DeCure for ACTH-Producing Pituitary Gland Carcinoma
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for ACTH-Producing Pituitary Gland Carcinoma — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleACTH-Producing Pituitary Gland Carcinoma maps to a 3-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 acth-producing pituitary gland carcinoma 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
HRas proto-oncogene, GTPase (HRAS) — HRAS 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 gnpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8ELT · 1.66 Å · ligand PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER (GNP). Experimental structure, not a prediction.
What the evidence adds up to
A 37-year-old man with Cushing’s disease developed Nelson’s syndrome after adrenalectomy, caused by a pituitary carcinoma that metastasised to spinal cord, cauda equina, heart, liver, and pancreas. The primary tumour and its metastases stained for ACTH, beta-lipotrophin, and variably for beta-endorphin and alpha-MSH. Only nine cases of Cushing’s disease with pituitary carcinoma were documented in the literature at that time. Pituitary carcinoma is defined by blood- or lymph-borne metastases; it is extremely rare and carries a very poor prognosis. Most are functioning, with ACTH- and PRL-secreting types the most frequent. Treatment includes surgery, radiotherapy, medical therapy and chemotherapy, but results are poor.
A 2021 review of 61 case reports of ACTH-secreting pituitary carcinoma found a median age at diagnosis of 45 years. Metastases to multiple organs occurred in 61% of patients. Adjuvant therapy was frequently used: radiotherapy in 78%, temozolomide in 34%, and other medical therapy in 29%. Mortality was 53%, with median time to death from diagnosis of one year. The natural history and management remain poorly understood. A 2017 case described a 67-year-old woman with recurrent ACTH-producing pituitary adenoma who presented with a cervical lymph node metastasis; fine needle aspiration showed epithelioid cells with marked atypia and a Ki-67 proliferation index of approximately 25%.
A separate 2008 case report describes a 44-year-old man with ectopic ACTH syndrome due to a thymic carcinoid, not a pituitary carcinoma. His plasma ACTH was 536–625 pg/ml (normal 12–78), 24-hour urine free cortisol 3859 µg (normal 20–90), and serum potassium 1.97 mmol/L. After resection of a 14 cm mediastinal mass, ACTH fell to normal within three hours and to 25 pg/ml by day three. He remained in good health at six-year follow-up. RT-PCR of the tumour showed overexpression of POMC, Tpit, and NeuroD1. Thymic carcinoids have a ten-year survival rate below 50%, with the lowest reported at 35%.
What is still missing is a reliable way to distinguish pituitary carcinoma from adenoma before metastasis occurs; no specific morphologic features exist. The molecular pathogenesis is only partly clarified, and no targeted therapies have been validated. Larger prospective studies are impossible given the rarity of the disease, so progress depends on international case registries, consistent reporting of Ki-67 and other markers, and funding for preclinical models of ectopic POMC expression.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Clinical Endocrinology · 1986 · 49 citations
PITUITARY PRO‐OPIOMELANOCORTIN‐CELL CARCINOMA OCCURRING IN CONJUNCTION WITH A GLIOBLASTOMA IN A PATIENT WITH CUSHING'S DISEASE AND SUBSEQUENT NELSON'S SYNDROME
AbstractPituitary carcinoma is defined as a malignant pituitary tumour associated with blood- or lymph-borne metastases. Cushing's disease is frequently present in patients with this condition. After adrenalectomy for Cushing's disease, a 37-year-old man developed Nelson's syndrome resulting from a pituitary carcinoma with metastases to the spinal cord, cauda equina, heart, liver, and pancreas. The primary tumour and its metastases showed immunocytochemical staining for ACTH, beta-lipotrophin, and variably for beta-endorphin and alpha-melanocyte stimulating hormone (alpha-MSH). A coincidental glioblastoma was also present. Nine cases of Cushing's disease associated with pituitary carcinoma, including the present patient, are documented in the literature. The case reported is only the second in which immunohistochemical staining of the primary pituitary tumour and its metastases was performed, and the first in which ACTH-related peptides, in addition to ACTH itself, were demonstrated in the carcinoma cells.
