DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Cowden syndrome 7 — 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 7 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 7 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.
What the evidence adds up to
A pilot study gave 18 patients with germline PTEN mutations and Cowden syndrome a 56-day course of daily oral sirolimus. Regression of skin and gastrointestinal lesions was observed by dermoscopy or endoscopy. Neurological evaluation showed improvement in cerebellar function score at one month. Immunohistochemistry in skin and gastrointestinal benign lesions showed a decrease in the ratio of phosphorylated S6 to total S6 in response to sirolimus; ratios of pS6K to total S6 at days 14 and 56 were significantly lower than at baseline (p = 0.0026, p = 0.00391, respectively). The 56-day course was well tolerated. This was the first human interventional study in Cowden syndrome driven by germline PTEN inactivation.
Cowden syndrome is an autosomal dominant disorder caused by inactivating germline PTEN mutations, leading to aberrant PI3K-Akt-mTOR pathway activation. Patients have macrocephaly, multiple hamartomas, trichilemmomas, oral fibromas, and elevated risks of breast, thyroid, endometrial, kidney, and colorectal cancers. Lhermitte–Duclos disease can be a presenting feature. Most PTEN mutations are unique to a given family. Other genes such as KILLIN, SDH B/D, PIK3CA, and AKT1 contribute to a subset of cases. A 46-year-old woman with typical Cowden syndrome features was found to have a novel heterozygous PTEN mutation (c.403A > G, p.Ile135Val) in exon 5. A 49-year-old man with trichilemmomas, oral papules, thyroid lesions, and multiple upper gastrointestinal polyps was found to have a novel heterozygous PTEN variant (c.100G>C, p.Ala34Pro) in exon 2; bioinformatic tools predicted this variant as pathogenic, and tertiary structure prediction indicated loss of one beta-helix in the phosphatase domain.
The sirolimus pilot study was small, open-label, and only 56 days long. No controlled trial has been conducted. The novel PTEN variants reported are from single cases, and their pathogenicity remains uncertain without functional validation or segregation data. What is still missing is a larger, randomised, placebo-controlled trial of mTOR inhibition with longer follow-up, systematic collection of cancer incidence data, and validated biomarkers to stratify patients by mutation type or baseline mTOR pathway activation.
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 Oncologist · 2019 · 70 citations · open access
A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in <i>PTEN</i>
AbstractAbstract Lessons Learned This is the first human interventional study in patients with Cowden syndrome that is driven by inactivation of germline PTEN gene. Single-agent sirolimus, a mTOR inhibitor, suppressed mTOR signaling in surrogate human tissues without significant toxicity. Background Cowden syndrome is characterized by inactivating germline PTEN mutations, which can lead to activation of the PI3K-Akt-mTOR pathway. Methods Adult subjects with germline PTEN mutation who met international diagnostic criteria for Cowden syndrome and who had Eastern Cooperative Oncology Group (ECOG) performance status 0–2 and adequate organ function were enrolled. Subjects were treated with a 56-day course of daily oral sirolimus. In addition to symptom assessment and physical examination, dermatologic, endoscopic, neurologic (cerebellar), and radiographic assessments were conducted. Inhibition of the mTOR pathway in benign skin and gastrointestinal (GI) lesion was assessed by immunohistochemistry. Results A total of 18 patients and 16 families were enrolled. PTEN mutations were located at exons 1–8. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Neurological evaluation showed improvement in cerebellar function score at 1 month. Immunohistochemistry (IHC) analysis in skin and GI benign lesions showed a decrease in the ratio of phosphorylated (p)S6 to total S6 in response to sirolimus. Ratios of pS6K to total S6 at days 14 and 56 were significantly lower than at baseline (p = .0026, p = .00391, respectively). A 56-day course of sirolimus was well tolerated. Conclusion A 56-day course of sirolimus was well tolerated in subjects with Cowden syndrome and was associated with some evidence of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling.
Formosan Journal of Surgery · 2019 · 2 citations · open access
Cowden syndrome diagnosed by Lhermitte–Duclos disease
AbstractCowden syndrome (CS) is a rare genetic disease which puts patients at an increased risk of developing mucocutaneous lesion, multiple hamartomas, breast cancer, thyroid cancer, and Lhermitte–Duclos disease (LDD). This article reviews the role of LDD in the diagnosis of CS. It is important for all clinicians to identify these patients due to the high risk of other associated malignancies.
The Journal of Medical Investigation · 2020 · 2 citations · open access
A case of Cowden syndrome with a novel mutation in the PTEN gene
AbstractCowden syndrome (CS) is an autosomal dominant inherited disorder characterized by macrocephaly and multiple hamartomas. The responsible gene is PTEN (phosphate and tensin homolog detected on chromosome 10), which negatively regulates cell proliferation and survival. We herein present a 46-year-old woman with the typical clinical features of CS. A DNA sequencing analysis of the coding regions and flanking introns of the PTEN gene revealed a novel heterozygous mutation (c.403A > G, p.Ile135Val) in exon 5 that had not been previously reported in CS. J. Med. Invest. 67 : 200-201, February, 2020.
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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