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ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer

Science Advances 2023年第14期9卷 eadc9446页

作者： Li, Dan Zhan, Yu Wang, Naitao Tang, Fanying Lee, Cindy J. Bayshtok, Gabriella Moore, Amanda R. Wong, Elissa W.P. Pachai, Mohini R. Xie, Yuanyuan Sher, Jessica Zhao, Jimmy L. Khudoynazarova, Makhzuna Gopalan, Anuradha Chan, Joseph Khurana, Ekta Shepherd, Peter Navone, Nora M. Chi, Ping Chen, Yu Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Sandra and Edward Meyer Cancer Center Department of Physiology and Biophysics Weill Cornell Medicine New YorkNY10065 United States Weill Cornell Graduate School of Medical Sciences Weill Cornell Medicine New YorkNY10065 United States Department of Medical Oncology Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Department of Pathology Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Department of Medicine Thoracic Oncology Service Memorial Sloan Kettering Cancer Center New YorkNY10065 United States Institute for Computational Biomedicine Weill Cornell Medical College New YorkNY10021 United States Department of Physiology and Biophysics Weill Cornell Medical College New YorkNY10021 United States Englander Institute for Precision Medicine Weill Cornell Medicine New YorkNY10021 United States Genitourinary Medical Oncology MD Anderson Cancer Center 1515 Holcombe Boulevard HoustonTX77030 United States Department of Medicine Division of Hematology and Medical Oncology Weill Cornell Medicine New YorkNY10065 United States Department of Medicine Memorial Sloan Kettering Cancer Center New YorkNY10065 United States AbbVie Cambridge Research Center CambridgeMA02139 United States Department of Molecular Oncology Genentech Inc. South San FranciscoCA94080 United States

The mechanisms underlying ETS-driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We generated a genetically engineered mouse wit... 详细信息

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Systematic Evaluation of GAPs and Gefs Identifies ARHGAP45 As a Targetable leukemia-Specific Dependency

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Blood 2024年 144卷 950-950页

作者： Pu Zhang Zhendong Cao Xiangyu Pan Yuqiao Liu Cynthia Castro Won Jun Kim Takeshi Fujino Jennifer Lewis Jahan Rahman Sanam Shahid Jasmine S. Um Erin R. Burns Bing-Yi Chen Winson Cai Juliana Ortiz-Pacheco Zhuoning Li Mara Monetti Anthony F. Daniyan Christopher R. Vakoc Omar Abdel-Wahab Junwei Shi Memorial Sloan Kettering Cancer Center New York University of Pennsylvania Philadelphia Memorial Sloan Kettering Cancer Center New York NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center NY Pediatrics Memorial Sloan Kettering Cancer Center New York NY Department of Medicine Cell Therapy Service Memorial Sloan Kettering Cancer Center New York NY Cold Springs Harbor Laboratory Cold Spring Harbor NY Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Department of Cancer Biology Perelman School of Medicine at the University of Pennsylvania Philadelphia PA

GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) function as negative and positive regulators of small GTPases, respectively, and play key roles in cell fate determination. The aberrant...

GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) function as negative and positive regulators of small GTPases, respectively, and play key roles in cell fate determination. The aberrant function of GAPs and GEFs has long been implicated in cancer development but their vast number and potential redundancy have hindered comprehensive understanding of their roles. Here we performed functional genomic screens of GAPs and GEFs in primary AML specimens to uncover an unexpected and selective role for ARHGAP45 in AML. Depletion of ARHGAP45 impedes AML growth without affecting normal human CD34 + cells in vivo . Epistasis screens revealed RhoA as the major substrate of ARHGAP45 and that depletion of the Rho GTPase CDC42 synergized with ARHGAP45 deletion. Consistent with this, pharmacologic CDC42 inhibition enhanced the effect of ARHGAP45 knockout (KO). ARHGAP45 gives rise to a minor histocompatibility antigen (termed HA-1), which can be recognized by antigen-specific T cells. CDC42 inhibition not only sensitized AML cells to ARHGAP45 depletion but also promoted the cytolytic activity of HA-1 antigen-specific T cells by upregulating ARHGAP45-derived epitope in AML cells. We generated a domain-focused CRISPR library of 1,320 sgRNAs targeting 187 GAPs, 103 GEFs, as well as negative and pan-essential controls, and conducted CRISPR KO screens in PDX models in vitro and in vivo from 2 AML patients and 1 AML cell line (MOLM-13). ARHGAP45 emerged as the top-ranking gene in vitro and vivo . Competition assays across cancer cell lines, including AML, B-ALL, myeloma, and solid tumors, validated ARHGAP45 as a lineage-specific dependency in AML. CRISPR-scanning of ARHGAP45's domains revealed the RhoGAP domain as essential in AML. Consistent with these findings, ARHGAP45 depletion in 3 AML PDX models and 1 cell line extended survival of recipient NSGS mice compared to controls. In contrast, deletion of ARHGAP45 in normal human cord blood CD34 + cells had no

