DeCure for Acute myeloid leukemia with mutated NPM1
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for acute myeloid leukemia with mutated NPM1 — screening already-approved drugs against its 29-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAcute myeloid leukemia with mutated NPM1 maps to a 29-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 acute myeloid leukemia with mutated npm1 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
isocitrate dehydrogenase (NADP(+)) 2 (IDH2) — IDH2 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 ndpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5I96 · 1.55 Å · ligand NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NDP). Experimental structure, not a prediction.
What the evidence adds up to
In newly diagnosed acute myeloid leukaemia, NPM1 mutations are the most common genetic alteration, found in about 30–35% of adult cases and more than 50% of cases with normal karyotype. The mutation causes aberrant cytoplasmic dislocation of the NPM1 protein and is regarded as a distinct genetic entity in the WHO classification. Several potential targeted strategies have been explored preclinically or in early clinical testing, including compounds that interfere with NPM1 oligomerisation (NSC348884), abnormal trafficking (avrainvillamide, XPO1 inhibitors), selective mutant protein degradation (ATRA/ATO, deguelin, epigallocatechin-3-gallate, imidazoquinoxaline derivatives), and nucleolar structure integrity (actinomycin D). Immunotherapeutic approaches such as immune checkpoint inhibitors and CAR or TCR T-cell therapies targeting neoantigens created by NPM1 mutations are also under review.
In relapsed or refractory AML, NPM1 mutations are associated with higher remission rates compared to wild-type NPM1: complete remission or complete remission with incomplete count recovery was 56% versus 37% after first salvage, 33% versus 22% after second salvage, and 24% versus 14% after third salvage. However, these higher remission rates did not translate into improved relapse-free survival or overall survival. Median overall survival after first, second, and third salvage therapy was 7.8 versus 6.0 months, 5.3 versus 4.1 months, and 3.5 versus 3.6 months, respectively, for mutated versus wild-type NPM1. The addition of venetoclax to salvage regimens in patients with mutated NPM1 did improve outcomes in this retrospective analysis: median relapse-free survival 15.8 versus 4.6 months, and median overall survival 14.7 versus 5.9 months.
Despite the favourable prognosis of NPM1 mutations at diagnosis, some patients ultimately relapse or fail to respond. The minimal impact of mutational status on survival in relapsed or refractory disease means novel treatment strategies are needed. What is still missing are prospective trials that stratify patients by NPM1 mutational status and co-occurring mutations, dedicated funding for combination regimens such as venetoclax-based salvage, and validation of targeted agents like menin inhibitors in randomised settings rather than single-arm or preclinical studies.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Leukemia · 2022 · 126 citations · open access
Current status and future perspectives in targeted therapy of NPM1-mutated AML
AbstractNucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30-35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.
Blood Advances · 2022 · 56 citations · open access
Clinical outcomes associated with <i>NPM1</i> mutations in patients with relapsed or refractory AML
AbstractMutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity.
Frontiers in Oncology · 2022 · 42 citations · open access
Targeted therapy in NPM1-mutated AML: Knowns and unknowns
AbstractAcute myeloid leukemia (AML) is a heterogeneous disease characterized by malignant proliferation of myeloid hematopoietic stem/progenitor cells. NPM1 represents the most frequently mutated gene in AML and approximately 30% of AML cases carry NPM1 mutations. Mutated NPM1 result in the cytoplasmic localization of NPM1 (NPM1c). NPM1c interacts with other proteins to block myeloid differentiation, promote cell proliferation and impair DNA damage repair. NPM1 is a good prognostic marker, but some patients ultimately relapse or fail to respond to therapy. It is urgent for us to find optimal therapies for NPM1-mutated AML. Efficacy of multiple drugs is under investigation in NPM1-mutated AML, and several clinical trials have been registered. In this review, we summarize the present knowledge of therapy and focus on the possible therapeutic interventions for NPM1-mutated AML.
