News - EZH2 mutation - LARVOL VERI

16h

SYMPHONY-1: Study of Tazemetostat Versus Placebo When Given in Combination With Lenalidomide and Rituximab in Participants With Relapsed/Refractory Follicular Lymphoma (clinicaltrials.gov)

P3, N=612, Recruiting, Epizyme, Inc. | Trial completion date: Mar 2029 --> Apr 2032 | Trial primary completion date: Mar 2026 --> Sep 2029

16 hours ago

Trial completion date • Trial primary completion date • Combination therapy

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

EZH2 mutation

Rituxan (rituximab) • lenalidomide • Tazverik (tazemetostat)

11d

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

11 days 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)

15d

Ascorbic Acid and Chemotherapy for the Treatment of Relapsed or Refractory Lymphoma, CCUS, and Chronic Myelomonocytic Leukemia (clinicaltrials.gov)

P2, N=80, Recruiting, Mayo Clinic | N=55 --> 80

15 days ago

Enrollment change

IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • SF3B1 (Splicing Factor 3b Subunit 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CD4 (CD4 Molecule) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

IDH2 mutation • DNMT3A mutation • TET2 mutation • SF3B1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation

cisplatin • carboplatin • gemcitabine • Rituxan (rituximab) • cytarabine • cyclophosphamide • ifosfamide • oxaliplatin • etoposide IV • decitabine • Hemady (dexamethasone tablets) • Mabtas (rituximab biosimilar) • Starasid (cytarabine ocfosfate) • dexamethasone injection

Ascorbic Acid and Combination Chemotherapy for the Treatment of Relapsed or Refractory Lymphoma or CCUS (clinicaltrials.gov)

P2, N=55, Recruiting, Mayo Clinic | Trial completion date: Mar 2024 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Dec 2025

1 month ago

Trial completion date • Trial primary completion date

IDH2 mutation • DNMT3A mutation • TET2 mutation • SF3B1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation

cisplatin • carboplatin • gemcitabine • Rituxan (rituximab) • cytarabine • cyclophosphamide • ifosfamide • oxaliplatin • etoposide IV • Hemady (dexamethasone tablets) • Starasid (cytarabine ocfosfate) • dexamethasone injection

Study of Valemetostat Tosylate as a Single Agent in Patients With Relapse/Refractory B-cell Lymphoma (clinicaltrials.gov)

P2, N=141, Active, not recruiting, The Lymphoma Academic Research Organisation | Recruiting --> Active, not recruiting | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Oct 2024

1 month ago

Enrollment closed • Trial completion date • Trial primary completion date

SLC1A5 (Solute Carrier Family 1 Member 5)

EZH2 mutation

Ezharmia (valemetostat)

Evaluate the Safety and Clinical Activity of HH2853 (clinicaltrials.gov)

P1/2, N=168, Recruiting, Haihe Biopharma Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

1 month ago

Trial completion date • Trial primary completion date • Metastases

ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1)

ARID1A mutation • BAP1 mutation • EZH2 mutation • SMARCA4 mutation

HH2853

TP53 mutation is frequent in mantle cell lymphoma with EZH2 expression and have dismal outcome when both are present. (PubMed, Hum Pathol)

p53 mutant pattern is due to TP53 mutation. MCL patients with EZH2 expression or TP53 mutation show inferior outcome and when both are present, patients have dismal outcome.

1 month ago

Journal

TP53 (Tumor protein P53) • ATM (ATM serine/threonine kinase) • RB1 (RB Transcriptional Corepressor 1) • NOTCH1 (Notch 1) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • CCND1 (Cyclin D1) • KMT2D (Lysine Methyltransferase 2D) • KMT2C (Lysine Methyltransferase 2C) • NOTCH2 (Notch 2) • BIRC3 (Baculoviral IAP repeat containing 3) • UBR5 (Ubiquitin Protein Ligase E3 Component N-Recognin 5)

TP53 mutation • EZH2 mutation • TP53 expression

Mandolin: A Study to Assess Efficacy and Safety of Oral Tazemetostat in Adult Participants With Relapsed/Refractory Follicular Lymphoma That Does Not Have an "EZH2 Gain-of-function" Genetic Mutation (clinicaltrials.gov)

P2, N=55, Not yet recruiting, Epizyme, Inc. | Initiation date: Dec 2023 --> Sep 2024

1 month ago

Trial initiation date

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

EZH2 mutation • EZH2 wild-type

Tazverik (tazemetostat)

ETCTN 10500: Testing the Safety of the Anti-cancer Drugs Tazemetostat and Belinostat in Patients With Lymphomas That Have Resisted Treatment (clinicaltrials.gov)

P1, N=64, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

1 month ago

Trial completion date • Trial primary completion date

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

RAS wild-type • EZH2 mutation • EZH2 wild-type

Tazverik (tazemetostat) • Beleodaq (belinostat)

2ms

Broad next generation integrated sequencing of myelofibrosis identifies disease-specific and age-related genomic alterations. (PubMed, Clin Cancer Res)

Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression, and potential targets for therapeutic intervention.

