relative to control. We then investigated the role of REST during cancer-promoting injuries such as chronic pancreatitis. Mice were administered a 10-week series of caerulein injections, and histology was evaluated. As expected, REST KO mice experienced greater inflammation, injury, and pre-neoplastic lesions. Further directions include investigating REST KO during later stages of pancreatic cancer injury by crossing REST KO mice with mutant KRAS mice, as oncogenic KRAS is a leading driver of pancreatic cancer. We expect REST KO to increase neuroendocrine properties that will accelerate KRAS-induced pancreatic cancer development. In conclusion, we hypothesize that loss of REST increases neuroendocrine-like properties of the pancreas that leads to a greater injury, suggesting that REST plays a protective effect against pancreatic damage and pancreatic cancer development. Furthermore, our novel REST KO mice may prove to be a useful model to investigate how neuroendocrine properties may promote pancreatic cancer development and drug resistance. Understanding neuronal influences during pancreatic cancer development could have multiple implications for cancer patients and warrants further investigation.Citation Format: Julie K. Bray, Ola Elgamal, Lais Da Silva, Dhruvit Sutaria, Xiuli Liu, Kristianna Fredenburg, Thomas D. Schmittgen. Repression of neuronal genes protects the pancreas from certain injuries and aberrant plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5222.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
