DeCure for Myeloid neoplasm associated with PDGFRB rearrangement
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for myeloid neoplasm associated with PDGFRB rearrangement — 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 moduleMyeloid neoplasm associated with PDGFRB rearrangement 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
approvedSorafenibApproved drug
Structures already discussed alongside myeloid neoplasm associated with pdgfrb rearrangement 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
Sorafenib inhibited ETV6-PDGFRbeta in a laboratory study of haematopoietic cells transformed by that fusion, inducing cell cycle block and apoptosis in two FLT3-ITD acute myeloid leukaemia cell lines but not in four other AML lines. The imatinib-resistant KIT(D816V) mutant was resistant to sorafenib. The authors concluded that further clinical studies of sorafenib for PDGFRbeta-driven myeloid malignancies were warranted.
A single case report described transformation from atypical chronic myeloid leukaemia to chronic myelomonocytic leukaemia in a patient with PDGFRB rearrangement; imatinib showed no clinical therapeutic effect in that patient, and the transformation was interpreted as disease progression.
A single-centre series of 126 patients with hypereosinophilic syndrome identified 9 with PDGFRB rearrangement (6 of 41 by FISH, 3 of 85 by RT-PCR). Median time to molecular confirmation was 12 months. Eight patients received imatinib 400 mg daily (one started at 100 mg daily for four years). Complete haematologic response was achieved in 5 of 8 (62.5%). Complete cytogenetic response occurred in all 3 patients assessed after 3 months of imatinib. Molecular response (negative FISH and/or RT-PCR) was achieved in 3 of 4 patients after 6, 9 and 60 months; in the last case the response came only after the dose was increased from 100 mg to 400 mg daily. One patient on 400 mg daily remained FISH-positive and RT-PCR-positive at 14 months; after dose escalation to 600 mg daily FISH became negative but RT-PCR remained positive at 4 months. The authors concluded that imatinib effectiveness in PDGFRB-positive neoplasms is ambiguous, possibly depending on the partner gene, and that allogeneic stem cell transplantation should be discussed when imatinib is insufficient.
What is still missing is prospective data on sorafenib in PDGFRB-rearranged patients, a systematic understanding of which fusion partners predict imatinib resistance, and a trial design that stratifies patients by molecular subtype rather than lumping all PDGFRB rearrangements together.
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 · 2007 · 93 citations · open access
The ability of sorafenib to inhibit oncogenic PDGFR and FLT3 mutants and overcome resistance to other small molecule inhibitors
AbstractBACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3.
Journal of Cancer Research and Therapeutics · 2015 · 1 citations · open access
Transformation from atypical chronic myeloid leukemia to chronic myelomonocytic leukemia as progression of myeloid neoplasm with platelet-derived growth factor ß rearrangement
AbstractMyeloid neoplasms associated with platelet-derived growth factor b (PDGFRB) rearrangement usually keep only one morphologic type unless blast crisis. We describe a unique case of hematological features transformation from atypical chronic myeloid leukemia to chronic myelomonocytic leukemia, and imatinib showed no clinical therapeutic effects. The phenomenon indicates that different types of myeloid neoplasms associated with PDGFRB rearrangement can transform into one another with the progression of the disease, and to some extent, this transformation suggests the aggravation of disease.
P1063: A SINGLE CENTER EXPERIENCE OF DIAGNOSTICS AND TREATMENT OF RARE MYELOID/LYMPHOID NEOPLASMS WITH PDGFRB GENE REARRANGEMENT
AbstractTopic: 16. Myeloproliferative neoplasms - Clinical Background: A clonal nature of hypereosinophilic syndromes (HES) is rarely confirmed (about 10%). Rearrangements of the PDGFRB gene in patients (pts) with HES are observed only in about 15% of those cases while PDGFRA markers are found in 70%. The combination of both genes anomalies is not observed. More than 30 partner genes of PDGFRB fusion gene and various chromosomal aberrations have been described. The most frequent is ETV6::PDGFRB fusion gene resulting from t(5;12)(q31-33;p13) translocation. A high sensitivity to targeted therapy with imatinib (IM) is expected. Aims: Summarize a single center data diagnostic and treatment in pts with rare PDGFRB-positive neoplasms. Methods: A total of 126 pts with HES were examined for clonal markers in a period from 2003 to 2021. At the first stage, PDGFRA marker was excluded. Two molecular genetic methods were used to detect PDGFRB gene rearrangements. Before 2014, a qualitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to find ETV6::PDGFRB in 85 pts. Since 2014, fluorescent in situ hybridization (FISH) was used to detect rearrangements of the PDGFRB/5q31-33 gene locus in 41 pts. Median (Me) time to molecular confirmation of diagnosis was 12 months (mo) (2 mo - 22 years). Eight pts received therapy with IM 400 mg QD but one of them (№7, tab. 1) got IM 100 mg QD for the first 4 years. The pt with blast transformation (№1, tab. 1) got IM after achieving BM remission (blasts <5%) on chemotherapy. Me duration of IM use is 25 mo (2-105). Me follow-up for pts with CHR on IM is 48 mo (range 18-105). Results: Involvement of PDGFRB gene was found in 9 pts: 6/41 (14.3%) by FISH, 3/85 (3.5%) by RT-PCR. Me age at diagnosis was 46 years (17-59), male/female=7/2. All pts had typical manifestations of myeloproliferative disease (MPD) with eosinophilia in peripheral blood and/or bone marrow (BM). In patient №1 (tab. 1), 36.9% of myeloid blasts were detected in BM at disease onset. The 5q31-33 anomalies were found in 4/7 pts by a standard cytogenetic assay. In 3 pts the chromosome 5 aberration was cytogenetically cryptic. Complete hematologic response (CHR) was achieved in 5 pts (62.5%). A complete cytogenetic response with disappearance of initial chromosomal aberrations was achieved in 3/3 (100%) pts with CHR after 3 mo of IM treatment. Molecular response (MR) was defined as a negative FISH and RT-PCR (pts №2, №8) and FISH only (pts №1, №7). MR was achieved in 3/4 (75%) pts after 6 (pt №1), 9 (pt №2) and 60 months (№7) on IM. In the last case no MR was achieved after 48 mo on IM 100 mg QD. The IM dose was increased to 400 mg QD and MR was achieved at 9 mo. In case №8 on IM 400 mg QD day the RT-PCR and FISH were positive at mo 2, 6 and 14. After increasing dose to 600 mg QD FISH was negative but RT-PCR was positive at mo 4. Summary/Conclusion: A long-term experience of rare PDGFRB–positive diseases observation reveals that FISH is an optimal method for detection of various PDGFRB gene rearrangements and it should be done in all pts with HES and previously excluded PDGFRA (including those with unchanged karyotype). The IM effectiveness in PDGFRB-positive neoplasms is ambiguous which may be due to the partner gene of PDGFRB. The choice of IM dose should be 400 mg QD. If possible, the molecular response should be assessed by two methods. The PCR method reveals a residual clone with FISH-negativity. An allogeneic stem cell transplantation should be discussed in cases with not sufficient efficacy of IM.Keywords: PDGFRB, Myeloproliferative disorder
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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