2 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCR (BCR Activator Of RhoGEF And GTPase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CALR (Calreticulin) • ELTD1 (Adhesion G Protein-Coupled Receptor L4) • DNASE1L3 (Deoxyribonuclease 1 Like 3)

KRAS mutation • NRAS mutation • NF1 mutation • RAS mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation

2ms

Clinical characteristics and prognosis of acute myeloid leukemia patients with Runt-related transcription factor 1 mutation: A single-center retrospective analysis. (PubMed, Hematol Oncol)

EZH2 co-mutation, DNMT3A co-mutation, old age and high WBC count were associated with inferior survival of AML-RUNX1mut . Allo-HSCT can significantly improve the prognosis of AML-RUNX1mut .

2 months ago

Retrospective data • Journal

NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • RAS (Rat Sarcoma Virus) • BCORL1 (BCL6 Corepressor Like 1)

NPM1 mutation • DNMT3A mutation • RUNX1 mutation • EZH2 mutation

2ms

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML. (PubMed, Leukemia)

In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

2 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • SF3B1 (Splicing Factor 3b Subunit 1) • BCOR (BCL6 Corepressor)

KRAS mutation • NRAS mutation • SF3B1 mutation • EZH2 mutation

Venclexta (venetoclax) • Vyxeos (cytarabine/daunorubicin liposomal formulation)

3ms

A miniaturized mode-of-action profiling platform enables high throughput characterization of the molecular and cellular dynamics of EZH2 inhibition. (PubMed, Sci Rep)

The market approval of Tazemetostat (TAZVERIK) for the treatment of follicular lymphoma and epithelioid sarcoma has established "enhancer of zeste homolog 2" (EZH2) as therapeutic target in oncology...These inhibitors interact in a more entropy-driven fashion and show the most persistent effects in cellular washout and antiproliferative efficacy experiments. Our work provides mechanistic insights for the largest cohort of EZH2 inhibitors reported to date, demonstrating that-among several other binding parameters-target residence time is the best predictor of cellular efficacy.

3 months ago

Journal

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

EZH2 mutation • EZH2 Y641 • EZH2 wild-type

Tazverik (tazemetostat)

3ms

BMP-ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B-Cell Lymphoma. (PubMed, Adv Sci (Weinh))

Although PRC2 inhibitors, such as tazemetostat, have demonstrated anti-lymphoma activity in patients, the clinical efficacy is not limited to EZH2-mutant lymphoma...Furthermore, high levels of BMP6 and BMP7, along with ACVR1, are associated with longer survival in lymphoma patients, underscoring the clinical relevance of this study. Altogether, BMP-ACVR1 exhibits anti-lymphoma function and represents a critical PRC2-repressed pathway contributing to the efficacy of PRC2 inhibitors.

3 months ago

Journal

ACVR1 (Activin A Receptor Type 1) • BMP6 (Bone Morphogenetic Protein 6)

EZH2 mutation

Tazverik (tazemetostat)

3ms

The Clinical Utility of Plasma Circulating Tumor DNA in the Diagnosis and Disease Surveillance in non-DLBCL non-Hodgkinâ€™s Lymphomas (ACMG 2024)

Plasma ctDNA demonstrated high concordance with tumor biopsy in detecting genetic aberrations for non-DLBCL NHLs and serves as a promising surrogate of tumor biopsy in monitoring treatment response and disease progression in non-DLBCL NHLs.

