DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for thyroid gland oncocytic adenoma — screening already-approved drugs against its 48-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleThyroid gland oncocytic adenoma maps to a 48-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 thyroid gland oncocytic adenoma 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
protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) — PRKAR1A 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 pcgdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5KJZ · 1.347 Å · ligand CYCLIC GUANOSINE MONOPHOSPHATE (PCG). Experimental structure, not a prediction.
What the evidence adds up to
In 1996, a study of toxic thyroid adenomas found that all such adenomas, whether or not they carried activating mutations in the TSH receptor or Gs alpha genes, showed increased expression of both the stimulatory Gs alpha protein and the inhibitory Gi alpha protein. Basal adenylate cyclase activity was high only in tissues with mutations and was only slightly increased in adenomas without detected mutations. No correlation was found between adenylate cyclase activity and the levels of either Gs alpha or Gi alpha. The authors concluded that mutational activation of the cAMP cascade may not be sufficient to generate toxic nodules and adenomas, and that more complex mechanisms, including alterations of G protein signalling, may be involved.
A 2001 study sequenced the Epac and Rap1 genes in cold thyroid follicular adenomas from 10 patients. No mutations in either Epac or Rap1 cDNAs were found in any of the nodules. A polymorphism in Epac at codon 332 (Gly to Ser) was observed in five patients. The authors concluded that the cAMP–Epac–Rap1 signalling pathway does not play a major role in generating cold thyroid follicular adenomas.
A 1989 case report described a patient with a thyrotrophin-secreting pituitary adenoma. Thyrotrophin secretion was inhibited by circulating thyroid hormones, dopaminergic agonists, and the somatostatin analogue SMS 201-995, but could not be stimulated by thyrotrophin-releasing hormone or further inhibited by exogenous triiodothyronine. Prolonged treatment with SMS 201-995 caused tumour shrinkage on successive CT scans but was accompanied by tumour desensitisation and the development of diabetes mellitus. This was the first thyrotroph adenoma in which somatostatin receptors were directly demonstrated. Growth hormone mRNA and growth hormone were found throughout the tumour, but the patient showed no evidence of inappropriate growth hormone secretion during surgery or in response to insulin stress tests.
A 2009 case report described a C cell thyroid adenoma in a 47-year-old woman that progressed over 34 years. Histologic examination revealed no atypical features or capsular infiltration. Eight years after excision there was no recurrence or metastases. What is still missing for these rare tumour types is systematic genetic and signalling pathway analysis in larger, prospectively collected cohorts, as well as functional studies that account for the complex, non-linear interactions between multiple G protein subunits and second messenger systems. No trial has yet tested a targeted intervention in oncocytic thyroid adenomas, and patient stratification by mutation status or protein expression profile remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Clinical Endocrinology & Metabolism · 1996 · 46 citations · open access
Constitutive activation of the Gs alpha protein-adenylate cyclase pathway may not be sufficient to generate toxic thyroid adenomas.
AbstractIn toxic thyroid adenomas, mutations in the TSH receptor (TSH-R) gene or the gene encoding the alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gs alpha) have been demonstrated to constitutively activate the cAMP cascade, which subsequently stimulates the growth and function of these tumors. However, the widely varying thyroid phenotypes in patients with TSH-R germline mutations, ranging from only slightly enlarged diffuse to multinodular goiters, suggest that additional mechanisms may be effective in the pathogenesis of toxic adenomas. We have investigated the levels of stimulatory and inhibitory G protein alpha-subunits together with basal and TSH-stimulated adenylate cyclase (AC) activity in toxic adenomas with or without activating mutations and in nodular and extranodular tissues of a toxic goiter due to a germline mutation in the TSH-R gene. Augmented expression of Gs alpha protein was detected in all toxic adenomas, independent of the presence of mutations, and in the nodular tissue of the toxic goiter, but not in the nonnodular hyperplastic tissue of the toxic goiter with the mutated TSH-R. Analogously, the expression of the alpha-subunit of the inhibitory G protein (Gi alpha) was also increased in all adenomas and the nodular tissue of the goiter, but, again, not in the hyperplastic goiter tissue. Basal AC activity was high in all tissues with mutations, but was only slightly increased in adenomas without detected mutations. No correlation was detectable between basal or TSH-stimulated AC activity and the levels of Gs alpha and Gi alpha. Our data suggest that mutational activation of the cAMP cascade may not be sufficient to generate toxic nodules and adenomas, but far more complex mechanisms, including alterations of G protein signaling, may be effective in the pathogenesis of these tumors.
