DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for gastrin-producing neuroendocrine tumor — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGastrin-producing neuroendocrine tumor maps to a 2-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
No approved-drug candidate for gastrin-producing neuroendocrine tumor is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
menin 1 (MEN1) — MEN1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 1r,2s,4rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8IG0 · 2.6 Å · ligand (1R,2S,4R)-4-[[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methylamino]-2-[methyl-[6-[2,2,2-tris(fluoranyl)ethyl]thieno[2,3-d]pyrimidin-4-yl]amino]cyclopentan-1-ol (7IX). Experimental structure, not a prediction.
What the evidence adds up to
Three patients with type I gastric neuroendocrine tumours received octreotide-LAR 20 mg intramuscularly every 28 days for one year. During treatment serum gastrin and chromogranin levels normalised, and tumours regressed in all three patients by six months. After therapy stopped, serum gastrin rose back to pre-treatment levels, but chromogranin remained normal. Gastroscopy and biopsy showed no tumour recurrence during follow-up of three years in two patients and two and a half years in one patient. The sample is three patients, no control group, and the tumours were type I gastric NETs, which are gastrin-dependent and generally indolent.
A separate study of 18 patients with advanced neuroendocrine tumours treated with dacarbazine, fluorouracil, and leucovorin reported an overall response rate of 27%. Among nine carcinoid tumours only one partial response occurred; among the other tumour types (seven neuroendocrine tumours of unknown primary, one insulinoma, one paraganglioma) there was one complete and three partial responses. The authors state efficacy was insufficient for carcinoid tumours but that the regimen could be effective for neuroendocrine tumours of unknown primary site. Toxicity included grade 3 vomiting in two patients, grade 3 leukopenia in three, and grade 3 mucositis in one.
The role of gastrin in colorectal carcinoma has been investigated for decades. Early reports that colorectal carcinomas produce gastrin and express gastrin receptors, suggesting an autocrine growth loop, were not universally confirmed in later studies. There is now abundant evidence that most colorectal carcinomas synthesise progastrin, but the proportion that contain amidated gastrin varies widely across studies. In vitro and animal models show that prolonged hypergastrinaemia may be linked to higher cancer rates, but in humans the risk of developing cancer appears similar in normo- and hypergastrinaemic patients. Some tumours produce their own gastrin, which can promote growth in an autocrine manner, and intermediates of gastrin processing may exert greater proliferative effects than fully amidated forms.
What remains missing is a prospective trial large enough to confirm whether octreotide-LAR prevents recurrence in type I gastric NETs beyond three patients, and whether any gastrin-targeted strategy (receptor blockade, processing inhibition, or somatostatin analogues) improves survival in advanced gastrin-producing neuroendocrine tumours. The dacarbazine-based regimen has not been tested specifically in gastrin-producing NETs, and no randomised comparison with streptozotocin-based chemotherapy exists for that subset. Patient stratification by gastrin processing status and tumour site is absent from the available data.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Gut · 1998 · 75 citations · open access
Gastrin, gastrin receptors and colorectal carcinoma
AbstractThe possibility that gastrin may play a role in the development of colorectal carcinoma has aroused considerable interest over the past decade. In early reports some colorectal carcinomas and colorectal carcinoma cell lines were shown to produce gastrin,1 to express gastrin receptors,2 and to respond mitogenically to exogenous gastrin.2 The most favoured explanation for these observations was an autocrine or paracrine loop in which gastrin was produced by the tumour, bound to tumour receptors, and stimulated tumour growth. However, gastrin may also have acted as an endocrine agent as hypergastrinaemia has been reported in a number of patients with colorectal carcinoma, although the source of the gastrin has not been defined.3-5 Further studies of the expression of gastrin6-8 and gastrin receptors9 10 in colorectal carcinomas and colorectal carcinoma cell lines, and of hypergastrinaemia in patients with colorectal carcinoma,11-15 indicated that the early positive reports were not universally correct. Recent information on the nature and source of the gastrin produced, and the discovery of novel receptors selective for non-amidated gastrins, makes it timely to reconsider the involvement of progastrin derived peptides in colorectal carcinoma.