3 months ago

Clinical • Tumor mutational burden • IO biomarker • Circulating tumor DNA

TMB (Tumor Mutational Burden) • BCL2 (B-cell CLL/lymphoma 2) • CCND1 (Cyclin D1)

EZH2 mutation

Hemasalus™

3ms

Discovery of a germline EZH2 variant reveals Weaver syndrome during sequencing of a B-cell acute lymphoblastic leukemia (B-ALL) (ACMG 2024)

Hematologic malignancies developing in infancy and childhood - including ALL - have been described in two other patients with Weaver syndrome, although heightened cancer surveillance is not currently recommended. Interestingly, one of these patients - who harbored the same EZH2 E745K variant - developed non-Hodgkin lymphoma at 13 years old. This unusual case of ALL arising in both childhood and adulthood supports a potential link between Weaver syndrome and susceptibility to hematologic cancers.

3 months ago

TET2 (Tet Methylcytosine Dioxygenase 2)

EZH2 mutation

TruSight Myeloid Sequencing Panel

3ms

FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia. (PubMed, Leukemia)

These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML.

3 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

FLT3-ITD mutation • EZH2 mutation

4ms

Prognosis and risk factors for ASXL1 mutations in patients with newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. (PubMed, Cancer Med)

Our study indicated that mutations in G646W or RUNX1 co-mutations are closely associated with a dismal clinical outcome in patients with AML and MDS harboring ASXL1 . Considering the poor prognosis and risk factors in patients with ASXL1 , more available treatments should be pursued.

4 months ago

Journal

NRAS (Neuroblastoma RAS viral oncogene homolog) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • STAG2 (Stromal Antigen 2) • SETBP1 (SET Binding Protein 1)

NRAS mutation • RUNX1 mutation • ASXL1 mutation • EZH2 mutation • SRSF2 mutation • STAG2 mutation

4ms

NUP214 Rearrangements in Leukemia Patients: A Case Series From a Single Institution. (PubMed, Ann Lab Med)

We examined the characteristics and concurrent test results, including gene mutations, of 11 leukemia patients with NUP214 rearrangement. We hope that the elucidation of the context in which they occurred will aid future research on tailored monitoring and treatment.

4 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NOTCH1 (Notch 1) • WT1 (WT1 Transcription Factor) • NUP214 (Nucleoporin 214)

EZH2 mutation

4ms

Performance of the cobas EZH2 mutation test on clinical samples from non-Hodgkin lymphoma patients. (PubMed, PLoS One)

cobas EZH2 Test data demonstrated that the test is reliable and will perform well in a commercial customer environment.

4 months ago

Journal

EZH2 mutation

cobas® EZH2 Mutation Test

4ms

Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations. (PubMed, Exp Hematol)

The identified EZH2 mutations had drastically reduced catalytic activity, resulting in lower cellular H3K27me3 levels and were associated with decreased EZH2 and PRC2 component EED protein levels. Overall, this study provides an important understanding of the role of EZH2 dysregulation in blood cancers and may indicate disease etiology for these poor prognosis AML and MDS/MPN cases.

4 months ago

Journal

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

EZH2 mutation

4ms

Recurrent mutations in Refractory/Relapsed Diffuse Large B cell Lymphoma by targeted gene sequencing. (PubMed, Cytogenet Genome Res)

Co-occurrence of loss of function mutations of TNFAIP3 and missense mutations in MYD88 was associated with a non-responsive cohort. Discussion-The study highlights mutations associated with chemotherapeutic response in DLBCL with implications for initial diagnostic biopsy response prediction.

4 months ago

Journal

TP53 (Tumor protein P53) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • TNFAIP3 (TNF Alpha Induced Protein 3) • CD58 (CD58 Molecule)

TP53 mutation • NOTCH1 mutation • MYD88 mutation • EZH2 mutation

5ms

A Novel and Potent EZH1/2 Dual Inhibitor, HM97662 Demonstrated a Wide Spectrum of Therapeutic Potential for Hematological Malignancies (ASH 2023)

The enhancer of zeste homolog 2 (EZH2) and its homolog EZH1 are catalytic components of polycomb repressive complex 2 (PRC2), which tri-methylate histone H3 at lysine 27 (H3K27me3) to repress transcription of their target genes. In conclusion, the present preclinical studies demonstrated that HM97662, an EZH1/2 dual inhibitor, had a promising and wide spectrum of therapeutic potential for hematological malignancies. It is urgent to assess the effectiveness of HM97662 in further clinical trials.