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Author Correction: Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives

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Nature reviews. Clinical oncology 2024年第9期21卷 701页

作者： Antonio Marra Sarat Chandarlapaty Shanu Modi Division of New Drugs and Early Drug Development European Institute of Oncology IRCCS Milan Italy. Human Oncology and Pathogenesis Program (HOPP) Memorial Sloan Kettering Cancer Center New York NY USA. Breast Medicine Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Weill Cornell Medical College New York NY USA. Breast Medicine Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. modis@***. Weill Cornell Medical College New York NY USA. modis@***.

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Characteristics and Prognostic Effects of IDH Mutations across the Age Spectrum in AML: A Collaborative Analysis from COG, SWOG, and ECOG

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BLOOD 2020年 136卷 31-32页

作者： Zarnegar-Lumley, Sara Alonzo, Todd A. Othus, Megan Sun, Zhuoxin Ries, Rhonda E. Wang, Yi-Cheng Leonti, Amanda R. Kutny, Matthew A. Stirewalt, Derek Radich, Jerald P. Appelbaum, Frederick R. Pogosova-Agadjanyan, Era L. O'Dwyer, Kristen Marie Erba, Harry P. Abdel-Wahab, Omar Tallman, Martin S. Litzow, Mark Atallah, Ehab L. Luger, Selina M. Levine, Ross L. Cooper, Todd M. Gamis, Alan S. Aplenc, Richard Kolb, Anders E. Meshinchi, Soheil Tarlock, Katherine Vanderbilt University Medical Center Nashville TN Children's Oncology Group Monrovia CA Department of Preventive Medicine University of Southern California Monrovia CA Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA Dana Farber Cancer Institute ECOG-ACRIN Statistical Center Boston MA Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA Clinical Research Division Fred Hutchinson Cancer Research Center Mountlake Terrace WA Department of Pediatrics Division of Hematology and Oncology University of Alabama at Birmingham Birmingham AL Departments of Oncology and Hematology University of Washington Seattle WA University of Rochester Medical Center Rochester NY Division of Hematologic Malignancies and Cellular Therapy Duke University Durham NC Department of Medicine Leukemia Service Memorial Sloan Kettering Cancer Center New York NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Memorial Sloan-Kettering Cancer Center New York NY Weill Cornell Medical College New York NY Division of Hematology Mayo Clinic Rochester MN Medical College of Wisconsin Wauwatosa WI Abramson Cancer Center University of Pennsylvania Philadelphia PA Division of Hematology and Oncology Seattle Children's Hospital Seattle WA

Background: Somatic mutations in the IDH genes are common in acute myeloid leukemia (AML). Mutations occur at active site arginine residues in IDH1 (R132) and IDH2 (R140, R172). IDH inhibitors, ivosidenib (IDH1) and e...

