DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for Mast Cell Sarcoma — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMast Cell Sarcoma maps to a 2-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 drugapprovedPonatinibApproved drug
Structures already discussed alongside mast cell sarcoma 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
Two infants with solitary mastocytoma were treated with 5 mg/kg/day of oral tranilast, a mast cell stabilising compound. In one infant a topical corticosteroid was also applied. The nodules resolved almost completely after eight weeks, and no relapses were observed after six months of therapy. The authors speculated that tranilast reduced the number of mast cells as well as inhibiting degranulation. This is a single report from 1996 on two patients with a benign, localised form of mast cell disease, not mast cell sarcoma.
A 2018 single-centre study from Vienna analysed 24 patients with aggressive systemic mastocytosis, mast cell leukaemia and mast cell sarcoma. Two patients had mast cell sarcoma. One of them, a 33-year-old woman, received two cycles of CLAG chemotherapy (cladribine, cytarabine, G-CSF) and achieved a good partial response of the remaining tumour mass after surgery. The other, a 30-year-old woman, also had a good partial response after CLAG and then underwent haematopoietic stem cell transplantation, achieving long-term complete remission under maintenance midostaurin. Among all 21 treated patients, 17 (81%) showed some response: one complete remission, two good partial responses, five partial responses, and nine stable disease. Median survival until loss of response to first-line therapy was 20 months. Three patients were still alive at follow-up, seven developed secondary acute myeloid leukaemia, and three died from unrelated causes. The median survival after secondary AML was 4 months. The authors concluded that treatment remains an unmet need and that controlled studies are needed.
Two 2024 review articles discuss mast cell biology and systemic mastocytosis but provide no new clinical data on mast cell sarcoma. One review notes that mast cell sarcoma is classified as a localised form of mastocytosis distinct from systemic disease, and that some variants of mastocytosis are among the most aggressive known malignancies.
What is still missing: prospective, controlled trials specifically for mast cell sarcoma, which is too rare for conventional randomised designs. The 2018 study is retrospective, single-centre, and includes only two sarcoma patients. No standardised first-line regimen exists. The role of haematopoietic stem cell transplantation and maintenance therapy is unclear. Patient stratification by KIT mutation status and associated haematologic neoplasms is not yet validated. Funding for international registries and collaborative trials is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Haematologica · 2013 · 44 citations · open access
Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V
AbstractPatients with advanced systemic mastocytosis, including mast cell leukemia, have a poor prognosis. In these patients, neoplastic mast cells usually harbor the KIT mutant D816V that confers resistance against tyrosine kinase inhibitors. We examined the effects of the multi-kinase blocker ponatinib on neoplastic mast cells and investigated whether ponatinib acts synergistically with other antineoplastic drugs. Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells. Ponatinib induced growth inhibition and apoptosis in HMC-1.1 cells (KIT G560V(+)) and HMC-1.2 cells (KIT G560V(+)/KIT D816V(+)) as well as in primary neoplastic mast cells. The effects of ponatinib were dose-dependent, but higher IC50-values were obtained in HMC-1 cells harboring KIT D816V than in those lacking KIT D816V. In drug combination experiments, ponatinib was found to synergize with midostaurin in producing growth inhibition and apoptosis in HMC-1 cells and primary neoplastic mast cells. The ponatinib+midostaurin combination induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk. We then applied a Btk short interfering RNA and found that Btk knockdown sensitizes HMC-1 cells against ponatinib. Finally, we were able to show that ponatinib synergizes with the Btk-targeting drug dasatinib to produce growth inhibition in HMC-1 cells. In conclusion, ponatinib exerts major growth-inhibitory effects on neoplastic mast cells in advanced systemic mastocytosis and synergizes with midostaurin and dasatinib in inducing growth arrest in neoplastic mast cells.
AbstractTwo infants with solitary mastocytoma were treated with 5 mg/kg/day of tranilast [N-(3',4'-dimethoxycinnamoyl)anthranilic acid], a mast cell stabilizing compound extracted from Nandina domestica. Tranilast was administered orally in three divided doses. In one infant, a topical corticosteroid was also applied in combination with the oral tranilast. Patients experienced symptomatic relief, and nodules resolved almost completely after eight weeks of treatment. Tranilast therapy was continued for six months. No relapses were observed after discontinuation of therapy. We speculated that tranilast not only inhibited mast cell degranulation but also reduced the number of mast cells.