5 months ago

IO biomarker

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • CD38 (CD38 Molecule) • PRDM1 (PR/SET Domain 1) • CDKN1C (Cyclin Dependent Kinase Inhibitor 1C) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)

EZH2 mutation • EZH2 Y641 • EZH2 overexpression

27 • HM97662

5ms

Mutational Landscape of Diffuse Large B-Cell Lymphoma (DLBCL) in Mexican Patients (ASH 2023)

Inclusion criteria: patients > 18 years, diagnosis of DLBCL, without previous treatment and candidate to be treated with RCHOP... This is the first approach to describe the genomic landscape in Latino-american population. The presence of EZH2 and KMT2 mutations were more frequent in female patients with mediastinal and bulky disease. After multivariate analysis, only the presence of EZH2 mutations was the only genomic factor influencing on OS.

5 months ago

Clinical

TP53 (Tumor protein P53) • ARID1A (AT-rich interaction domain 1A) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • KMT2D (Lysine Methyltransferase 2D) • CREBBP (CREB binding protein)

TP53 mutation • MYD88 mutation • KMT2D mutation • EZH2 mutation

Rituxan (rituximab)

5ms

Next Generation Sequencing and Cytogenetics in Acute Myeloid Leukemia - Therapeutic and Prognostic Impact: A Retrospective Cohort from a Private Centre of Reference in Latin America (ASH 2023)

Next-Generation Sequencing, combined with cytogenetic analysis, has improved precision in prognosis prediction of AML patients of each patient, allowing safe implementation of appropriate individualized therapy. This study showed and association between high-risk cytogenetics and worse prognosis in AML, but no association was observed between molecular risk and AML morbimortality. Further studies with a bigger population and longer follow-up should be conducted in Latin America in order to better clarify and delve deeper into the results reported in this cohort.

5 months ago

Retrospective data • Next-generation sequencing

TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

TP53 mutation • ASXL1 mutation • SF3B1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation

5ms

Characterization of Cases with the Rare Cytogenetic Abnormality I(7)(p10) Reveals an Association with IDH2 Mutated Acute Myeloid Leukemia (ASH 2023)

(1) The rare but recurrent cytogenetic aberration i(7)(p10) is mainly found in AML, where associations with mutations in IDH2, DNMT3A and BCOR were observed. By contrast, other AML-defining mutations ( NPM1, FLT3-ITD, CEPBA) were largely absent, further no defining fusions/rearrangements or a complex karyotype were detected. (2) The vast majority of patients were female and younger than patients with IDH2 mutation without i(7)(p10).

5 months ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • ARG1 (Arginase 1) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

FLT3-ITD mutation • IDH1 mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation • DNMT3A mutation + IDH mutation

5ms

Pharmacokinetics, Drug Interaction, and Exposure-Safety Analyses of Tazemetostat When Co-Administered with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Phase 1b Results of Symphony-1 (ASH 2023)

TAZ + R 2 combination demonstrates consistent and unaltered PK for TAZ and lenalidomide, and delivered an optimal target engagement, and favorable safety profile. There is no DDI when TAZ is given in combination with R 2. The exposure safety analysis demonstrated that there were no obvious trends in increasing Grade ≥3 AEs with increasing exposure when combined with R 2.

5 months ago

Clinical • P1 data • PK/PD data

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

EZH2 mutation

Rituxan (rituximab) • lenalidomide • Tazverik (tazemetostat)

5ms

NGS Profile and the Mathematical Prediction Model for Venetoclax Combination Therapy in HM-Screen-Japan 02 Study (ASH 2023)

Introduction Azacitidine and venetoclax combination therapy (Aza/Ven) is a novel strategy for acute myeloid leukemia (AML). Our mathematical model, involving gene mutations and WT1, could efficiently predict the response of Aza/Ven, which may support the selection of 1 st line treatment. In conclusion, our study revealed the genetic landscape of real-world Aza/Ven therapy and provided a potential prognostic model.

5 months ago

Combination therapy • Next-generation sequencing

TP53 (Tumor protein P53) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

TP53 mutation • IDH2 mutation • NPM1 mutation • RUNX1 mutation • ASXL1 mutation • SF3B1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation • CEBPA mutation • STAG2 mutation • WT1 mutation • ZRSR2 mutation

Venclexta (venetoclax) • azacitidine

5ms

SYMPHONY-1: Study of Tazemetostat Versus Placebo When Given in Combination With Lenalidomide and Rituximab in Participants With Relapsed/Refractory Follicular Lymphoma (clinicaltrials.gov)

P3, N=540, Recruiting, Epizyme, Inc. | Phase classification: P1b --> P3

5 months ago

Phase classification • Combination therapy

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

EZH2 mutation

Rituxan (rituximab) • lenalidomide • Tazverik (tazemetostat)

5ms

Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis. (PubMed, Leukemia)

Both myeloid and T-cell leukemias engrafted in immunocompromised hosts. These data underline the potential of Xenopus tropicalis for modeling human leukemia, where mosaic gene disruption, combined with deep amplicon sequencing of the targeted genomic regions, can rapidly and efficiently expose co-operating driver gene mutations.

