DeCure for Cushing syndrome due to macronodular adrenal hyperplasia
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for Cushing syndrome due to macronodular adrenal hyperplasia — 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 moduleCushing syndrome due to macronodular adrenal hyperplasia 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 cushing syndrome due to macronodular adrenal hyperplasia 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
lysine demethylase 1A (KDM1A) — KDM1A 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 faddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5L3D · 2.6 Å · ligand FLAVIN-ADENINE DINUCLEOTIDE (FAD). Experimental structure, not a prediction.
What the evidence adds up to
In 1998, nine patients with ACTH-independent macronodular adrenal hyperplasia were reviewed. All had biochemical evidence of Cushing syndrome, though repetitive testing was often needed, and diagnosis was delayed by 1 to 20 years. Neither low- nor high-dose dexamethasone suppressed cortisol secretion. After curative bilateral adrenalectomy, no patient developed Nelson syndrome over 1 to 8.5 years of follow-up. The authors concluded this condition is a separate cause of Cushing syndrome.
A 2007 report described two sisters with mild Cushing syndrome and bilateral macronodular adrenal enlargement. In vivo tests showed cortisol increases after terlipressin and metoclopramide. Unilateral adrenalectomy was performed in one sister. Tissue analysis revealed expression of 5-HT4 receptor isoforms and vasopressin receptors V1 and V2. Their father and brother had subclinical Cushing syndrome with moderate adrenal enlargement, but the brother’s pharmacological screening for aberrant receptors was negative. Three children of the sisters had no clinical or biological features of Cushing syndrome and normal adrenal CT scans. The authors suggested familial AIMAH may be autosomal dominant, with phenotypic expression more pronounced in females.
A 2013 article proposed classifying AIMAH into subclinical, clinical, and high-risk types based on serum cortisol and clinical manifestations, and described three patients representing these subtypes. No treatment outcomes or survival data were provided.
In 2016, 12 patients with bilateral macronodular adrenal hyperplasia were treated with laparoscopic subcutaneous transposition of a pedicled adrenal. After an average follow-up of 45.5 months (range 24–60 months), clinical symptoms disappeared in all patients, and 24-hour plasma-free and urinary-free cortisol levels were within normal range. The authors called this a new and effective method for long-term remission.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
European Journal of Endocrinology · 2007 · 101 citations
Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors
AbstractACTH-independent macronodular adrenocortical hyperplasia (AIMAH) is rare and generally presents as a sporadic disease. We describe a familial case of AIMAH with in vivo and in vitro demonstration of aberrant 5-HT4 and vasopressin adrenal receptors. Two sisters presented with clinical and biological features of mild Cushing's syndrome with bilateral macronodular adrenal enlargement on computerized tomography (CT)-scan evaluation. In vivo pharmacological tests showed a significant increase in plasma cortisol after terlipressin and metoclopramide administration. Unilateral adrenalectomy was performed in one of these patients. Reverse transcriptase-PCR analysis of the hyperplastic tissue revealed expression of 5-HT4 receptor isoforms (a), (b), (c), (i), and (n), and of vasopressin receptors, V1 and V2. Their father and brother were overweight, had easy bruisability and presented with biological features of subclinical Cushing's syndrome. CT scan showed moderate adrenal enlargement. In vivo pharmacological screening tests for the detection of adrenal aberrant receptors in the brother were negative. Finally, three out of the two sisters' children were evaluated. They had neither clinical nor biological features of Cushing's syndrome. Their adrenal glands were normal on CT-scan evaluation. In vivo evaluation for the detection of aberrant adrenocortical receptors performed in one of these subjects was negative. In conclusion, this study shows that (i) familial AIMAH could be an autosomal dominantly inherited disorder; (ii) aberrant 5-HT4 serotonin and vasopressin receptors can be expressed in familial AIMAH; and (iii) phenotypic expression of familial AIMAH could be varied in a same family and more pronounced in female than in male patients.
AbstractOBJECTIVES: To investigate the clinical presentation, laboratory findings, and pathologic characteristics of patients with corticotropin (ACTH)-independent macronodular adrenal hyperplasia. DESIGN: Retrospective review. SETTING: Academic medical center. PATIENTS: All patients with bilateral adrenocortical nodules associated with ACTH-independent hypercortisolism without clinicopathologic features of primary pigmented nodular adrenocortical disease with atrophic internodular adrenal cortex. MAIN OUTCOME MEASURES: Compare and contrast our findings with those previously reported; assess response to adrenalectomy. RESULTS: Nine patients met the criteria for corticotropin-independent macronodular adrenal hyperplasia. All patients had biochemical evidence of Cushing syndrome, although repetitive testing was frequently required. As a result, the diagnosis was delayed from 1 to 20 years. In all patients, both the low- and high-dose dexamethasone suppression tests failed to suppress cortisol secretion. No patient had elevated ACTH levels, and following curative bilateral adrenalectomy, no patient subsequently developed Nelson syndrome, with follow-up ranging from 1 to 8.5 years. Unique histologic features were identified in all cases. CONCLUSION: Amalgamating this series with other clinical reports plus basic research information, corticotropin-independent macronodular adrenal hyperplasia must be considered a separate and legitimate cause of Cushing syndrome.
Canadian Urological Association Journal · 2013 · 6 citations · open access
Classification, diagnosis and treatment of ACTH-independent macronodular adrenal hyperplasia
AbstractACTH-independent macronodular adrenal hyperplasia (AIMAH) is a distinctive subtype of Cushing's syndrome (CS), with different clinical manifestations according to the level of serum cortisol. Based on clinical manifestations and serum cortisol, we divide AIMAH into three types, subclinical AIMAH, clinical AIMAH and high-risk AIMAH, with varied treatment methods being adapted to different subtypes. At the same time, we describe 3 patients who represent these subtypes of this disease, and review some cases of AIMAH which have been previously reported in the English literature. To our knowledge, this is the first article discussing classification, diagnosis and treatment of this disease and should be useful for future therapy of AIMAH.
Laparoscopic Subcutaneous Transposition of a Pedicled Adrenal for ACTH-Independent Bilateral Macronodular Adrenal Hyperplasia
AbstractBACKGROUND AND PURPOSE: Bilateral adrenalectomy or unilateral adrenalectomy and contralateral partial adrenalectomy are indicated for the treatment of ACTH-independent macronodular adrenal hyperplasia. Independent of the surgical procedure, the prognosis is poor. This article discusses a new treatment method and its efficacy for treating nodular adrenal hyperplasia. METHODS: We performed a retrospective review of the medical records of 12 patients operated on between January 2008 and October 2014 at the First Affiliated Hospital of Zhengzhou University. All patients were treated by laparoscopic subcutaneous transposition of a pedicled adrenal. We performed postoperative monitoring of patients, including clinical symptoms and 24-hour levels of serum-free and urinary-free cortisol. RESULTS: All 12 patients were pathologically confirmed to have nodular adrenal hyperplasia and were followed for an average of 45.5 months (range 24-60 months). The clinical symptoms of all patients disappeared, and the 24-hour plasma-free cortisol and urinary-free cortisol levels were within the normal range. CONCLUSIONS: Laparoscopic subcutaneous transposition of a pedicled adrenal is a new and effective method for treating bilateral macronodular adrenal hyperplasia and can achieve long-term remission of Cushing's syndrome.
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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