The Long-Term Outcome Of Adult Patients With Acute Myeloid Leukemia NPM+ and FLT3/ITD- Is Not Significantly Improved By The Application Of An Allogeneic Stem Cell Transplantation
AbstractAbstract Introduction The discovery of the NPM mutation in acute myeloid leukemia (AML) allowed to identify a distinct entity with intermediate-good prognosis particularly when the FLT3/ITD mutation is absent. The most appropriate consolidation treatment of these patients upon the achievement of the first complete remission has not been established yet and the role of allogeneic stem cell transplantation (SCT) is still debated. Aim to assess long-term outcome of adult patients with NPM positive acute myeloid leukemia according to type and intensity of consolidation therapy. Patients and methods Between May 2000 and February 2012, 1155 patients were enrolled into two consecutive, prospective Northern Italy Leukemia Group (NILG) trials (00/01 and 02/06). Six-hundred sixty nine were studied for NPM mutation and 218 (33%) proved positive (by immunohistochemistry or by molecular analysis) (Falini et al, Haematologica. 2007 Apr;92(4):519-32). Median age of NPM+ patients was 50 years (range 16-72) and 134 (61%) were female. Median WBC was 33.3 x 10^9/L (range 0.9-313.9), 71 (33%) had myelomonocytic leukemia (FAB M4), and 211 (96%) had de novo AML. According to the European Leukemia Net (ELN) classification, cytogenetic risk groups were: normal 178 (82%), intermediate 26 (12%), unfavorable 2 (1%) and unknown 12 (5%). Eighty-two (38%) patients had a concurrent FLT3/ITD mutation and 31 (14%) a FLT3/TKD mutation. According to cytogenetics and additional risk factors (late response, WBC count >50x10^9/L, FAB class M0/6/7, hepato/splenomegaly, MDS-related/secondary AML, FLT3/ITD mutation), patients were stratified in standard (SR) and high (HR) risk groups. In both studies the remission induction was based on combination of cytarabine with idarubicin. Post-remission therapy was allogeneic SCT in HR while high-dose cytarabine or busulfan/cyclophosphamide with autologous SCT was given to SR patients. The molecular evaluation of minimal residual disease (MRD) was planned after induction, before the post-remission consolidation and the follow-up. Results Complete remission (CR) was achieved in 196/218 (90%) NPM+ patients. One hundred sixty-eight out of 196 remitters (86%) received post-remission consolidation therapy: allogeneic SCT 72 (37%), high dose Ara-C 74 (38%), autologous SCT 14 (7%), other therapy 8 (4%); 28 patients did not receive consolidation due to early relapse (n=24), CR death (n=3), and loss to follow-up (n=1). With a median follow-up of 1.8 years (range 0.008-12.66), 99 CR patients (50.5%) were alive in 1st CR, 13 (6.5%) died of complications, and 84 (43%) had recurrent AML. In a cumulative analysis, 5-year overall and disease-free survival were 46% (OS) and 43% (DFS), respectively. In univariate analysis FLT3/ITD mutation (n=82) affected negatively 5-year OS (29% vs. 49%, P < .0001) and DFS (27% vs. 46%, P < .0001), whereas FLT3/TDK mutation did not. In patients with FLT3/ITD mutation able to receive consolidation therapy (n=49), the application of allogeneic SCT improved DFS significantly (55% vs. 18%, P = .03) and reduced the cumulative incidence of relapse (CIR) (39% vs. 81%, P = .026). In patients with NPM+ and FLT3/ITD- AML, the risk of relapse after high dose cytarabine or autologous SCT (n=68) was more than doubled compared to that observed after allogeneic SCT (n=42) (50% vs. 23%, P= .08) (Figure). However, DFS (48% vs. 69.5%, p= .17), and OS (60% vs. 72%, p= .80) were not significantly different since allogeneic SCT was associated with higher treatment related mortality, albeit effective in the salvage of some relapsed patients. In multivariate analysis, FLT3/ITD mutation was the most powerful factor that unfavorably affected OS, DFS and CIR, while age > 55 years negatively affected OS and DFS. No other clinical factor was predictive for relapse in FLT3- patients. The relationship between MRD and clinical outcome is currently being studied and will be presented. Conclusions Our data indicate that allogeneic SCT is the most active post-remission treatment for NPM+ AML, but its benefit over chemotherapy may be limited in patients without FLT3/ITD. For this reason the evaluation of MRD could help identify the patients for whom an allogeneic SCT should be preferable. Disclosures: No relevant conflicts of interest to declare.