5 months ago

Journal • Epigenetic controller

NOTCH1 (Notch 1) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

NOTCH1 mutation • EZH2 mutation

5ms

Proteomic Profiling Identifies Unique IDH Mutant Signatures and Novel Therapeutic Opportunities in Adult Acute Myeloid Leukemia Patients (ASH 2023)

We analyzed 151 patients with IDH mutations (IDH1 = 56, IDH2 = 76, both = 19), treated with AraC-based combination therapy (N=71, including 5 with IDHi, 11 with Venetoclax (VTX)) or Hypomethylating agent based (HMA, N=65, + IDHi=5, +VTX=11, or both=2) and 3 received IDHi monotherapy, Proteins prognostic for Overall Survival (OS) were identified using pairwise LogRank tests (p<0.05) adjusted for False Discovery Rate (FDR), followed by unbiased hierarchical clustering... Proteomics identified unique protein profiles that were independently prognostic for outcome in IDH mutant AML patients. We identified upregulated proteins for which inhibitors are in development, suggesting potential therapeutic synergies to improve outcomes. Finally, we defined 5 proteins that accurately stratifies IDH patients for novel treatment recommendations.

5 months ago

Clinical

TP53 (Tumor protein P53) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • RAD50 (RAD50 Double Strand Break Repair Protein) • CD34 (CD34 molecule) • PIK3CB (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) • TGM2 (Transglutaminase 2) • ANXA1 (Annexin A1) • PRMT1 (Protein Arginine Methyltransferase 1) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2) • TP53BP1 (Tumor Protein P53 Binding Protein 1) • PTK2 (Protein Tyrosine Kinase 2) • WTAP (WT1 Associated Protein)

TP53 mutation • FLT3-ITD mutation • IDH1 mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • EZH2 mutation • JAK2 mutation

Venclexta (venetoclax)

5ms

Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease. (PubMed, Nat Med)

This work sheds light on HSC clonal dynamics and the mutational landscape after GT in SCD, highlighting the enhanced fitness of some HSCs harboring pre-existing driver mutations. Future studies should define the long-term fate of mutant clones, including any contribution to expansions associated with myeloid neoplasms.

5 months ago

Journal • Tumor mutational burden • Gene therapy

TMB (Tumor Mutational Burden) • DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • EZH2 mutation

5ms

Genomic alterations in blast phase of BCR::ABL1-negative myeloproliferative neoplasms. (PubMed, Int J Lab Hematol)

These mutations are also correlated with, and can contribute to, the progression of MPN-BP. In this review, we summarize their common mutational profiles, functions, and associations with progression of MPN-BP.

5 months ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • SH2B3 (SH2B Adaptor Protein 3)

TP53 mutation • KRAS mutation • ASXL1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation

5ms

The median age at the time of diagnosis was 50 years (range 45-73), all patients underwent a minimum of 2 lines of standard chemotherapy (including at least 1 platinum-based regimen) before PARP-i oral maintenance; 10 patients (58%) had been exposed to Olaparib, 5 (29.5%) to Niraparib and 2 (11.5%) to Rocuraparib. Recurrent molecular alterations were not found in our patients. Our data show how MN-pCT occurring after the combination of platinum-based chemotherapy and PARP-i oral maintenance share common cytogenetic alterations, mostly involving chromosome 5 and 7, and NGS-detectable mutations.

5 months ago

Clinical • BRCA Biomarker • PARP Biomarker

TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • IKZF1 (IKAROS Family Zinc Finger 1) • BRCA (Breast cancer early onset) • CSF3R (Colony Stimulating Factor 3 Receptor)

TP53 mutation • BRCA2 mutation • KIT mutation • RUNX1 mutation • EZH2 mutation • BRCA mutation • PARP1 mutation

Lynparza (olaparib) • Zejula (niraparib)

5ms

THE COMBINATION OF NAVITOCLAX AND RUXOLITINIB IN JAK INHIBITOR–NAÏVE PATIENTS WITH MYELOFIBROSIS MEDIATES RESPONSES SUGGESTIVE OF DISEASE MODIFICATION (SIE 2023)

Spleen volume reductions ≥35% (SVR35) in subgroups at Week 24. Abbreviations: DIPSS, Dynamic International Prognostic Scoring System; HMR, high molecular risk; Int, intermediate; MF, myelofibrosis.