Frontiers of hormone research · 2010 · 29 citations
Pituitary Carcinomas
AbstractPituitary carcinoma is a extremely rare and is characterized by a very poor prognosis. Even if at diagnosis the presence of metastases is required to define a pituitary carcinoma, the lesion was almost invariably diagnosed first as a benign pituitary tumor, that after a variable period of latency, ranging from few months to many years, changed its natural course to an aggressive pituitary tumor poorly responsive to therapy. Recent studies have partially clarified its molecular pathogenesis and found possible markers of aggressiveness in order to make an earlier diagnosis, when still treatment could improve their prognosis. Most pituitary carcinomas are functioning, and ACTH- and PRL-secreting carcinomas are the most frequent. Treatment includes surgery, radiotherapy, medical therapy and chemotherapy, but the poor results with current therapies should prompt all investigators to better understand its pathogenesis and searching new molecular targets for treatments.
Metastatic Pituitary Carcinoma to Cervical Lymph Node: Diagnosis by Fine Needle Aspiration and Review of the Literature
AbstractBACKGROUND: Pituitary carcinomas are rare neoplasms whose designation requires demonstration of metastatic disease. No specific morphologic features can reliably distinguish pituitary carcinomas from pituitary adenomas, rendering the diagnosis particularly challenging. Furthermore, as reports of pituitary carcinoma on fine needle aspiration (FNA) biopsy are exceedingly rare in the literature, the cytological features of pituitary carcinoma are poorly characterized. CASE REPORT: Here we describe a case of pituitary carcinoma in a 67-year-old woman with history of recurrent adrenocorticotropic hormone (ACTH)-producing pituitary adenoma who presented with a persistent left cervical nodule for 2 years. Ultrasound-guided FNA of the nodule consisted of loosely cohesive clusters of epithelioid cells with marked cytologic atypia, intermediate to large nuclei, relatively irregular nuclear contour, coarse granular chromatin, prominent nucleoli, and delicate finely granular cytoplasm. Immunohistochemical stains performed on the cell block revealed positivity for synaptophysin, chromogranin and ACTH with an increased Ki-67 proliferation index (approximately 25%). Review of the patient's previously resected pituitary tumor showed similar cytomorphologic features. CONCLUSION: Given the similar cytologic features of pituitary carcinomas compared to other neuroendocrine tumors, it is important to obtain a complete clinical history and maintain a high index of suspicion in order to make a correct diagnosis of pituitary carcinoma on FNA.
Chinese Medical Journal · 2008 · 5 citations · open access
Characteristics of ectopic adrenocorticotropic hormone syndrome due to thymic carcinoid and analysis of the molecular mechanism
AbstractEctopic adrenocorticotropic hormone (ACTH) secretion from a non-pituitary tumor is a main cause of Cushing's syndrome, which is associated with significant morbidity and mortality. Although early studies showed that the predominant cause of ectopic Cushing's syndrome is small cell carcinomas of the lungs, the incidence of carcinoid, including thymic carcinoid, has increased substantially in recent surveys.1 This evidence suggested that the clinical syndrome of ectopic ACTH production only occurs in tumors with high proopiomelanocortin (POMC, the precursor to ACTH) transcripts generated from the start of the pituitary transcription initiation site.2 Recently a series of transcription factors that participate both in the differentiation and in POMC gene expression in mature pituitary corticotroph cells3 have been identified, but the molecular mechanism for ectopic POMC overexpression remains obscure. We report here a case of Cushing's syndrome caused by an ACTH-producing thymic carcinoid. We analyzed the expression of several corticotroph-associated transcription factors in the tumor tissue to reveal a possible underlying molecular mechanism. CASE REPORT A 44-year-old man presented with significant weight gain, weakness and a psychiatric symptom. A physical examination showed pigmentation, moon-like face, central obesity, and edema in the eyelids