Journal of Neuroendocrinology · 1989 · 28 citations
Somatostatin and Thyrotrophin‐Releasing Hormone Response and Receptor Status of a Thyrotrophin‐Secreting Pituitary Adenoma: Clinical and <i>in vitro</i> Studies
AbstractAbstract We have described a patient with a thyrotrophin-secreting pituitary adenoma and correlated a detailed physiological and anatomical investigation of the surgically resected tumour with its in vivo regulation. Thyrotrophin secretion was inhibited by circulating thyroid hormones, dopaminergic agonists and the somatostatin analogue SMS 201-995 but could not be stimulated by thyrotrophin-releasing hormone or further inhibited by exogenous triiodothyronine. Prolonged treatment with SMS 201-995 caused tumour shrinkage as shown by successive computed tomography scans but was accompanied by tumour desensitization and the development of diabetes mellitus. This is the first thyrotroph adenoma in which somatostatin receptors have been directly demonstrated and shown to completely block thyrotrophin-releasing hormone-induced inositol phospholipid accumulation when occupied. In addition, preincubation with triiodothyronine significantly inhibited thyrotrophin-releasing hormone-induced inositol phospholipid turnover in dispersed pituitary cells indicating that in this tumour, circulating thyroid hormones were exerting feedback inhibition at the level of the pituitary either by reducing the number of thyrotrophin-releasing hormone receptors and/or their coupling to second messenger pathways. In keeping with this hypothesis, the acute reduction in intrapituitary triiodothyronine by sodium ipodate in vivo had no effect on peripheral thyrotrophin over 6 h suggesting that the onset of the effect of triiodothyronine withdrawal on thyrotrophin secretion was suitably delayed. The importance of the inositol phospholipid second messenger pathway in transducing the secretory response in this tumour was further corroborated by electrophysiological studies which demonstrated thyrotrophin-releasing hormone-induced changes in K(+) currents which are dependent on intracellular Ca(2+) ions, presumably mobilized via the inositol phospholipids. In addition to thyrotrophin and alpha subunit, growth hormone mRNA and growth hormone were found throughout the tumour as were two populations of cells distinguished electron microscopically by the size of their secretory granules. Although acromegalic features are not unusual in thyrotroph adenomas, our patient showed no evidence of inappropriate growth hormone secretion during surgery or in response to pre- or post-operative insulin stress tests.
European Journal of Endocrinology · 2001 · 24 citations · open access
Mutation analysis of the Epac--Rap1 signaling pathway in cold thyroid follicular adenomas
AbstractOBJECTIVE: The cyclic AMP (cAMP) cascade is the main regulatory pathway in thyrocytes. Whilst activating mutations in the TSH receptor or in the Gs alpha-subunit, which increase cAMP levels, have been shown to be responsible for 80% of the autonomous adenomas, no such mutations have been observed in the other types of thyroid tumors, suggesting that other mechanisms exist. The discovery of Epac ('exchange nucleotide protein directly activated by cAMP'), a novel cAMP-binding protein, which is strongly expressed in the thyroid, raised the possibility of a role for this protein in the generation of the unexplained cold thyroid follicular adenomas. Thus, we investigated whether activating mutations in either Epac or Rap (the downstream target of Epac) could be responsible for the generation of these thyroid nodules. DESIGN: Epac and Rap1 (Rap1A and Rap1B) cDNAs were sequenced in 10 patients. The sequencing of the cDNAs was realized on both strands in the cold nodule and the juxtanodular tissue of each patient. RESULTS: No mutations in either Epac or Rap1 cDNAs were found. For five patients, a polymorphism in Epac at codon 332 (Gly--Ser) was observed. CONCLUSIONS: In this report, we show that the cAMP--Epac--Rap1 signaling pathway in the thyroid gland does not play a major role in the generation of cold thyroid follicular adenomas, since no mutations in either Epac or Rap1 could be observed in the 10 nodules studied.
AbstractA case of C cell thyroid adenoma in a 47-year-old female patient is described. The nodule showed progression over 34 years. The adenoma cells showed histochemical and ultrastructural properties characteristic for C cells. Histologic examination revealed no atypical features of nodule cells nor infiltration of capsule by neoplastic cells. In the period of 8 years following the excision there was neither recurrence nor metastases.
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.
