DeCure for Diaphyseal medullary stenosis-bone malignancy syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for diaphyseal medullary stenosis-bone malignancy syndrome — 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 moduleDiaphyseal medullary stenosis-bone malignancy syndrome 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 diaphyseal medullary stenosis-bone malignancy syndrome 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
methylthioadenosine phosphorylase (MTAP) — MTAP 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 2s,3s,4r,5sdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5TC6 · 1.48 Å · ligand (2S,3S,4R,5S)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-[(propylsulfanyl)methyl]pyrrolidine-3,4-diol (7A6). Experimental structure, not a prediction.
What the evidence adds up to
In a 2012 abstract, the hereditary bone dysplasia/cancer syndrome diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) was linked to mutations in a newly identified terminal exon of the methylthioadenosine phosphorylase (MTAP) gene. The mutations cause exon skipping and dysregulated alternative splicing of MTAP isoforms. In a sample of 16 sporadic osteosarcoma tumours, all expressed similar levels of the archetype MTAP RNA sequence, but the expression pattern of splice variants varied markedly: 11 of 16 did not express splice variant SV1, and 9 of 16 did not express SV6. A 2000 study had previously mapped the DMS-MFH locus to chromosome 9p21–22 and found loss of heterozygosity (LOH) in that region in 5 of 7 informative sporadic bone malignant fibrous histiocytoma (MFH) specimens, narrowing the candidate gene to a 2-cM interval. That study noted that 35% of individuals with DMS-MFH develop bone MFH, which accounts for 6% of all bone cancers in its sporadic form.
A 2009 imaging study of chronic sclerosing osteitis of the diaphysis of tubular bones followed 11 diaphyseal lesions in seven patients aged 13 months to 14.5 years. The authors concluded that marked cortical hyperostosis, medullary narrowing, and cortical lucencies in 8 of 11 lesions are helpful for recognition, and that early identification can prevent unnecessary repeat invasive procedures. No drug treatment was tested.
A 2018 surgical study of benign and low-grade malignant intramedullary chondroid lesions of the distal femur included 22 patients treated with intralesional resection and bone cement filling, with or without additional osteosynthesis using a locking compression plate. Mean follow-up was 55 months. No tumour recurrence occurred. However, the complication rate was high: fractures occurred in 2 of 12 patients with osteosynthesis and in 2 of 10 without, all in lesions reaching the diaphysis. Patients with additional osteosynthesis had significantly longer surgery time, more blood loss, longer hospital stay, more complications, more pain, less satisfaction, and worse functional outcome. The authors concluded that additional osteosynthesis worsened clinical outcome and that meta-epiphyseal lesions rarely need it, whereas diaphyseal lesions with cortical thinning remain at high fracture risk regardless of osteosynthesis.
No drug therapy for diaphyseal medullary stenosis-bone malignancy syndrome has been tested in these studies. What is missing is any clinical trial of a pharmacological intervention, adequate funding for such a trial, and a clear strategy for patient stratification given the rarity of the syndrome and the variability in MTAP splice variant 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.
Strategies in Trauma and Limb Reconstruction · 2018 · 8 citations · open access
Surgical therapy of benign and low-grade malignant intramedullary chondroid lesions of the distal femur: intralesional resection and bone cement filling with or without osteosynthesis
AbstractSurgical treatment of benign and low-grade malignant intramedullary chondroid lesions at the distal femur is not well analyzed compared to higher-grade chondrosarcomas. Localization at the distal femur offers high biomechanical risks requiring sophisticated treatment strategy, but scientific guidelines are missing. We therefore wanted to analyze a series of equally treated patients with intralesional resection and bone cement filling with and without additional osteosynthesis. Twenty-two consecutive patients could be included with intralesional excision and filling with polymethylmethacrylate bone cement alone (n = 10) or with compound bone cement osteosynthesis using a locking compression plate (n = 12). Clinical and radiological outcome was retrospectively evaluated including tumor recurrences, complications, satisfaction, pain, and function. Mean follow-up was 55 months (range 7-159 months). Complication rate was generally high with lesion-associated fractures both in the osteosynthesis group (n = 2) and in the non-osteosynthesis group (n = 2). All fractures occurred in lesions that reached the diaphysis. No fractures were found in meta-epiphyseal lesions. No tumor recurrence was found until final follow-up. Clinical outcome was good to excellent for both groups, but patients with additional osteosynthesis had significantly longer surgery time, more blood loss, longer postoperative stay in the hospital, more complications, more pain, less satisfaction, and worse functional outcome. Intralesional resection strategy was oncologically safe without local recurrences but revealed high risk of biomechanical complications if the lesion reached the diaphysis with an equal fracture rate no matter whether osteosynthesis was used or not. Additional osteosynthesis significantly worsened final clinical outcome and had more overall complications. This study may help guide surgeons to avoid overtreatment with additional osteosynthesis after curettage and bone cement filling of intramedullary lesions of the distal femur. Meta-epiphyseal lesions will need additional osteosynthesis rarely, contrary to diaphyseal lesions with considerable cortical thinning.