and lower extremities. The patient's blood pressure was elevated to a systolic blood pressure of 160-180 mmHg and a diastolic blood pressure of 100-110 mmHg. The laboratory studies indicated severe hypokalemia (serum potassium 1.97 mmol/L, normal range 3.5-5.1 mmol/L) and hyperglycemia (fasting blood glucose 11.07 mmol/L, normal range 3.9-6.1 mmol/L). The thyroid function tests revealed hypothyroidism with TT3 0.6 nmol/L (normal range 0.89-2.44 nmol/L), TT4 56.9 nmol/L (normal range 62.67-150.84 nmol/L), FT3 1.09 pmol/L (normal range 2.62-6.49 pmol/L), FT4 7.35 pmol/L (normal range 9.01-19.04 pmol/L) and TSH 0.3 μIU/ml (normal range 0.1-10.0 μIU/ml). The basal serum cortisol level was 41.8 μg/dl (normal range 7-22 μg/dl) at 8:00 a.m., and the circadian rhythm disappeared with 25.9 μg/dl and 43.8 μg/dl at 4:00 p.m. and 12:00 p.m. respectively (serum samples were collected in one day). The levels of plasma ACTH (536.3-625.0 pg/ml, normal range 12-78 pg/ml) and the 24 hours urine free cortisol (UFC, 3859 μg/24 h, normal range 20-90 μg/24 h) were markedly raised. After the administration of 2 mg and 8 mg dexamethasone, the 24 hours UFC changed to 3260 μg/24 h and 2972 μg/24 h respectively. These negative suppression results combined with pigmentation, edema and hypokalemia suggested that endogenous hypercortisolism is sustained by an ACTH-secreting non-pituitary tumor. The magnetic resonance imaging (MRI) revealed normal pituitary and the abdominal computed tomography scan showed bilateral adrenal hypertrophy. A chest X-ray and a computed tomography imaging detected a mediastinal mass measuring more than 10 cm in diameter (Figure 1).Figure 1.: X-ray chest film (A) and chest computed tomography scan (B) showed a mass in the middle and inferior mediastinum.The patient underwent a median sternotomy and a resection of the mediastinal mass. The resected tumor measured 14 cm × 9.0 cm × 6.0 cm. After the procedures, the serum potassium, fasting blood glucose, and cortisol level immediately fell within the normal ranges (Table 1). The plasma ACTH level decreased gradually after the resection; it was below the upper limit of the normal range 3 hours after surgery and decreased to 25 pg/ml on the third day (Figure 2). The clinical symptoms, including skin pigmentation, were significantly improved after surgery.Table 1: Hormonal measurement before and after surgeryFigure 2.: ACTH level was showed at a series of time after surgery. Dramatic decline was observed immediately after the resection of the tumor, and 3 hours later the ACTH level was normal. Since then the level further decreased to 25 pg/ml on the third day. ACTH: adrenocorticotropic hormone.A histological examination revealed round and polygonal cells with cytoplasmic lucent granules and increased vascularity, which are consistent with thymic carcinoid. Infiltration of the peripheral vessels and adipocyte tissue was detected. The immunohistochemistry test stained positive for ACTH (Figure 3).Figure 3. A:: Histological examination revealed thymic carcinoid (HE stain, original magnification ×200). B: Arrow indicated strong positive ACTH staining. ACTH: adrenocorticotropic hormone.The patient has been followed up for 6 years since the treatments and remains in good health. RT-PCR analysis of corticotroph-associated genes expression To further investigate how a tumor cell outside pituitary acquired the ability to produce ACTH, we analyzed the expression of several corticotroph-associated transcription factors in the thymic carcinoid tissue. RNA extraction and RT-PCR procedures were previously described.4 The primers are listed in Table 2. As expected, a strong RT-PCR signal was detected for the POMC gene in the tumor tissue. The T-box binding factor, Tpit gene and the NeuroD1 gene were also overexpressed (Figure 4).Table 2: The primers of POMC, Tpit and NeuroD1 geneFigure 4.: RT-PCR analysis of the expression of the corticotroph-associated transcription factors. TC: thymic carcinoid. NT: normal thymus. POMC: proopiomelanocortin.DISCUSSION Thymic carcinoids are classified as neuroendocrine carcinomas, ranging from well-differentiated neuroendocrine carcinomas (carcinoids) to small cell carcinomas and accounting for approximately 2% to 4% of all anterior mediastinal