Real-world outcomes in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia treated with ponatinib – final 6-year results from a Belgian registry
AbstractPonatinib is a third-generation tyrosine kinase inhibitor (TKI) for treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in patients who fail or are intolerant to a second generation TKI or who carry the <i>T315I</i> mutation. This is the final analysis of the Belgian ponatinib registry evaluating use of ponatinib in clinical practice, with data available for up to 6 years after reimbursement. Forty-eight percent of 54 CML and 28% of 29 Ph+ ALL patients had received ≥3 previous TKIs. Before ponatinib, most patients had already achieved a response, including at least a major molecular response (MMR), in 19% of CML and 17% of Ph+ ALL patients. Ponatinib was initiated due to intolerance to previous TKIs in 50% of CML and 41% of Ph+ ALL patients. Median follow-up was 545 and 258 days for CML and Ph+ ALL patients, respectively. Best response to ponatinib was at least an MMR in 65% of CML and 55% of Ph+ ALL patients. Overall and progression-free survival were 85.8% and 83.8% in CML patients after 48 months of treatment, and 82.5% and 54.2% in Ph+ ALL patients after 30 months of treatment. Adverse reactions were reported by 85% of CML and 76% of Ph+ ALL patients, with 33% of CML and 24% of Ph+ ALL patients experiencing cardiovascular events. In line with previously published trials, these real-world data support use of ponatinib in CML and Ph+ ALL patients with resistance or intolerance to previous TKIs or carrying the <i>T315I</i> mutation. <b>Trial registration:</b>ClinicalTrials.gov identifier: NCT03678454; September 19, 2018. <b>What is this study about?</b>Chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are types of blood cancer.Ponatinib belongs to a group of medicines called tyrosine kinase inhibitors (TKIs). People with CML or Ph+ ALL can use ponatinib if they no longer benefit from or cannot tolerate treatment with at least two previous TKIs, or if their cancer cells have a gene change (or mutation) called <i>T315I</i>.This study looked at people with CML and Ph+ ALL being given ponatinib at Belgian hospitals over 6 years and how they responded to ponatinib treatment. Chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are types of blood cancer. Ponatinib belongs to a group of medicines called tyrosine kinase inhibitors (TKIs). People with CML or Ph+ ALL can use ponatinib if they no longer benefit from or cannot tolerate treatment with at least two previous TKIs, or if their cancer cells have a gene change (or mutation) called <i>T315I</i>. This study looked at people with CML and Ph+ ALL being given ponatinib at Belgian hospitals over 6 years and how they responded to ponatinib treatment. <b>What were the results?</b>Almost 50% of people with CML and 30% of people with Ph+ ALL received treatment with three or more TKIs before ponatinib.Many people started taking ponatinib because they could not tolerate their previous TKI.86% of people with CML were alive after 48 months of ponatinib treatment. The cancer did not get any worse in 84% of people during this time.83% of people with Ph+ ALL were alive after 30 months of ponatinib treatment. The cancer did not get any worse in 54% of people during this time.33% of people with CML and 24% of people with Ph+ ALL experienced cardiovascular side effects Almost 50% of people with CML and 30% of people with Ph+ ALL received treatment with three or more TKIs before ponatinib. Many people started taking ponatinib because they could not tolerate their previous TKI. 86% of people with CML were alive after 48 months of ponatinib treatment. The cancer did not get any worse in 84% of people during this time. 83% of people with Ph+ ALL were alive after 30 months of ponatinib treatment. The cancer did not get any worse in 54% of people during this time. 33% of people with CML and 24% of people with Ph+ ALL experienced cardiovascular side effects <b>What do the results mean?</b>This real-world study shows that people with CML and Ph+ ALL who do not respond to or cannot tolerate another TKI, or who carry the <i>T315I</i> mutation, may benefit from ponatinib treatment and toxicity is generally acceptable. This real-world study shows that people with CML and Ph+ ALL who do not respond to or cannot tolerate another TKI, or who carry the <i>T315I</i> mutation, may benefit from ponatinib treatment and toxicity is generally acceptable.
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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