DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Cowden syndrome 5 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCowden syndrome 5 maps to a 1-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 cowden syndrome 5 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
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) — PIK3CA 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 2sdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4JPS · 2.2 Å · ligand (2S)-N~1~-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl}pyrrolidine-1,2-dicarboxamide (1LT). Experimental structure, not a prediction.
What the evidence adds up to
Cowden syndrome is a rare genetic disorder caused by abnormal development of all three germ layers; because mesenchymal tissue gives rise to the vascular system, cerebral blood vessel pathology can occur and cause cerebrovascular disease in these patients. The syndrome is primarily driven by PTEN gene mutations, leading to aberrant cell proliferation and characteristic manifestations including multiple hamartomas, trichilemmomas, and elevated risks of breast, thyroid, and endometrial tumours. Other genes such as KILLIN, SDH B/D, PIKCA, and AK1 contribute to a subset of cases.
A 2024 report describes a 49-year-old male with a long history of vitiligo, prior thyroidectomy for multinodular goitre, and a family history of thyroid disease and thyroid cancer. Physical examination revealed an ogival palate, skin-coloured oral papules, and multiple facial rose-coloured papules confirmed as trichilemmomas by skin biopsy. Endoscopy showed multiple adenomatous and hyperplastic polyps in the oesophagus, stomach, and duodenum with duodenal lymphoid hyperplasia and intense glycogenic acanthosis. Nuclear magnetic resonance imaging showed a cerebellar venous angioma. Genetic sequencing detected a heterozygous transversion variant at exon 2, c.100G>C, resulting in the missense variant p.Ala34Pro (A34P), not previously described for Cowden syndrome or any other condition, and therefore classified as a variant of uncertain significance. Both PolyPhen-2 and SIFT tools predicted this variant as pathogenic, and tertiary protein structure prediction indicated the change causes loss of one beta-helix in the PTEN phosphatase domain. After genetic diagnosis the patient was referred for genetic counselling and will undergo thyroid, dermatological, and mammary exploration as well as neoplastic screening; only the mother was tested among first-degree relatives, and she was negative.
The PTEN gene is a negative regulator of the PI3K-AKT and mTOR signalling pathways, critical for cell proliferation, cell cycle progression, and apoptosis. Loss of PTEN function contributes to oncogenesis, and germline mutations are found in many patients with Cowden syndrome type 1 and other diseases, with most mutations unique to a given family. The 2024 report notes that identifying the exact PTEN mutation in a given family is essential for genetic counselling and may be useful for families with incomplete criteria in whom no other mutation has been found. What remains missing is systematic screening data for this specific variant across larger populations, prospective studies linking the A34P variant to cancer incidence, and any clinical trial testing whether early surveillance improves prognosis in mutation carriers.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Bulletin of Siberian Medicine · 2016 · 1 citations · open access
Cowden syndrome is a risk factor for ischemic stroke
AbstractCowden syndrome is a rare genetic disorder caused by the abnormal development of all three germ layers. Taking into consideration the mesodermal origin of mesenchymal tissue that gives rise to the vascular system, the pathology of cerebral blood vessels can occur in conjunction with this disease and cause the development of cerebrovascular disease in such patients.
Indian Journal of Community and Family Medicine · 2024 · 0 citations · open access
Cowden syndrome: Familial presentation and genetic insights
AbstractCowden syndrome (CS), primarily driven by PTEN gene mutations, leads to aberrant cell proliferation and presents with characteristic manifestations including multiple hematomas, hamartomatous polyps, and trichilemmomas. Beyond these, patients face elevated risks of breast, thyroid, and endometrial tumors. While PTEN mutations predominate, other genes such as KILLIN, SDH B/D, РІКСА, and AK1 contribute to a subset of cases. Here, we present the familial case of CS, underscoring its genetic complexity and clinical implications.