5 months ago

Clinical

IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • JAK2 (Janus kinase 2) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CALR (Calreticulin)

ASXL1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation

Jakafi (ruxolitinib) • navitoclax (ABT 263)

5ms

Conformationally constrained potent inhibitors for enhancer of zeste homolog 2 (EZH2). (PubMed, Bioorg Med Chem Lett)

Based on the structure of 1 (EPZ-6438), a series of novel conformationally constrained derivatives were designed and synthesized aiming to improve the EZH2 inhibition activity, especially for mutated EZH2...28 exhibited high anti-proliferation activity against different lymphoma cell lines including WSU-DLCL2, Pfeiffer and Karpas-422 (IC = 2.36, 1.73, and 1.82 nM, respectively). In vivo, 28 showed acceptable pharmacokinetic characteristics (oral bioavailability F = 36.9%) and better efficacy than 1 in both Pfeiffer and Karpas-422 xenograft mouse models, suggesting that it can be further developed as a potential therapeutic candidate for EZH2-associated cancers.

5 months ago

Journal

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

EZH2 mutation

Tazverik (tazemetostat)

5ms

Absence of BTK, BCL2, and PLCG2 Mutations in Chronic Lymphocytic Leukemia Relapsing after First-Line Treatment with Fixed-Duration Ibrutinib plus Venetoclax. (PubMed, Clin Cancer Res)

Of the 29 patients with PD, 19 have required retreatment (single-agent ibrutinib, n = 16, or ibrutinib plus venetoclax, n = 3); 17 achieved partial response or better, 1 achieved stable disease, and 1 is pending response assessment. First-line fixed-duration combination treatment with ibrutinib plus venetoclax may mitigate development of resistance mechanisms associated with continuous single-agent targeted therapies, allowing for effective retreatment.

5 months ago

Journal • IO biomarker

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • SF3B1 (Splicing Factor 3b Subunit 1) • BTK (Bruton Tyrosine Kinase) • IGH (Immunoglobulin Heavy Locus) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • BIRC3 (Baculoviral IAP repeat containing 3) • PLCG2 (Phospholipase C Gamma 2) • POT1 (Protection of telomeres 1) • CHD2 (Chromodomain Helicase DNA Binding Protein 2)

TP53 mutation • BRAF mutation • ATM mutation • Chr del(11q) • EZH2 mutation • PLCG2 mutation • TS 12

Venclexta (venetoclax) • Imbruvica (ibrutinib)

5ms

Epigenetic regulation of enhancer of zeste homolog 2 (EZH2) -Yin Yang 1 (YY1) axis in cancer. (PubMed, Pathol Res Pract)

Due to its mutation and overexpression, the cells that help combat cancer are suppressed and carcinogenicity is promoted. The association of EZH2 and YY1 poses an intriguing mechanism in relation to cancer.

5 months ago

Review • Journal • IO biomarker

CD8 (cluster of differentiation 8) • YY1 (YY1 Transcription Factor)

EZH2 mutation

5ms

EZH2 inhibition stimulates repetitive element expression and viral mimicry in resting splenic B cells. (PubMed, EMBO J)

Together, the results reveal chemokine expression induced by EZH2 inhibitors in B cells as a novel inflammatory response to genomic repeat expression. Given the overlap of genes induced by EZH2 inhibitors and Epstein-Barr virus infection, this response can be described as a form of viral mimicry.

5 months ago

Journal

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • IFIH1 (Interferon Induced With Helicase C Domain 1)

EZH2 mutation

6ms

Discovery of dihydropyridinone derivative as a covalent EZH2 degrader. (PubMed, Eur J Med Chem)

Starting from an approved EZH2 inhibitor EPZ-6438, we used covalent drug design and medicinal chemistry approaches to discover a novel covalent EZH2 degrader 38, which forms a covalent bond with EZH2 Cys663 and showed strong biochemical activities against EZH2 WT and mutants...The mass spectrometry, washout and competition experiments confirmed the covalent binding of 38 to EZH2. This study demonstrates that covalent EZH2 degraders could provide an opportunity for the development of promising new drug candidates.

6 months ago

Journal

EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

EZH2 mutation • EZH2 overexpression

Tazverik (tazemetostat)