Background: Somatic mutations in the IDH genes are common in acute myeloid leukemia (AML). Mutations occur at active site arginine residues in IDH1 (R132) and IDH2 (R140, R172). IDH inhibitors, ivosidenib (IDH1) and enasidenib (IDH2), have shown improved clinical outcomes in patients with relapsed/refractory IDH -mutant AML and are approved for use in this setting, while investigations in combination with chemotherapy are underway in de novo AML. The prognostic significance of IDH mutations remains controversial. We hypothesize that refining our understanding of IDH -mutated AML will contribute to risk-adapted treatment strategies, including optimal use of IDH-targeted agents. The objective of our study was to identify characteristics that affect outcome in de novo IDH- mutated AML across the age spectrum utilizing a large cohort of patients enrolled on several pediatric and adult trials. Methods: The total cohort (N=3588) included patients age <1 month - 88 years. Pediatric and young adult (YA) patients were treated on recent CCG/COG AML trials (CCG2961, COG 03P1, 0531, 1031, N=2231) and YA/adult patients were treated on SWOG S0106 (N=396), ECOG E1900 AML trials (N=398), Beat AML (N=363), or included in the TCGA biology study (N=200; outcomes not evaluated for this group). Patients were analyzed according to three defined age groups: “younger” 0-29 years of age (N=2401), “intermediate” 30-59 years of age (N=819) and “older” 60 years of age and above (N=319). Data regarding clinical characteristics and treatment outcomes were collected and evaluated according to the standard practices of each cooperative or research groups for the respective studies. Mutational profiling was performed by targeted sequencing for patient samples from COG trials, Beat-AML, ECOG, and SWOG; whole-genome or whole-exome sequencing for the TCGA cohort. Prevalence of IDH mutations, co-occurring mutations, and outcomes (5-year event-free survival [EFS]) were analyzed across the defined age gr

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Increased Interleukin-8 (IL8)-CXCR2 Signaling Promotes Progression of Bone Marrow Fibrosis in Myeloproliferative Neoplasms

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BLOOD 2020年 136卷 6-7页

作者： Dunbar, Andrew Lu, Min Farina, Mirko Park, Young Yang, Julie Kim, Dongjoo Karzai, Abdul Salama, Mohamed E. Snyder, Jenna Krishnan, Aishwarya Koche, Richard P. Fan, Rong Levine, Ross L. Hoffman, Ronald Department of Medicine Leukemia Service Memorial Sloan Kettering Cancer Center New York NY MPN Research Consortium New York NY Division of Hematology/Medical Oncology Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY Bone Marrow Transplant Unit ASST-Spedali Civili di Brescia Dpt of Clinical and Experimental Sciences University of Brescia Pavia Italy Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY Department of Biomedical Engineering Yale University New Haven CT Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York City NY Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY

Introduction: Elevated pro-inflammatory cytokines are a hallmark feature of myeloproliferative neoplasms (MPNs). The pro-inflammatory cytokine interleukin-8 (IL8) is increased in patients with myelofibrosis (MF) and c...

Introduction: Elevated pro-inflammatory cytokines are a hallmark feature of myeloproliferative neoplasms (MPNs). The pro-inflammatory cytokine interleukin-8 (IL8) is increased in patients with myelofibrosis (MF) and correlates with adverse outcome, including overall survival. Previously, the Levine/Fang labs identified increased IL8 secretion from individual CD34+ stem cells in a subset of MF patients. The role of IL8 and its cognate receptors CXCR1/2 in MF pathogenesis has not been delineated. Methods: Single-cell cytokine assays were performed on isolated CD34+ cells from 60 clinically annotated MPN patients (20 MF, 20 PV, 20 ET) using a previously described micro-chip platform (Kleppe et al, Can Disc 2013). 10 healthy donors (CD34+ cells from hip replacements) were used as controls. Integrated RNA-Seq and Assay for Transposase-Accessible Chromatin followed by next-generation sequencing (ATAC-Seq) was performed on CD34+ cells from MPN patients with and without expanded IL8 secreting clones for gene expression/chromatin accessibility analysis. To model the role of IL8-CXCR2 on fibrosis in vivo , the human MPL W515L transplant model (hMPL W515L ) of MF was used. Specifically, wild-type (WT) murine bone marrow ( Cre neg -Cxcr2 f/f ; Cxcr2 WT ) or marrow lacking the CXCR2 receptor ( VavCre-Cxcr2 f/f ; Cxcr2 KO )were retrovirally infected with MSCV-hMPL W515L -IRES-GFP and transplanted into lethally irradiated WT recipient mice and monitored for disease. Blood counts, chimerism, and flow cytometry were assayed. Moribund mice were sacrificed and assayed for grade reticulin fibrosis and overall survival. Results: Single-cell cytokine assays confirmed an increased proportion of IL8-secreting CD34+ cells in MF patients (40%) in comparison to other MPN sub-types (10% PV/0% ET) (Figure 1A) . MF patients with expanded IL8 secreting clones (defined as >50% of total CD34+ cells) had increased leukocytosis (p<0.0001), larger spleen sizes (p=0.0004), greater prevalence of constit

