DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for childhood acute myeloid leukemia — screening already-approved drugs against its 6-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleChildhood acute myeloid leukemia maps to a 6-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
approvedBosutinibApproved drugapprovedSorafenibApproved drug
Structures already discussed alongside childhood acute myeloid leukemia in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Human P38 MAP kinase — Sorafenib has a real, experimentally solved structure in complex with this target (PDB 3GCS, 2.1 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 baxdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3GCS · 2.1 Å · ligand Sorafenib (BAX). Experimental structure, not a prediction.
What the evidence adds up to
Contemporary treatment for childhood acute myeloid leukaemia gives a 5-year event-free survival of almost 60%, according to a 2011 review. For the roughly 365 children diagnosed annually in the US, 5-year survival on Children’s Oncology Group trials is 83% for low-risk, 62% for intermediate-risk, and 23% for high-risk disease, as reported in a 2012 blueprint. A single-centre Saudi Arabian study of 84 patients treated between 1986 and 2011 found that 5-year overall survival improved from 10.5% in the earlier era (AML-BFM-78 protocol) to 56% in the later era (MRC AML10 protocol). That improvement was linked to a drop in treatment-related mortality from 76% to 11.5%. Within the same MRC AML10 protocol, further introduction of supportive care measures reduced treatment-related mortality from 48.6% to 4.7% and raised overall survival from 33.3% to 56.2%.
Relapse remains a major problem. In the French LAME 89/91 protocol, 106 of 308 children relapsed. Among 96 who received reinduction therapy, 71% achieved a second complete remission. Bone marrow transplantation was performed in 78% of those patients. The 5-year overall survival for all 106 relapsed patients was 33%, and disease-free survival for children in second remission was 45%. Longer first remission (more than 12 months) predicted better survival after relapse (54% vs 24%). Maintenance therapy after first remission was associated with worse outcome (12% survival) compared with chemotherapy without maintenance (40%) or HLA-identical bone marrow transplant (52%). For patients who reached second remission, 5-year disease-free survival did not differ significantly between matched sibling donor transplant (60%), autograft (47%), or alternative donor transplant (44%).
High-resolution genome-wide analyses have identified many novel subtypes and cooperative mutations in cell differentiation, cell cycle regulation, tumour suppression, drug responsiveness, and apoptosis. The 2012 blueprint notes that childhood AML remains uniquely different from adult AML in subtype prevalence and overall response. Current strategy incorporates targeted agents to pathways specific to childhood AML and methods to increase sensitivity of leukaemic stem cells, first in phase II feasibility trials then phase III efficacy trials. What is still missing is a standardised scoring system to evaluate centre-specific supportive care measures, prospective trials defining the optimal reinduction regimen and megadose chemotherapy, and assessment of late effects of salvage therapies.
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 Clinical Oncology · 2011 · 838 citations · open access
Biology, Risk Stratification, and Therapy of Pediatric Acute Leukemias: An Update
AbstractPURPOSE: We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research. METHODS: A review of English literature on childhood acute leukemias from the past 5 years was performed. RESULTS: Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients. CONCLUSION: The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.
Journal of Clinical Oncology · 2003 · 102 citations
Outcome in Children With Relapsed Acute Myeloid Leukemia After Initial Treatment With the French Leucémie Aiquë Myéloïde Enfant (LAME) 89/91 Protocol of the French Society of Pediatric Hematology and Immunology
AbstractPURPOSE: After present first-line therapies for childhood acute myeloid leukemia (AML), nearly 40% of patients still relapse. The goals of this retrospective study were to determine whether these children could be treated successfully with a salvage regimen and to establish the optimal therapeutic strategy. PATIENTS AND METHODS: In the multicentric, prospective, Leucémie Aiquë Myéloïde Enfant 89/91 protocol, 106 of the 308 children enrolled between 1988 and 1998 relapsed. Initial treatment after the first complete remission (CR1) had been allogenic HLA-identical bone marrow transplantation (BMT; n = 21) or chemotherapy (n = 85). Treatment procedures were scheduled according to the choice of each participating institution. RESULTS: When reinduction therapy was attempted, second complete remission (CR2) was obtained in 71% of patients (68 of 96 patients). BMT was performed in 53 (78%) of these 68 patients (autograft, mainly harvested in CR1, n = 25; matched sibling-donor BMT, n = 12; or alternative-donor BMT, n = 16). The 5-year overall survival (OS) rate for all 106 patients was 33%, and the disease-free survival (DFS) rate for children in CR2 was 45%. Multivariate analysis of re-treated children showed that the 5-year OS was higher if the CR1 had been longer than 12 months compared with less than 12 months (54% v 24%, respectively; P =.001) and lower if maintenance therapy had been given after CR1 compared with chemotherapy without maintenance therapy or HLA-identical BMT (12% v 40% v 52%, respectively; P =.002). For patients attaining CR2, the 5-year DFS rate was not significantly different for matched sibling-donor BMT (60%), autograft (47%), or alternative-donor BMT (44%). CONCLUSION: After aggressive first-line therapy, one third of unselected, relapsing AML children could be cured. Further prospective trials are warranted to define the optimal reinduction regimen and megadose chemotherapy and to evaluate the late effects of these therapies.
