DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Mastocytosis — screening already-approved drugs against its 30-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMastocytosis maps to a 30-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
approvedDasatinibApproved drug
Structures already discussed alongside mastocytosis in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of EphA4 kinase domain — Dasatinib has a real, experimentally solved structure in complex with this target (PDB 2Y6O, 1.543 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet 1n1drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2Y6O · 1.543 Å · ligand Dasatinib (1N1). Experimental structure, not a prediction.
What the evidence adds up to
Systemic mastocytosis is a clonal disorder of mast cells for which no curative therapy presently exists. Conventional management has relied on agents that antagonise mediators released by mast cells, inhibit mediator secretion, or modulate mast cell proliferation. The identification of the KIT D816V mutation has improved diagnosis and provided new therapeutic targets, including novel tyrosine kinase inhibitors.
Dasatinib was tested in a pilot phase II trial of 30 patients with systemic mastocytosis, 24 of whom were evaluable. The cohort included 6 with aggressive disease, 4 with an associated haematological non-mast cell disease, and 14 with indolent disease and uncontrolled symptoms. Two patients (8%) achieved complete remission; both were c-KIT mutation negative and had low tryptase levels. Symptoms improved significantly in 7 patients (29%). The overall response rate was 37%. Six patients stopped therapy due to toxicity, and 12 required dose reductions. A separate case report described a patient with systemic mastocytosis and chronic myelomonocytic leukaemia who carried the D816V mutation; dasatinib was stopped after 13 weeks due to fatigue, and laboratory results were inconsistent.
Masitinib was evaluated in a randomised, double-blind, placebo-controlled phase 3 study of 135 patients with severely symptomatic indolent or smouldering systemic mastocytosis unresponsive to optimal symptomatic treatments. By 24 weeks, masitinib produced a cumulative response of 18.7% compared with 7.4% for placebo (odds ratio 3.6, p=0.0076). Frequent severe adverse events included diarrhoea (11% vs 2%), rash (6% vs none), and asthenia (6% vs 2%). No life-threatening toxicities occurred. The study was funded by AB Science.
What is still missing are trials that reliably show benefit in patients with the common KIT D816V mutation, which confers resistance to imatinib and may limit dasatinib’s activity. The masitinib trial enrolled only patients with indolent or smouldering disease, leaving aggressive forms unaddressed. No therapy has demonstrated an improvement in overall survival in a randomised setting. Patient stratification by mutation status and disease subtype, and adequately powered trials with hard endpoints, remain absent.
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.
AbstractMastocytosis refers to a spectrum of clinical and laboratory abnormalities attributable to tissue infiltration by large numbers of mast cells and to the discharge of various biologically active substances by these cells. It most commonly results in cutaneous manifestations during childhood but may develop at any age or involve almost any organ system. The treatment of mastocytosis has become considerably more practicable in recent years with the availability of agents that directly inhibit mast cells or temporarily reduce their quantity in the skin.
Annual Review of Pathology Mechanisms of Disease · 2017 · 60 citations
Pathogenesis and Pathology of Mastocytosis
AbstractSystemic mastocytosis is a clonal disorder of mast cells that may variably present with characteristic skin lesions, episodes of mast cell mediator release, and disturbances of hematopoiesis. No curative therapy presently exists. Conventional management has relied on agents that antagonize mediators released by mast cells, inhibit mediator secretion, or modulate mast cell proliferation. Recent advances in the molecular understanding of the pathophysiology of systemic mastocytosis have provided new therapeutic considerations, including new and novel tyrosine kinase inhibitors.
AbstractMastocytosis is a disease characterized by an abnormal increase in mast cells. Rare in occurrence, protean in its manifestations, it is a disease which is very seldom thought of and hence, possibly even overlooked. The last few decades have witnessed an upsurge in the understanding of the physiology and pathobiology of mast cells. Better means for diagnosis and follow-up have become available. Once a diagnosis is established histamine antagonists remain the mainstay of treatment. Most patients live and die with the disease rather than of it. The objective of this review is to discuss this entity with a special focus on diagnosis and treatment.
Dasatinib (Sprycel™) Therapy for Patients with Systemic Mastocytosis.