Treatment of Patients with Aggressive Systemic Mastocytosis, Mast Cell Leukemia and Mast Cell Sarcoma: A Single Center Experience
AbstractAbstract Aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) and mast cell sarcoma (MCS) are rare, life-threatening mast cell disorders, characterized by an aggressive clinical course, drug resistance and a poor survival. Established disease-modifying therapies include interferon-alpha (INF-A), cladribine (2CdA) and midostaurin (PKC412). However, these treatment approaches are unable to exert curative effects in advanced mastocytosis. Intensive therapy, including poly-chemotherapy and hematopoietic stem cell transplantation (HSCT) have also been suggested for patients with rapidly progressing ASM and MCL (Ustun et al, J Clin Oncol 2014;32:3264-3274). However, little is known about long-term outcome and survival in these patients. We analyzed the clinical course and treatment responses in 24 patients with ASM, MCL and MCS seen at the Medical University of Vienna between May 1994 and December 2017. According to World Health Organization criteria, patients were diagnosed as ASM (n=11), ASM with associated chronic myelomonocytic leukemia (ASM-CMML, n=6), ASM with associated chronic eosinophilic leukemia (ASM-CEL, n=1), MCL (n=4) and MCS (n=2). The median age at diagnosis was 59 years (range 21-90 years) and the f:m ratio was 1:2.4. Patients received first-line therapy with INF-A (3x106 units three times a week, n=8), 2-CdA (0.13 mg/kg, days 1-5, n=5); CLAG (cladribine 5mg/m2, days 1-5, ARA-C 2g/m2 day 1-5, G-CSF, 300 µg from day 6 until recovery; n=2), alternating 2CdA and midostaurin (n=2), midostaurin alone (2x100 mg/day, n=2), FLAG (fludarabine, 30mg/m², days 1-5; ARA-C 2 g/m² days 1-5; G-CSF 300µg from day 6 until recovery, n=1) and brentuximab-vedotin (1.6 mg/kg every 3 weeks, n=1). In 3 patients (ASM, n=1; MCL, n=2) no therapy could be administered because of poor performance status. Detailed information on therapies and responses in our patients are provided in Figure 1. In 17 of 21 patients (81%) a response to therapy was observed, namely a complete remission (CR) in one female MCL patient, age 54 yrs (years) receiving 2 cycles of FLAG; a good partial response (GPR) of the remaining tumor mass (after surgery) in one female patient with MCS aged 33 yrs after 2 cycles of CLAG; a partial response (PR) in 5 additional patients; and a stable disease (SD) in 9 patients (Figure 1). Two patients, one female ASM patient, age 54 yrs with PR after 6 cycles of 2CdA and one female patient with MCS, age 30 yrs, with a GPR after CLAG, underwent HSCT and achieved long-term CR under maintenance with midostaurin. Median survival until loss of response to first-line therapy was 20 months (range: 3-73 months). Interestingly, in all 4 patients who had received both 2CdA and midostaurin, no progression of the disease occurred. In the follow up, 3 patients are still alive, 7 developed a secondary acute myeloid leukemia (sAML) and in one patient with ASM-CMML, the CMML component progressed without overt AML. Three patients died due to unrelated (non-SM) events (age at death: 93, 90, and 67 yrs). The patient with CR following FLAG had a relapse of MCL after 4 months. In 3 patients receiving IFN-A, the disease showed progression under therapy and in 2 patients receiving midostaurin, therapy had to be withdrawn due to treatment-related toxicity prior to response evaluation. Interestingly, the risk to develop sAML was significantly higher in patients with ASM/CMML or ASM/CEL (71.4%) compared to patients with ASM (27.2%) or MCL/MCS without an associated hematologic neoplasm (0%) (p<0.05). Salvage therapy in patients with progressive disease (PD or toxicity under first-line therapy, n=4; PD/relapse following response to first-line therapy in patients eligible for further therapy, n=10) included 2CdA, polychemotherapy, INF-A, azacitidine and hydroxyurea. The median number of treatment lines of salvage therapy was 1.7 (range 1-4) and resulted in a median duration of response of 8 months (range: <1 to 44 months). The median survival of patients developing sAML was 4 months and was markedly shorter compared to patients without sAML (median survival 13 months). In conclusion, treatment of ASM, MCL and MCS remains a clinical challenge and unmet treatment-need. The combination of conventional therapy such as chemotherapy with novel tyrosine kinase inhibitors and/or HSCT may be a new promising approach in these patients and may lead to cure in some of them. However, controlled studies are necessary to confirm this hypothesis. Figure 1. Figure 1. Disclosures Valent: Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria.
Immunology and Cell Biology · 2024 · 2 citations · open access
Highlight of 2023: Advances in mast cells
AbstractIn this article for the Highlights of 2023 Series, we consider the growing understanding of mast cell heterogeneity and interactions that has developed from single cell RNA sequencing studies. We also discuss novel concepts concerning mast cell interactions with the central nervous system and evidence for their role in host defense against SARS-CoV-2 infection.
Canadian Hematology Today · 2024 · 0 citations · open access
Systemic Mastocytosis: Diagnosis and Management in 2024
AbstractMastocytosis is a group of clonal disorders characterized by an accumulation of neoplastic mast cells (MCs) in one or more organ systems. The clinical presentation of mastocytosis is heterogenous as are the clinical outcomes. For example, some variants are associated with near normal life expectancy, while others are amongst the most aggressive known malignancies. Mastocytosis can occur in both pediatric and adult populations and can be classified into three major groups: systemic mastocytosis (SM), cutaneous mastocytosis (CM), and localized mast cell sarcoma. This review will focus on SM in adults with the aim of providing a general overview of the (1) pathophysiology, (2) diagnostic approach, and (3) current treatment landscape in Canada.
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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