The Journal of Pediatric Pharmacology and Therapeutics · 2020 · 5 citations · open access
Pharmacokinetics, Efficacy and Safety of Bosutinib in a Pediatric Patient With Chronic Myeloid Leukemia
AbstractBosutinib is a second-generation tyrosine kinase inhibitor indicated for treatment of chronic myeloid leukemia (CML) in adult patients. The safety and efficacy of bosutinib in patients younger than 18 years of age have not been established. We here report the case of a 4-year-old male with CML who was treated with bosutinib during coordination of human leukocyte antigen–matched unrelated bone-marrow transplantation because of insufficient responses to imatinib and dasatinib. The patient achieved a complete cytogenetic response immediately after starting bosutinib at 180 mg/day (290 mg/m 2 /day). Because toxicity was tolerable, the dose was increased to 200 mg/day (330 mg/m 2 /day). A complete cytogenetic response was maintained, but a major molecular response was not achieved 6 months after initiation of treatment with bosutinib. At steady state, maximum plasma concentration, minimum plasma concentration, and area under the plasma concentration-time curve were 89.2 ng/mL, 16.7 ng/mL, and 1017.4 ng·hr/mL, respectively, at 290 mg/m 2 /day; and 141.1 ng/mL, 18.9 ng/mL, and 1278.5 ng·hr/mL, respectively, at 330 mg/m 2 /day. To the best of our knowledge, this is the first case report to show the pharmacokinetics of bosutinib with efficacy and safety in a pediatric patient with CML. This rare case in a very young child with CML can also be valuable reference for clinical practice.
Treatment Related Mortality of AML Pediatric Patients in a Single Center in Saudi Arabia
AbstractAbstract Abstract 4291 Despite minimal changes in therapeutic approach, the outcome of acute myeloid leukemia (AML) in pediatric patients has improved significantly in the past two decades. Supportive care measures may have contributed to this success by reducing treatment related mortality (TRM) and thereby improving the overall survival (OS) of patients. Yet their impact on outcome remained unknown and masked under protocol effect. To assess the impact of supportive care measures on outcome, we undertook a retrospective review of all pediatric patients diagnosed with AML between 1986 and 2011and treated in our institution, the Princess Norah Oncology Center, King Abdulaziz Medical City, Jeddah. A total of 87 patients were reviewed. Of these, two patients whose parents refused treatment and one lost to follow-up were excluded. A total of 84 patients were qualified for the study. These patients were treated with two different protocols based on treatment eras. Patients diagnosed between 1986 and 1995 (era 1) were treated following AML-BFM-78 protocol while patients diagnosed between 1996 and 2011 (era 2) were treated following the MRC AML10. The cumulative TRM incidence was 76% in era1 compared to 11.5% in era 2 (P = 0.0001). This resulted in an improved 5-year OS from 10.5% in era 1 to 56% in era 2 (P = 0.007). The protocols used in both eras were different and may have improved OS. Significant difference in TRM however, suggests that other factors contributed to the improved OS. To gain further insight of the contributing factors, patients who received only MRC AML10 protocol (in era2) were partitioned into two sub-eras based on supportive care measures introduced sequentially in our institution as follows: 1996 to 2002 (era 2a) and 2003 to 2011 (era 2b).The cumulative TRM incidence was 48.6% in era 2a and 4.7% in era 2b (P = 0.001). This also resulted in an improved OS from 33.3% in era 2a to 56.2% in era 2b despite using the same protocol (P = 0.007). Our findings highlight the importance of supportive care as a significant factor in outcome of children. Comparing protocols per se masks the importance of supportive care measures in impacting outcome. We suggest devising a standardized scoring system to evaluate center-specific supportive care measures to quantify the impact of supportive care on TRM and survival outcomes while simultaneously allowing us to distinguish the effect of supportive care from that of protocol and other factors such as ethnicity. Disclosures: No relevant conflicts of interest to declare.
Sorafenib as Effective Treatment for Newly Diagnosed AML in Younger Patients
AbstractAcute myeloid leukemia, a common form of leukemia with a high mortality rate, is difficult to treat. In the SORAML trial, sorafenib, a multikinase inhibitor, prolonged event-free and relapse-free survival compared with a placebo in younger patients with acute myeloid leukemia. However, this benefit was accompanied by a higher rate of infections and bleeding.
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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