AbstractAbstract Background Systemic mastocytosis (SM) is characterized by abnormal proliferation and accumulation of neoplastic mast cells. Patients (pts) with SM are treated with recombinant interferon-alpha or cladribine. Responses to these agents are poor. Malignant mast cells in SM carry, in most cases, a mutation involving codon 816 of the c-KIT gene (D816V) resulting in constitutively activated c-kit receptor tyrosine kinase believed to be important for disease progression. Agents that antagonize this mutated form of c-kit may have clinical benefit in SM. Dasatinib is one such agent, proven effective in pre-clinical in vitro and in vivo models of SM. Study Design In pilot Phase II trial for SM, Dasatinib was administered at 70mg PO BID. Response was assessed after minimum of 3 months (3 cycles) of therapy. Therapy was discontinued in pts who showed no response after 6 cycles of therapy. Response was evaluated following guidelines proposed by Valent et al. (Leuk Res. 25;603–625, 2001). In addition, all symptoms related to SM were recorded and monitored. Results Thus far, a total of 30 pts have been treated; 24 are evaluable for response and toxicity, including 6 with aggressive SM (ASM), 4 with SM and associated hematologic non-mast cell disease (SM-AHNMD; 2 with chronic myelomonocytic leukemia and one each with myelofibrosis [SM-MF; JAK2 mutation positive and abnormal cytogenetics] and hypereosinophilic syndrome [SM-HES; FIP1L1-PDGFRa negative]) and 14 with indolent SM (ISM) with uncontrolled symptoms despite optimal supportive care measures. Median age is 57 years (range, 35–73); these were 10 males and 14 females; time from diagnosis to dasatinib therapy 49 months (range, 0–233), performance status 1 in 23 and 2 in 1 pt. Eleven patients were previously treated: imatinib mesylate in 6; denileukin diftitox in 4; and erythropoietin, interferon-alpha, or cladribine in 2 each. One pt, who had undergone splenectomy, had hepatomegaly prior to start of therapy. Median Hb 12.4g/dL (range, 8.5–15.4), WBC 6.7×109/L, (range, 3.5–53.3), and platelets 263×109/L (range, 60–377); no patient was transfusion dependent. Percent bone marrow mast cell varied from <10% in 9 pts, to 60% in 4 pts; blood tryptase level was ≤20ng/mL (not significant) in 7 pts and >200ng/mL (upper limit of the test) in 7 pts. A total of 94 cycles of therapy were administered. The median number of cycles was 4 (range, 1–8). Ten patients stopped therapy: 1 due to progression of AHNMD to acute leukemia, 1 lost a response (symptomatic improvement), 2 had no response after 3 months of therapy, and 6 due to toxicity. No grade 4 toxicity was observed. Twelve patients decreased the dose of dasatinib to 50mg PO BID, of which four to 40mg PO BID. Two patients (8%) achieved complete remission, one with SM-MF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). No significant response in % bone marrow mast cells (4 pts are too early in therapy) or blood tryptase levels have been observed in other patients so far. Symptoms related to SM improved significantly in 7 patients (29%). Conclusion Dasatinib is active in SM (overall response rate 37%). Updated clinical and molecular results will be presented.
Systemic Mastocytosis with c-KITD816V Mutation Treated with Dasatinib.
AbstractAbstract Objectives: Systemic mastocytosis (SM) is mainly a clonal disease with a variable clinical outcome. Prognosis is very much related to additional symptoms. If so called c-findings are present, survival is often limited to months. Until recently only Interferon and Cladribine could show some effect on the disease progression. With the introduction of Imatinib some hope grew to treat the disease by acting on c-KIT (CD 117; stem cell factor receptor). However, the substitution of valine for aspartic acid at position 816 in c-KIT (D816V) leads to prolonged mast cell survival and increased proliferation because of constitutive activation of the tyrosine kinase of c-KIT. Between 31% and 100% of patients with SM harbour the c-KIT D816V mutation which is invariably related to Imatinib resistance. Fortunately, the new tyrosinkinase inhibitor Dasatinib (BMS-354825) could show a much higher inhibition of the c-KIT D816V mutated receptor in vitro. Therefore we treated a patient with systemic mastocytosis with associated hematologic clonal non mast cell lineage disease (SM-AHNMD) and c-findings with Dasatinib. Case description: A 69 year old patient was diagnosed 5 years ago with cutaneous mastocytosis. Because of a markedly increased tryptase levels of 130μg/l he was referred to our clinic for further investigation. In a bone marrow biopsy, the classical signs of SM could be found together with a chronic myelomonocytic leukemia (CMML) without any cytogenetic alterations. During 2 years the patient remained clinically stable without any treatment. Subsequently the patient droped weight and got strong lumbar pain. A MRI scan revealed fractures of L2 and L4 without signs for osteoporosis. Additionally, splenomegaly and hepatomegaly have been noticed with enlarged lymph nodes in the retroperitoneal space together with profound thrombocytopenia. Even SM-AHNMD is by definition of the ‘year 2000 Working Conference on Mastocytosis’ a distinct entity, the occurring c-findings together with a rapid increase in tryptase levels have been associated with an aggressive disease course. A c-KIT mutation analysis showed a D816V mutation. We decided after approval from the medical council to start the patient on Dasatinib. We started with 50mg daily for 3 days. Because no signs of acute mastcell degranulation we increased the dose to 50mg BID and continued the treatment for 13 weeks. Due to non-hematologic toxicity (fatigue) Dasatinib had to be stopped. Hepatosplenomegaly remained stable, lumbar pain disappeared even after cessation of analgetic therapy and weight increased gradually. However, laboratory follow up (tryptase, soluble interleukin 2 receptor) showed inconsistent results. Conclusion: Our patient with SM-CMML had many signs of systemic aggressive mastocytosis which is a mostly fatal variant of SM. With the introduction of Imatinib, a potent c-kit inhibitor, a novel approach to inhibit mastcell-proliferation was described. However, the most common mutation in CD117 of mastcells (D816V mutation) turned out to be resistant to Imatinib. However, Dasatinib a recently introduced tyrosinkinase inhibitor showed significant efficacy in vitro. A phase II study of Dasatinib in patients with Philadelphia-negative myeloproliferative disorders, including SM has recently been presented by Verstovsek and colleagues showing an overall response rate of 42% in SM. However, these patients were c-KIT mutation negative. This case report shows first evidence of clinical activity of Dasatinib in a patient with systemic aggressive mastocytosis harbouring the c-KIT mutation D816V. Further clinical studies in this patient population are warranted.
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
Open Science Framework · 2017 · 0 citations · open access
Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study
AbstractBackground:Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.Methods:In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. Findings: Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). Interpretation:These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding: AB Science (Paris, France)
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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