Indian Journal of Dermatology · 2024 · 0 citations · open access
A New Variant of the PTEN Gene in Relation to Cowden Syndrome Type 1
AbstractSir, Cowden syndrome-1 (CWS1), also known as Cowden’s disease or multiple hamartoma syndrome, is the best-described phenotype within the phosphatase and tensin homolog (PTEN) hamartoma tumour syndromes (PHTS), which are autosomal dominant spectrums of hamartomatous overgrowth disorders with variable phenotypic manifestations characterised by germline mutations of the tumour suppressor gene PTEN located at 10q22–23. Besides multiple hamartomas in a variety of tissues, patients have characteristic dermatologic manifestations such as trichilemmomas, oral fibromas, and punctate palmoplantar keratoses, as well as an increased risk of breast, endometrial, thyroid, kidney, and colorectal cancers. On occasion, they can also present other clinical features such as macrocephaly or genitourinary abnormalities. We report a patient presenting symptoms suggestive of CWS1, harbouring a novel molecular alteration in PTEN, which, to the best of our knowledge, has not been previously reported, and whose affected position was the same as another mutation reported in a patient diagnosed with Bannayan Riley Ruvalcaba syndrome. Both syndromes share gastrointestinal characteristics (hamartomatous polyps), mucocutaneous lesions and an increased risk of developing neoplasms.[1-3] A 49-year-old male presented to the dermatology department with a long history of vitiligo, prior thyroidectomy due to multinodular goitre, and a family history of thyroid disease and thyroid cancer. Physical examination revealed an ogival palate, skin-coloured oral papules and multiple facial rose-coloured papules compatible with cutaneous adnexal tumours. The differential focused on follicular or sebaceous neoplasms due to their location on the head (trichoadenoma, trichoblastic carcinoma, and sebaceoma) which were confirmed as trichilemmomas by skin biopsy [Figure 1]. Suspecting a PHTS, an endoscopy was performed, revealing multiple adenomatous and hyperplastic polyps in the oesophagus, stomach and duodenum with duodenal lymphoid hyperplasia and intense glycogenic acanthosis. According to the International Cowden Consortium operational criteria, a diagnosis of CWS1 was made meeting two pathognomonic (facial trichilemmoma and oral papules) and one minor (thyroid lesions) criteria.Figure 1: Ogival palate in a 49-year-old male (a), multiple and millimetric flesh-coloured papules around the mouth (b), on the forehead and nasal dorsum (c)Nuclear magnetic resonance imaging (NMRI) showed cerebellar venous angioma. Blood tests revealed a deficiency of vitamin D. Peripheral blood samples were collected to undergo a Sanger sequencing in genomic DNA for all the exons with the adjacent intronic regions of the PTEN gene. We studied the PTEN gene to carry out the genetic study, and nine pairs of primers were designed using National Center for Biotechnology Information (NCBI) Primer Blast, so that only the PTEN gene was amplified [Figure 2a] and not the pseudogene (PTENP1), which is structurally very similar to the first one. The polymerase chain reaction (PCR) products were purified to perform Sanger sequencing, whose sequences were resolved on an ABI PRISM 3100 sequencer and compared to the gene reference sequence.Figure 2: Primers used for the amplification of genomic DNA of the PTEN gene (a) and Sanger sequencing of exon 2 of the PTEN showed a heterozygous c.100G>C transversion variant (pAla34Pro) in the patient (b)Genetic sequencing detected a heterozygous transversion variant at exon 2, c.100G>C, resulting in the missense variant p.Ala34Pro (A34P), not previously described for CWS1 or any other condition; so we are faced with a variant of uncertain significance [Figure 2b]. Our intention with this study was to provide insight on a novel molecular alteration that may explain the clinical manifestation of CWS1 in the patient. Several pieces of evidence allowed us to classify this variant as pathogenic, confirming the clinical suspicion of CWS1. To predict the possible impact of an amino acid substitution on the structure and function of the PTEN protein, we used (Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant For Tolerant (SIFT) tools based on sequence homology and the physical properties of amino acids. Both tools predicted this variant as pathogenic, being a non-conservative amino acid change that affects a highly conserved region of the protein. Tertiary protein structure prediction programs (Protein Homology/AnalogY Recognition Engine [Phyre2]) indicate that the introduction of a proline at position 34 causes a change in the structure of the PTEN phosphatase domain [Figure 3]. We found five beta-helix structures in the secondary structure of wild-type PTEN, whereas when a change from alanine to proline occurs, this leads to the loss of one of the beta-helices of the PTEN phosphatase domain, supporting the theory that such a change affects the structure of the protein and therefore its normal operation.Figure 3: Conformation of PTEN phosphatase domain wild type A34 (a) and conformation of PTEN phosphatase domain mutated P34 (b)After the genetic diagnosis, our patient was referred for genetic counselling and will undergo thyroid, dermatological and mammary exploration as well as participation in studies of neoplastic screening. It was also recommended to study first-degree relatives, but only the mother was checked, which was negative. The phosphatase and tensin homolog (PTEN) gene is a negative regulator of the phosphoinositide-3-kinase (PI3K)-serine/threonine kinase (AKT) and the mechanistic target of rapamycin (mTOR) signalling pathways, which are critical for cell proliferation, cell cycle progression, and apoptosis.[4] Loss of function of the PTEN gene contributes to oncogenesis, and somatic mutations have been frequently identified in various malignancies, so the PTEN gene has been considered to be a tumour suppressor gene. Germline mutations in PTEN have also been found in many patients with both CWS1 and other diseases. Most mutations are unique to a given family.[5] In summary, we report a new genetic variant of uncertain significance in the PTEN gene, occurring in a patient with multiple criteria for the diagnosis of CWS1, and a family history of thyroid cancer. We also report other clinical features that may be related to the phenotypic spectrum of this specific mutation (gastrointestinal tumours other than the usual hamartomas). Identifying the exact mutation of the PTEN gene in a given family with CWS1 is essential in the genetic counselling of other families. It may also be useful for other families with incomplete criteria in which no other mutation has been found. All of those patients might be managed with screening for neoplasms to improve their prognosis. In addition, reporting those genetic variants and their correlation with clinical findings may be helpful for further knowledge of pathogenicity. Clinical findings in the patient such as trichilemmomas or mucocutaneous papules are hallmarks of the CWS1, but other findings like multiple gastrointestinal hamartomas or macrocephaly are variable. In our patient, we found multiple polyps in the upper gastrointestinal tract and duodenal lymphoid hyperplasia with intense glycogenic acanthosis. Although the new omic genetic techniques allow us to know more and more variants with likely pathogenic significance, we must not underestimate the classical analysis based on a well-founded clinical suspicion from which we can search for the genetic cause. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
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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