American Journal of Roentgenology · 2009 · 8 citations
Imaging Chronic Sclerosing Osteitis of the Diaphysis of Tubular Bones
AbstractOBJECTIVE: The purpose of this study is to report the radiographic changes seen in chronic sclerosing osteitis of the diaphysis of tubular bones during progression or healing, with CT and MRI correlation. Chronic sclerosing osteitis is an inflammatory condition of bone that can be considered a pediatric subset of the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) spectrum of disease. Previous descriptions of long-bone involvement focus predominately on metaphyseal lesions. Eleven diaphyseal lesions in seven patients (age range, 13 months-14.5 years) were followed. CONCLUSION: The marked degree of cortical hyperostosis, medullary narrowing, and cortical lucencies seen in eight of 11 lesions is helpful for recognition of diaphyseal chronic sclerosing osteitis. Early identification of the disorder can prevent unnecessary repeat invasive procedures.
Malignant fibrous histiocytoma: Inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21–22—evidence for a common genetic defect
Abstract LB-89: Discovery and characterization of novel MTAP splice variants resulting in a hereditary form of osteosarcoma and demonstration of their dysregulation in sporadic forms of this cancer
AbstractAbstract Hereditary cancer syndromes represent a powerful and tractable biologic system for identifying cancer-causing genes. Though the syndromes themselves may be rare, their study can provide insights into the basis of the more common sporadic forms of the cancer. Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal dominant bone dysplasia / bone cancer syndrome. This hereditary cancer syndrome is characterized by bone infarctions, cortical growth abnormalities, and pathologic fractures. Most notably, 35% of affected individuals develop bone MFH, a sarcoma that in its sporadic form accounts for 6% of all bone cancers and is believed to be etiologically related to osteosarcoma. Indeed, one of our affected family members developed histologically-proven osteosarcoma, thus further supporting a genetic link between these tumor types. Using a linkage based approach, we previously mapped the DMS-MFH tumor suppressor gene locus to chromosome 9p21-22 (1) and then through LOH analysis demonstrated that hereditary and sporadic forms of MFH most likely share a single underlying genetic etiology (2). We now demonstrate that DMS-MFH results from mutations in the most proximal of three previously unrecognized terminal exons of the methylthioadenosine phosphorylase (MTAP) gene. MTAP is a ubiquitously expressed homotrimeric-subunit enzyme critical to polyamine metabolism and adenine/methionine salvage pathways and was believed to be encoded as a single transcript from the eight previously described exons. Intriguingly, two of the novel MTAP exons arose from early and independent retroviral integration events in primate genomes at least 40 MYR ago and since their genomic integration have gained a functional role. Six distinct retroviral-sequence containing MTAP isoforms, each of which can physically interact with archetype MTAP (i.e., exons 1-8), are identified. The disease-causing / cancer-associated mutations occur within one of these retroviral-derived exons. The mutations result in exon skipping and dysregulated alternative splicing of all MTAP isoforms. Based on these findings in a hereditary form of bone sarcoma, we then analyzed the expression of these MTAP isoforms in a sample set (n=16) of sporadic osteosarcoma samples. All tumor samples expressed similar levels of the archetype MTAP RNA sequence but the expression pattern of the splice variants varied markedly between nearly all the samples. The majority of samples did not express SV1 (n=11/16) and nearly half did not express SV6 (n=9/16). Taken together, these results identify the first gene involved in the development of bone MFH / osteosarcoma and have potential implications for the treatment of this human cancer. References: 1. Am J Hum Genet. 64:801-7; 1999. 2. Genes Chromosomes Cancer. 27:191-5; 2000. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-89. doi:1538-7445.AM2012-LB-89
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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