DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for Juvenile Myelomonocytic Leukemia — screening already-approved drugs against its 32-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleJuvenile Myelomonocytic Leukemia maps to a 32-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 juvenile myelomonocytic leukemia 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
NRAS proto-oncogene, GTPase (NRAS) — NRAS 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 gdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6ZIO · 1.55 Å · ligand GUANOSINE-5'-DIPHOSPHATE (GDP). Experimental structure, not a prediction.
What the evidence adds up to
In a retrospective analysis of 21 children with juvenile myelomonocytic leukaemia (JMML) diagnosed between 2013 and 2018, 14 received the South Korean A-3V chemotherapy regimen. The effective response rate was 78.5%. The three-year overall survival rate was 76.2 ± 14.8% and the three-year disease-free survival rate was 66.2 ± 14%. Single factor analysis identified platelet count ≤33×10⁹/L, LDH >500 U/L, HbF >10%, and chemotherapy alone as significant factors for poor prognosis. Cox multivariate analysis indicated that the choice of treatment plan affected prognosis, and patients who received chemotherapy alongside haematopoietic stem cell transplantation (HSCT) had a better outcome.
Relapse after HSCT remains the main cause of treatment failure, occurring in about one third of transplanted patients. In an analysis of 137 patients with relapsed disease from the EWOG-MDS study, the probability of overall survival at 5 years was 30%. Treatment strategies that did not include a second stem cell transplantation — such as chemotherapy, donor leukocyte infusions, or a hypomethylating agent — showed extremely low remission rates. A second allograft, when feasible, cured about one third of children with relapsed disease, but a considerable portion of patients could not receive this procedure and died of aggressive disease before it could be applied.
A phase II trial using the MEK inhibitor trametinib in patients with relapsed and refractory JMML reported an objective response rate of 50% and an overall survival of 80% after 4 years. In a single case report, a 5-year-old boy with JMML that had evolved to acute myeloid leukaemia and relapsed after two transplants and tipifarnib treatment received single-agent clofarabine induction (52 mg/m²/d for 5 days). After three courses, he attained a remission marrow with 5% blasts and disappearance of cytogenetic abnormalities.
In a small series of 4 children who received HSCT combined with decitabine (20 mg/m²/d for 5 days before transplant and 10 mg/m²/d for 5 days after), all patients had complete remission before transplant. At a median follow-up of 21 months, overall survival and disease-free survival were both 100%, with no relapses and 100% engraftment. Toxicities included infection with neutropenia in all 4 patients, acute GVHD grades II–III in 50%, and CMV infection in 75%. The sample is very small and follow-up short. What is still missing are prospective trials large enough to stratify patients by mutation type and prior treatment, reliable pre-transplant therapies that reduce disease burden without excessive toxicity, and post-transplant strategies that consolidate remission and prevent relapse.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Hematology · 2019 · 5 citations · open access
Diagnosis and treatment of juvenile myelomonocytic leukemia
AbstractObjective: To investigate clinical features, diagnosis, treatment strategies and prognosis of juvenile myelomonocytic leukemia (JMML).Methods: The clinical data of 21 patients with JMML who were diagnosed in our hospital from January 2013 to May 2018 were retrospectively analyzed.Results: Among the 21 children with JMML, 16 were male and 5 were female. Out of the 21 children who were diagnosed with JMML, 7 were lost after treatment while the remaining 14 received A-3V chemotherapy regimen of South Korea. The effective response rate was 78.5%. The three-year overall survival (OS) rate and three-year disease-free survival (DFS) rate were (76.2 ± 14.8)% and (66.2 ± 14)%, respectively. Single factor analysis showed that PLT count ≤33×109/L, LDH level >500 U/L and HbF level >10% and chemotherapy only were the significant factors that lead to poor prognosis in children. Cox multivariate analysis showed that the choice of treatment options affected the prognosis of JMML children. By taking prognostic factors for long-term efficacy into account, patients with treatment strategy of chemotherapy alongside hematopoietic stem cell transplantation (HSCT) have a better prognosis.Conclusion: The PLT count, LDH level, HbF level and choice of treatment plan are important for the evaluation of prognosis for children with JMML. Although there is a lack of consistency in terms of donors but the A-3V scheme is relatively stable, so HSCT should be preferred for children with poor prognostic factors.
Journal of Pediatric Hematology/Oncology · 2005 · 5 citations
Complete Remission Following Clofarabine Treatment in Refractory Juvenile Myelomonocytic Leukemia
AbstractJuvenile myelomonocytic leukemia (JMML) is the most common myeloproliferative/myelodysplastic disorder seen in children. The treatment of choice, allogeneic stem cell transplantation, provides the only known cure for the disease, but relapse after transplant is common. The authors describe a 5-year-old boy diagnosed at age 34 months with JMML that evolved to acute myeloid leukemia. Initial treatment consisted of fludarabine and cis-retinoic acid therapy, followed by a matched sibling bone marrow transplant. After a relapse, he received a second transplant from the same donor, using peripheral blood stem cells, followed by repeated donor leukocyte infusions. After the second relapse, he received the farnesyltransferase inhibitor R115777 (tipifarnib, Zarnestra), but the leukemia persisted. When bone marrow blasts numbered 60% of the mononuclear cells, he received single-agent clofarabine induction (52 mg/m/d) for 5 days. After three courses, he attained a remission marrow with 5% blasts and disappearance of the 5q- and 9q- cytogenetic abnormalities.