tumors. Thymic carcinoids may be associated with ectopic ACTH syndrome (EAS) or form a part of the multiple endocrine neoplasms type 1 syndrome.5 Since year 2000, we have diagnosed 17 cases of EAS, 8 of which have been identified with localization including 6 cases of thymic carcinoid.6 The patient reported here was the most typical case. The neuroendocrine thymic tumors associated with EAS may occur at any age from 4 to 64 years, mostly between 20 and 40 years and as frequently in men as in women. The patients may present typical physical signs of hypercortisolism or primary metabolic disorders. The cushingoids are sometimes indistinguishable from Cushing's disease, but skin pigmentation, hypertension, edema, severe hypokalemic with myoasthenia are more predominant in EAS than in Cushing's disease.7 The patient here developed severe weakness caused by hypokalemia, visible pigmentation and edema in the eyelids and lower extremities. These features were shortly and significantly relieved after the resection of the tumor. Hypothyroidism can be sometimes indicated by the inhibition of the redundant adrenal cortical hormone's secretion of thyrotrophin-releasing hormone (TRH) and thyrotropic-stimulating hormone (TSH). The manifestation of Cushing's syndrome, hypercortisolism with negative results from the 2 mg dexamethasone suppression test, elevated ACTH levels, and bilateral adrenal hyperplasia suggested a pituitary adenoma or an ectopic secretion of ACTH. The establishment of the EAS diagnosis relies on the negative response to stimulating or inhibiting agents including the 8 mg dexamethasone, the corticotropin releasing hormone (CRH), or the metyrapone. However, EAS tumors may sometimes acquire more differentiation features of the pituitary cells; therefore none of these methods is accurate enough to definitively distinguish between pituitary or nonpituitary tumors. It has been indicated that when the inferior petrosal sinus and the peripheral vein samplings are combined with the CRH test, the results can reach an accuracy rating of 100%,8 but the possible false negative results and the potential risk of brain injury limit its application in clinical diagnosis.9 According to our own data, we recommend the 8 mg dexamethasone test for its convenience and accuracy. Among the 17 cases of EAS we have diagnosed, all 17 had negative suppression results including this case. Localization is another challenge for an endocrinologist because some ectopic ACTH-secreting tumors can be exceedingly small and may not be depicted on various imaging tests even after a long-term follow-up. However, if an ectopic source is highly suspected, a chest X-ray and a CT are strongly recommended especially for the follow-up of those with occult tumors. It should be emphasized that thymic remnant tissue and small thymic carcinoid tumours might have a similar appearance on the CT scan and will be potentially misleading, resulting in an incorrect diagnosis and unnecessary thoracotomy.10 Since thymic tissue regresses with age, this concern will be generally excluded in patients above 40.10 Positron emission tomography (PET) and octreotide radio-labeled scans may also be useful in the localization but no privileges were found in our survey.11 Once the tumor is clearly detected, resection is the best choice for the removal of the neuroendocrine tumor of the thymus. Thymic carcinoid tumors tend to undergo a progressive malignant transformation and metastasis into either a lymph node, or change haematogenously into other organs. Therefore an aggressive local resection such as median sternotomy is recommended for most cases. Despite the aggressiveness of the treatment, thymic carcinoid tumors have a poor prognosis with a ten-year survival rate less than 50% with the lowest survival rate of 35%.12 Local infiltration was demonstrated in this described case. The patient has been followed up for more than 6 years, and he still remains in good health. Physiologically, ACTH results primarily from a pituitary transcript of a POMC gene in the corticotroph cell. The POMC precursor molecule is cleaved by prohormone convertase 1 into ACTH. We detected the overexpression of the POMC gene in the thymic carcinoid tissue. However, due to the lack of in vitro cell