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BIOMARKER:

SYK mutation

i
Entrez ID:
Related biomarkers:
1year
Combined Single Cell Flow Cytometry and Imaging Analyses Reveal Immunomodulatory Effects Exerted By Targeted Phospho-SYK Inhibitors with Elevated Sensitivity in NPM1 Mutated AML (ASH 2023)
Entospletinib (ENTO) and lanraplenib (LANRA) are inhibitors of spleen tyrosine kinase (SYK); the latter is a next-generation SYK inhibitor and is currently being evaluated in combination with gilteritinib (GILT) in patients with relapsed or refractory FLT3-mutated AML (NCT05028751)...Two different AML patient cohorts were assessed by ex vivo treatment with ENTO, LANRA and combinations of LANRA (trametinib, gilteritinib (GILT), aPD-1) over a range of time points (2h, 4h, 3d and 9d) and readouts for cellular phenotype (e.g., differentiation state, immune cell populations) and functional readouts (pSYK, viability) for each cohort were analyzed by HP-FC and sc-MI and associated with available mutation information (bulk gene and single cell RNA sequencing)...These support studies investigating the use of pSYK inhibitors in combination with other therapies to reduce tumor burden, and as an improved line of treatment for AML. Acknowledgements: We are appreciative of the patients and families for their time and participation.
Immunomodulating
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FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • mTOR (Mechanistic target of rapamycin kinase) • SYK (Spleen tyrosine kinase)
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IDH1 mutation • IDH2 mutation • FLT3 mutation • NPM1 mutation • FLT3 mutation + NPM1 mutation • MLL mutation • SYK mutation
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Mekinist (trametinib) • Xospata (gilteritinib) • entospletinib (GS-9973) • lanraplenib (GS-9876)
1year
DNA Methylation-Based Classification of Hairy Cell Leukemia and Splenic B Cell Lymphoma (ASH 2023)
In summary, we have developed a DNA methylation-based classifier that resolves 4 SBLPN subgroups with distinct molecular features, and reclassifies a subset of SMZL and HCL patients, adding further information to the updated WHO/ICC entities. We reveal distinct biological pathways operating in M-SBLPN subgroups that may aid targeted therapy approaches.
Epigenetic controller
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BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • TERT (Telomerase Reverse Transcriptase) • IGH (Immunoglobulin Heavy Locus) • NOTCH2 (Notch 2) • CREBBP (CREB binding protein) • BIRC3 (Baculoviral IAP repeat containing 3) • IL2RA (Interleukin 2 receptor, alpha) • SYK (Spleen tyrosine kinase) • IGLL5 (Immunoglobulin Lambda Like Polypeptide 5)
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TP53 mutation • BRAF V600E • BRAF V600 • BIRC3 mutation • TERT mutation • NOTCH2 mutation • TERT promoter mutation • SYK mutation • TERT 124C>T
1year
Features of Loss-of-Function SYK-Mutated Advanced Melanoma (AMP 2023)
Our study provides an evaluation of LOF SYK mutations, demonstrating that it is frequently associated with rapid recurrence following the surgical removal of the primary tumor, with the majority of these patients featuring a nonsense SYK mutation. Additionally, this small cohort of patients demonstrated a high treatment response rate to immunotherapy. These observations may imply that, although LOF SYK mutations are associated with early relapse in melanoma patients, immunotherapy appears to be an effective treatment.
IO biomarker • Metastases
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BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • SYK (Spleen tyrosine kinase)
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TP53 mutation • BRAF V600E • NRAS mutation • BRAF V600 • SYK mutation
2years
A Phase 1/2 Dose Escalation Study of the Myeloid Kinase Inhibitor HM43239 in Patients with Relapsed or Refractory Acute Myeloid Leukemia (ASH 2022)
In a preclinical xenograft and orthotopic model of AML, HM43239 exhibited greater antitumor potency than FLT3 inhibitor gilteritinib, SYK inhibitor entospletinib, BCL-2 inhibitor venetoclax, and demethylation agent azacitidine. As of July 14, 2022, HM43239 has delivered CRc at 80 mg, 120mg and 160 mg, and was well tolerated at these dose levels over multiple cycles with no DLTs or drug-related SAEs. Pharmacokinetic data illustrate increasing drug exposures through 120 mg and observed objective responses through 160 mg in both FLT3-WT and FLT3-mutated R/R AML patients even after gilteritinib and midostaurin treatment. An update of this study, including a planned single agent and venetoclax combination expansion, will be presented at the meeting.
Clinical • P1/2 data • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • JAK1 (Janus Kinase 1) • SYK (Spleen tyrosine kinase)
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TP53 mutation • KRAS mutation • NRAS mutation • FLT3-ITD mutation • IDH2 mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • MLL mutation • SYK mutation • MLL-PTD
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • Rydapt (midostaurin) • entospletinib (GS-9973) • tuspetinib (HM43239)
over2years
Phase 2 Study of the SYK Inhibitor Mivavotinib in Relapsed/Refractory (R/R) NON-GCB Diffuse Large B-cell Lymphoma (DLBCL) With or Without MYD88 and/or CD79 Mutations (PPLC 2022)
Patients must have had ≥2 but no more than 5 prior lines of systemic anticancer therapy; following standard first-line R-CHOP (or equivalent), patients must have received 2nd line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2nd line salvage, ASCT, or CAR-T. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Results of this study will inform the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79bmutated DLBCL to guide further expansion in these biomarker-defined cohorts.
P2 data • IO biomarker
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD79B (CD79b Molecule) • SYK (Spleen tyrosine kinase)
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CD79B mutation • CD79B mutation • SYK mutation
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Rituxan (rituximab) • mivavotinib (CB-659)