There is now abundant evidence that most colorectal carcinomas synthesise progastrin. Gastrin mRNA has been detected by both polymerase chain reaction and northern hybridisation in colorectal carcinoma cell lines, normal human colonic mucosa and colorectal carcinomas.6 16-18 The gastrin mRNA is of low abundance but the major band of 0.7 kilobases is identical in sequence to antral gastrin mRNA.6 16 17 There is, however, considerable disparity in the literature on the proportion of colorectal carcinomas that contain amidated gastrin (table 1). The variable efficiency of translation and extent of postranslational processing of gastrin in peptide producing tumours20 offers an explanation for some of the contradictory reports as …
American Journal of Clinical Oncology · 1998 · 46 citations
Dacarbazine, Fluorouracil, and Leucovorin in Patients With Advanced Neuroendocrine Tumors
AbstractChemotherapy of neuroendocrine tumors must be improved. The most widely used regimen, which combines streptozotocin with fluorouracil, commonly obtains poor results. The best response rate that has been reported for carcinoid tumors is 33%. From July 1991 through September 1994, 18 patients who had advanced neuroendocrine tumors-including nine carcinoid tumors, seven neuroendocrine tumors of unknown primary site, one insulinoma, and one paraganglioma-were treated with a regimen of dacarbazine, 400 mg/m2/day, plus fluorouracil, 1 g/m2/day, with leucovorin, 200 mg/m2/day, for 2 days every 21 days (DTIC-LVFU2 protocol). The results were assessed according to the World Health Organization criteria of toxicity and response. Toxicity was moderate. The most severe side effects were grade 3 vomiting in two patients, grade 3 leukopenia in three patients, and grade 3 mucositis in one patient. The overall response rate was 27%, with only one partial response for carcinoid tumors but one complete and three partial responses for the other tumor types. Efficacy was insufficient in patients who had carcinoid tumors but the combination of dacarbazine with fluorouracil and leucovorin could be an effective regimen for the treatment of neuroendocrine tumors of unknown primary site.
World Journal of Gastroenterology · 2012 · 38 citations · open access
Role of gastrin-peptides in Barrett's and colorectal carcinogenesis
AbstractGastrin is the main hormone responsible for the stimulation of gastric acid secretion; in addition, gastrin and its derivatives exert proliferative and antiapoptotic effects on several cell types. Gastrin synthesis and secretion are increased in certain situations, for example, when proton pump inhibitors are used. The impact of sustained hypergastrinemia is currently being investigated. In vitro experiments and animal models have shown that prolonged hypergastrinemia may be related with higher cancer rates; although, this relationship is less clear in human beings. Higher gastrin levels have been shown to cause hyperplasia of several cell types; yet, the risk for developing cancer seems to be the same in normo- and hypergastrinemic patients. Some tumors also produce their own gastrin, which can act in an autocrine manner promoting tumor growth. Certain cancers are extremely dependent on gastrin to proliferate. Initial research focused only on the effects of amidated gastrins, but there has been an interest in intermediates of gastrin in the last few decades. These intermediates aren't biologically inactive; in fact, they may exert greater effects on proliferation and apoptosis than the completely processed forms. In certain gastrin overproduction states, they are the most abundant gastrin peptides secreted. The purpose of this review is to examine the gastrin biosynthesis process and to summarize the results from different studies evaluating the production, levels, and effects of the main forms of gastrin in different overexpression states and their possible relationship with Barrett's and colorectal carcinogenesis.
Journal of Gastroenterology and Hepatology · 2010 · 29 citations
Treatment of type I gastric neuroendocrine tumors with somatostatin analogs
AbstractBACKGROUND AND AIM: There are limited data on response and long-term follow-up of octreotide therapy in type-I gastric neuroendocrine tumors. The objective of the present study was to assess the response of type-I gastric neuroendocrine tumors to octreotide-long acting, repeatable (LAR) therapy and evaluate long-term follow up of such patients after therapy. METHODS: Three patients with documented type-I gastric neuroendocrine tumors from a tertiary gastroenterology centre were studied. Octreotide-LAR therapy 20 mg intramuscularly every 28 days was administered for one year. Serum gastrin and chromogranin levels, gastroscopies and biopsies from tumor nodules at 6 months and one year on therapy and every 6 months after completion of drug therapy were taken. Follow-up after completion of therapy extended for 3 years in two and 2.5 years in one patient. RESULTS: During octreotide therapy there was normalization of serum gastrin levels and serum chromogranin levels. Tumors in all three patients had regressed at 6 months of treatment. Following cessation of therapy, there was progressive rise of serum gastrin to pre-treatment levels. Serum chromogranin levels remained within normal limits. Gastroscopic and histologic examination of gastric biopsies did not reveal recurrence of tumors in any patients. All patients tolerated therapy well and became asymptomatic soon after drug therapy. CONCLUSIONS: Octreotide-LAR therapy causes regression of type-I gastric neuroendocrine tumors. After completion of drug therapy there was no recurrence of tumors even with continued hypergastrinemia. Octreotide therapy should be considered as one of the treatment options in such patients.
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.
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