models, why and how a POMC gene is expressed in an ACTH-producing carcinoid tissue remains obscure. We wonder whether the transcription factors acting on a POMC gene promoter are maintained not only in pituitary corticotroph tumors but also in a thymic carcinoid, which are both well differentiated and have slow proliferation. A RT-PCR study demonstrated that the Tpit and NeuroD1 expressions were specifically conserved in this carcinoid tissue, suggesting a possible role in ectopic POMC expression. NeuroD1 (BETA2) and Tpit are cell-specific activators of pituitary POMC gene transcription. The expression of both factors slightly precedes that of POMC at embryonic d 12.5 of a mouse's pituitary development.13 A gel-shift assay indicated that NeuroD1 was absent from the DMS-79 cell, a small cell lung carcinoma (SCLC) cell line as an in vitro model to study the ectopic ACTH syndrome.14 We found a sharp band of NeuroD1s in the carcinoid tissue, because carcinoids are better differentiated than SCLC tumors or because this particular mRNA cannot code for a bioactive protein. Messager et al15 also detected positive Tpit and NeuroD1 expression in bronchus carcinoids with positive ACTH staining. However, the conclusion of their exact roles in an ectopic POMC expression still needs further evidences. In conclusion, we have reported a case of EAS caused by thymic carcinoid. A specific RT-PCR test detected abnormal expression of POMC, Tpit, and NeuroD1 in the tumor tissue, suggesting that the mechanism of POMC transcription in a normal pituitary corticotroph may be partly reserved in the thymic carcinoid with EAS.
Diagnosis and Management of Adrenocorticotropic Hormone-Secreting Pituitary Carcinoma: A Case Report and Review of the Literature
AbstractAdrenocorticotropic hormone (ACTH)-secreting pituitary carcinomas (PC) are rare. The natural history and management of these carcinomas are poorly understood. We conducted a literature review using The MEDLINE database, including the search terms; ‘ACTH’ and ‘pituitary carcinoma’. We also describe in detail a case of ACTH-secreting PC. A total of 61 case reports were reviewed. Median age of diagnosis was 45 years (IQR: 34–54). Metastases to multiple organs were common (61%). Adjuvant therapy especially radiotherapy (78%), temozolomide (34%) and other medical therapy (29%) were frequently employed. The mortality was 53% with a median time to death from diagnosis of 1 year (IQR: 1–3). In conclusion, ACTH-secreting PC are associated with high mortality and a multidisciplinary team approach is recommended for optimal care due to the emerging modalities with possible efficacy.
The Journal of Clinical Endocrinology & Metabolism · 2005 · 0 citations · open access
Cushing’s Syndrome
AbstractCushing’s syndrome reflects the physical and mental changes that happen in the body from having too much cortisol in the blood for a long period of time. Cortisol is a steroid hormone produced by the adrenal glands (which are above the kidneys). In normal amounts, cortisol helps the body: ... There are two types of Cushing’s syndrome: exogenous and endogenous. The symptoms for both are the same. The only difference is how they are caused. The most common is exogenous Cushing’s syndrome and is found in patients taking cortisol-like medications such as prednisone. These medications are used to treat inflammatory disorders such as asthma and rheumatoid arthritis, or to suppress the immune system after an organ transplant. This type of Cushing’s is temporary and goes away after the patient has finished taking the cortisol-like medications. Endogenous Cushing’s syndrome is rare, it usually comes on slowly and can be difficult to diagnose. It is caused either by a problem with the adrenal glands or the pituitary (a gland located at the base of the brain). In the adrenal glands, the problem is caused by a tumor (usually non-cancerous) that produces too much cortisol. When the problem is with the pituitary, the problem is caused by a tumor that produces too much ACTH (the hormone that tells the adrenal glands to make cortisol). When the tumors form in the pituitary the condition is often called Cushing’s disease.
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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