cytarabine • idarubicin hydrochloride • mitoxantrone • Vesanoid (tretinoin) • arsenic trioxide • Hemady (dexamethasone tablets) • Starasid (cytarabine ocfosfate)

1year

PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression. (PubMed, Cancer Res)

Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML.

1 year ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • PRDM16 (PR/SET Domain 16)

FLT3-ITD mutation • FLT3 wild-type • FLT3 expression • FLT3-ITD expression

1year

In silico and in vitro study of FLT3 inhibitors and their application in acute myeloid leukemia. (PubMed, Mol Med Rep)

The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wild‑type (WT)‑FLT3 and ITD‑mutated (ITD‑FLT3) structural models of FLT3, in its inactive aspartic acid‑phenylalanine‑glycine motif (DFG‑out) and active aspartic acid‑phenylalanine‑glycine motif (DFG‑in) conformations. Thus, the current study presented novel information about molecular interactions between the FLT3 receptors (WT or ITD‑mutated) and some of their inhibitors. It also paves the way for the search for novel inhibitory molecules with potential use against AML.

1 year ago

Preclinical • Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3 mutation • FLT3 wild-type

sorafenib • Xospata (gilteritinib) • midostaurin • Vanflyta (quizartinib)

1year

Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins. (PubMed, Leukemia)

The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (p < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (p < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit.

1 year ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • BCL2L11 (BCL2 Like 11) • HSPH1 (Heat Shock Protein Family H (Hsp110) Member 1) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)

FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type • FLT3 expression

1year

Trial Evaluating MGTA-456 in Patients With High-Risk Malignancy (clinicaltrials.gov)

P2, N=22, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2024 --> Jun 2025

1 year ago

Trial completion date

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha)

FLT3-ITD mutation • NPM1 mutation • MLL rearrangement • MLL rearrangement • CEBPA mutation • FLT3 wild-type

cyclophosphamide • melphalan • fludarabine IV • busulfan • spanlecortemlocel (MGTA-456)

1year

Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy. (PubMed, Int J Mol Sci)

In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.

1 year ago

Retrospective data • Journal • Gene Expression Profile

BRAF (B-raf proto-oncogene) • FLT3 (Fms-related tyrosine kinase 3) • HRAS (Harvey rat sarcoma viral oncogene homolog) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • PIK3CB (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) • MAPK1 (Mitogen-activated protein kinase 1) • MAPK3 (Mitogen-Activated Protein Kinase 3) • PIK3R3 (Phosphoinositide-3-Kinase Regulatory Subunit 3)

FLT3 mutation • FLT3 wild-type • FLT3 expression • NUP98 rearrangement

over1year

Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models. (PubMed, Sci Rep)

Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

over 1 year ago

Preclinical • Journal

FLT3 (Fms-related tyrosine kinase 3) • CDK6 (Cyclin-dependent kinase 6) • CSF1R (Colony stimulating factor 1 receptor)

FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type

narazaciclib (HX301)

over1year

Mitoxantrone Versus Liposomal Daunorubicin in Induction of Pediatric AML With Risk Stratification Based on Flow Cytometry Measurement of Residual Disease. (PubMed, J Clin Oncol)

The intensification of induction therapy with risk stratification on the basis of response to induction and hSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior anti-leukemic effect than liposomal daunorubicin.

over 1 year ago

Journal

NPM1 (Nucleophosmin 1)

FLT3 wild-type

etoposide IV • mitoxantrone

over1year

Pemigatinib After Chemotherapy for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (clinicaltrials.gov)

P1, N=32, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Aug 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Aug 2025

over 1 year ago

Trial completion date • Trial primary completion date

TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • MECOM (MDS1 And EVI1 Complex Locus) • NUP214 (Nucleoporin 214) • GATA2 (GATA Binding Protein 2) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • DEK (DEK Proto-Oncogene) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

TP53 mutation • FLT3 mutation • RUNX1 mutation • ASXL1 mutation • EZH2 mutation • MLL rearrangement • SRSF2 mutation • U2AF1 mutation • BCOR mutation • Chr del(5q) • STAG2 mutation • FLT3 wild-type • Chr t(9;11) • ZRSR2 mutation

cytarabine • Pemazyre (pemigatinib) • daunorubicin • Starasid (cytarabine ocfosfate)

over1year

Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/KMT2A Gene (clinicaltrials.gov)

P1, N=28, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Feb 2024 --> Dec 2027 | Initiation date: Feb 2024 --> Nov 2024 | Trial primary completion date: Feb 2024 --> Dec 2027

over 1 year ago

Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Combination therapy

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • MLL rearrangement • FLT3 wild-type • MLL mutation

daunorubicin • Revuforj (revumenib) • Starasid (cytarabine ocfosfate)

almost2years

Clinical and genetic characteristics predict outcomes of acute myeloid leukemia patients with FLT3 mutations receiving venetoclax-based therapy. (PubMed, Cancer Med)

FLT3 mutations may influence response to VEN-based therapy in R/R AML patients but not in ND AML patients. Furthermore, clinical and genetic characteristics could predict outcomes of FLT3mut patients receiving VEN-based therapy.

almost 2 years ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1)

FLT3 mutation • NPM1 mutation • DNMT3A mutation • FLT3 wild-type

Venclexta (venetoclax)

almost2years

BRCC36 associates with FLT3-ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia. (PubMed, Cancer Sci)

Thiolutin efficiently affected leukemia cell lines expressing FLT3-ITD cell viability and exhibited mutual synergies with quizartinib, a standard clinical medicine for AML. Furthermore, mutation of the lysine at 609 of ITD led to significant suppression of K63 polyubiquitination and decreased its stability, suggesting that K609 is a critical site for K63 ubiquitination specifically recognized by BRCC36. These data indicate that BRCC36 is a specific regulator for FLT3-ITD, which may shed light on developing a novel therapeutic approach for AML.

almost 2 years ago

Journal • BRCA Biomarker

FLT3 (Fms-related tyrosine kinase 3) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)

FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type • FLT3 expression • FLT3-ITD expression

Vanflyta (quizartinib)