If You Build It, Patients with Rare Cancers Will Come: A Successful Clinical Trial in Relapsed and Refractory JMML
AbstractJuvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and an overall survival of 80% after 4 years. See related article by Stieglitz et al., p. 1590 (4) .
FreiDok plus (Universitätsbibliothek Freiburg) · 2023 · 0 citations · open access
Long-term outcomes of patients with relapse of juvenile myelomonocytic leukemia - analysis of the EWOG-MDS study
AbstractJuvenile myelomonocytic leukemia is a rare myeloproliferative disorder of early infancy and, for most patients, hematopoietic stem cell transplantation is the therapy of choice. Relapse is the main cause of treatment failure and occurs in about one third of transplanted patients. Aim of the present study is to identify the currently available treatment strategies for relapsed disease and to analyze their outcomes, with particular consideration for the role of the second stem cell transplantation. Data from 137 patients with relapsed disease registered in the EWOG-MDS study has been retrospectively analyzed. The prognosis of patients with relapsed juvenile myelomonocytic leukemia is generally poor, with a probability of overall survival at 5 years of 30%. Treatment strategies including chemotherapy, donor leukocyte infusions and a hypomethylating agent show, in the absence of a second stem cell transplantation, extremely low remission rates. A second allograft, when feasible, is able to cure about one-third of children with relapsed disease. A considerable portion of patients with relapsed juvenile myelomonocytic leukemia may, however, not be in the condition to benefit from this approach and succumb to aggressive disease before the procedure can be applied. Further research should aim at reducing relapse rates after the first transplantation and identifying pre-transplantation therapies able to efficiently reduce the disease burden prior to the allograft as well as to find post-transplantation approaches able to consolidate the obtained remission.
Feasibility and Outcome of Hematopoietic Stem Cell Transplantation Combined with Decitabine for Children with Juvenile Myelomonocytic Leukemia
AbstractAbstract Background Juvenile myelomonocytic leukemia(JMML) is a rare clonalmyelodysplastic/myeloproliferative disorder that occurs during infancy and early childhood with poor prognosis. Chemotherapy has not been found to be dffective, and Hematopoietic stem cell transplantation(HSCT) is currently the only curative treatment for JMML. Relapse and engraftment failure are the major causes of HSCT failure in JMML. Patients and method We report the outcomes of 4 patients with JMML who received HSCT combined with Decitabine between 2014-2015. Patient median age was 2 years(range,1-3years), and 3 were boys and 1 girl. Decitabine was given before and after the HSCT for one time(20mg/m2.d X 5d、10mg/m2 .d X 5d). Before HSCT, all the patients received mild chemotherapy(three or four course). The bone marrow evaluations of all the patients before HSCT were complete remission(CR). Two patients received human leukocyte antigen(HLA)-matched HSCT from unrelated donors, and two patients received haploidentical HSCT from parents followed by unrelated cord blood transplantation(UCB). Conditioning regimen of Unrelated donor-PBSCT was Busulfan+fludarabine+Thiotepa+Thymoglobuline, and the conditioning of haplo-HSCT was Busulfan+fludarabine+Cytarabine+Thymoglobuline. The number of nucleated cells of HLA-matched HSCT was 8×108/kg. The number of nucleated cells of Haplo-HSCT was 47.2×108/kg、61.26×108/kg , respectively, and the number of nucleated cells of UCB was 7.23×107/kg、9.4×107/kg, respectively. GVHD prophylaxis was based on post-transplant high-dose cyclophosphamide(PTCy, 50mg/kg on days +3 and +4) combined with mycophenolate plus cyclosporine A or tacrlimus. Results: The median follow-up was 21 months(range,11-27 months). The overall survival(OS) and the Disease free survival(DFS) both were 100%, All the patients got 100% engraftment(Unrelated-donor stem cell engrafted and Haploidentical-donor stem cell engrafted in 2 and 2 patients , respectively). None of the patients developed relaps, the bone marrow evaluations were complete remission(CR) after HSCT. The most common toxicities were infection with neutropenia(100%, n=4), The cumulative incidences of acute GVHD gradesII-III and CMV infection were 50% and 75% respectively. Conclusion: The combination of decitabine and HSCT shows encouraging results with highly effective and less toxicity for JMML. The futhuer study should be developed in the future. Disclosures No relevant conflicts of interest to declare.
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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