DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for aggressive systemic mastocytosis — 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 moduleAggressive systemic mastocytosis 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 aggressive systemic mastocytosis 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
RUNX family transcription factor 1 (RUNX1) — RUNX1 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1E50 · 2.6 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Aggressive systemic mastocytosis is a rare subtype of systemic mastocytosis characterised by multi-organ involvement, bone marrow dysfunction, osteolytic lesions, and palpable hepatomegaly or splenomegaly, which usually indicate a high mast cell burden. The condition meets criteria for systemic mastocytosis and has one or more C findings. Prognosis and treatment strategy are highly individualised due to variable factors.
In a series of 342 adult patients with systemic mastocytosis seen at the Mayo Clinic, life expectancy in indolent systemic mastocytosis was not significantly different from the control population, but prognosis was not as good in the smoldering variant. Prognosis in systemic mastocytosis associated with another myeloid malignancy was significantly better in the absence of morphological features of myelodysplasia or monocytosis. Cladribine and interferon alpha were therapeutically the most effective drugs, while experience suggested limited treatment success with imatinib mesylate or other anti-KIT D816V kinase inhibitors. TET2 mutations were described in approximately 29% of patients, but their pathogenetic or treatment relevance was unknown.
The first therapeutic agent to be FDA approved in decades was midostaurin in 2017, with a 60% response rate and improvement in both end-organ damage and symptoms. However, complete responses or remissions with midostaurin have been elusive. Additional clinical trials of tyrosine kinase inhibitors targeting the KIT mutation show promise, with avapritinib and DCC-2618 having early clinical trial data, and avapritinib showing potential to induce complete remissions. The NCCN guidelines note that the identification of KIT D816V mutation and novel targeted therapies have improved diagnosis and treatment, but aspects of clinical care, particularly assessment and management of mediator-related symptoms, continue to present challenges.
The Italian Mastocytosis Registry, including 600 patients diagnosed between 1974 and 2014, confirmed that in most patients with systemic mastocytosis, serum tryptase levels were greater than 20 ng/ml and KIT D816V was detectable. The registry revealed centre-specific approaches for diagnosis and therapy. What remains missing are large, randomised trials that can establish standardised treatment protocols for aggressive systemic mastocytosis, better understanding of the role of additional mutations such as TET2, and methods to achieve durable complete remissions rather than partial responses.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of the National Comprehensive Cancer Network · 2018 · 105 citations · open access
Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology
AbstractMastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.
Current Opinion in Hematology · 2010 · 98 citations
Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature
AbstractPURPOSE OF REVIEW: Systemic mastocytosis is a neoplastic disease of mast cells that often harbors a KIT mutation and involves the bone marrow. The current review provides an update on prognosis and treatment of systemic mastocytosis, including investigational drug therapy. RECENT FINDINGS: We have recently examined survival data and treatment outcome in 342 adult patients with systemic mastocytosis seen at our institution. Life expectancy in indolent systemic mastocytosis was not significantly different than that of the control population; however, prognosis was not as good in the WHO indolent systemic mastocytosis variant of smoldering mastocytosis. Prognosis in systemic mastocytosis associated with another myeloid malignancy was significantly better in the absence of morphological features of myelodysplasia or monocytosis. On the contrary, although prevalent, eosinophilia had little prognostic impact. Cladribine and interferon alpha were therapeutically the most effective drugs. Current experience suggests limited treatment success with either imatinib mesylate or other anti-KIT D816V kinase inhibitors. TET2 mutations have recently been described in approximately 29% of patients with systemic mastocytosis, but their pathogenetic or treatment relevance is unknown. SUMMARY: Primary data from a large series of patients have enabled delineation of well defined prognostic groups in systemic mastocytosis and clarification of the merits of conventional drugs for aggressive systemic mastocytosis.
The Italian Mastocytosis Registry: 6-year experience from a Hospital-Based Registry
AbstractAIM: We collected 'real-life' data on the management of patients with mastocytosis in the Italian Mastocytosis Registry. METHODS: Six hundred patients diagnosed with mastocytosis between 1974 and 2014 were included from 19 centers. RESULTS: Among adults (n = 401); 156 (38.9%) patients were diagnosed with systemic mastocytosis. In 212 adults, no bone marrow studies were performed resulting in a provisional diagnosis of mastocytosis of the skin. This diagnosis was most frequently established in nonhematologic centers. In total, 182/184 pediatric patients had cutaneous mastocytosis. We confirmed that in the most patients with systemic mastocytosis, serum tryptase levels were >20 ng/ml and KIT D816V was detectable. CONCLUSION: The Italian Mastocytosis Registry revealed some center-specific approaches for diagnosis and therapy. Epidemiological evidence on this condition is provided.
Current Opinion in Hematology · 2019 · 8 citations
Novel Approaches for Systemic Mastocytosis
AbstractPURPOSE OF REVIEW: The purpose of this review is to summarize the pathophysiology of systemic mastocytosis, review the most recent clinical trials and drug development in systemic mastocytosis, with a specific focus on the advanced systemic mastocytosis subtypes. RECENT FINDINGS: Systemic mastocytosis is a clonal neoplasm of mast cells that has had a number of successful therapeutic options being developed in the past few years. The first therapeutic agent to be Food and Drug Administration (FDA) approved in decades was midostaurin in 2017 with a 60% response rate % with improvement in both end-organ damage and symptoms. However, complete responses/remissions with midostaurin have been elusive. Additional clinical trials of tyrosine kinase inhibitors that target the proto-oncogene receptor tyrosine kinase (KIT) mutation show great promise. The two drugs with promising early clinical trial data include avapritinib and DCC-2618 with avapritinib showing potential to induce complete remissions. SUMMARY: Therapies for systemic mastocytosis are in a stage of evolution with further elucidation of additional mutations associated with oncogenesis in addition to the most commonly described KIT (give details), ongoing clinical trials could potentially with lead to further targeted therapy and increased complete responses and durable remissions.
Aggressive systemic mastocytosis:one case report and literatures review
AbstractObjective To improve the acknowledge of diagnosis and therapy of aggressive systemic mastocytosis (ASM).Methods One ASM patient was reported and the literatures were reviewed.Results As a rare subtype of SM,ASM is characterized by multiple organs involvement,and often accompanied by bone marrow dysfunction,osteolytic lesions and palpable hepatomegaly or splenomegaly which usually indicate the high mast cell burden.Conclusion ASM meets criteria for SM and has one or more C findings.Variable factors affect the prognosis of ASM patients and the formulation of the clinical treatment strategy which leads to the highly individualized therapies.
Key words:
Mastocytosis, systemic; Risk factor; Treatment
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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