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Two Decade Single Institution Experience Highlights Rare Survivors with Relapsed or Refractory Burkitt Lymphoma

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Blood 2024年 144卷 6520-6520页

作者： Rabeya Molla Ellin Berman Philip Caron Gerard Donnelly Lorenzo Falchi Paul A. Hamlin Steven Horwitz Andrew M. Intlekofer William T. Johnson Joseph G Jurcic Anita Kumar Jennifer Kimberly Lue Alison Moskowitz Colette Owens Parastoo B Dahi Maria Lia Palomba Carol S. Portlock Gilles Salles Craig S Sauter Santosha A. Vardhana Ariela Noy Memorial Sloan Kettering Cancer Center New York NY Department of Medicine Leukemia Service Memorial Sloan Kettering Cancer Center New York NY Lymphoma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY NYU Langone Lake Success NY Department of Medicine Lymphoma Service Memorial Sloan Kettering Cancer Center New York NY Herbert Irving Comprehensive Cancer Center and Columbia University Irving Medical Center New York NY Adult Bone Marrow Transplantation Service Memorial Sloan Kettering Cancer Center New York NY Department of Medicine Lymphoma Service Memorial Sloan Kettering Cancer Center New York Memorial Sloan Kettering Cancer Center New York Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Lymphoma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College New York NY

Burkitt lymphoma (BL) is a highly aggressive and curable disease, but associated with poor outcomes if relapsed/refractory (R/R). Those at highest risk of relapse were identified in a prospective trial as having centr...

Burkitt lymphoma (BL) is a highly aggressive and curable disease, but associated with poor outcomes if relapsed/refractory (R/R). Those at highest risk of relapse were identified in a prospective trial as having central nervous system (CNS), marrow or peripheral blood BL (Roschewsi, JCO 2020) or in retrospective series as age ≥ 40, ECOG ≥ 2, LDH > 3× ULN, and CNS as equally weighted independent factors (Olszewski JCO 2020). The outcome of R/R disease is dismal: 2/35 (Short, Am J Hematol. 2017) and 0/10 (Gamero, ASH, 2019), though one report had 11/74 survivors. (Manji, ASH, 2021) We retrospectively performed a database search at Memorial Sloan Kettering Cancer Center between 1/1/1988 to 12/21/2021, identifying 276 BL patients (pts) of whom 28 had R/R disease (1997-2021). Here we describe these 28 pts. High risk baseline features include stage IV disease (21), leptomeningeal disease (LMD) (7), bone marrow disease (7). Five had HIV. The vast majority received ‘intensive’ first line therapies, ie. CODOX/IVAC, DA-EPOCH; including 20 with rituximab on account of study time frame. Initial responses were complete response (CR) (8), partial response (PR) (10), and progression of disease (POD) (10). Among the 8 pts with complete response, the median time to relapse was 5 months. Salvage therapy was given in 13/28 with intention to achieve a CR, typically platinum based or high dose MTX +/-cytarabine; while others receiving a variety of palliative treatments. After 1 st salvage therapy, CR was 0% and POD 74%. Four pts achieved CR after >=1 salvage chemotherapy and 1 after radiation. Two pts received allogeneic stem cell transplant (BMT) but 1 died due to complications within a week of transplant and 1 had POD 5 months after BMT. Three pts were long term survivors: one with stage I and two with stage IV disease with bone marrow and leptomeningeal disease (LMD) at initial diagnosis. All received consolidative autologous BMT. Their unique trajectory of treatment was as follows.

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HMGA1 Chromatin Regulators Disrupt 3D Genome Architecture and Chromatin Looping to Repress MHC II Genes and Drive Immune Evasion during MPN Progression

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Blood 2024年 144卷 756-756页

作者： Linda Resar Joseph Kim Audrey-Ann Supreme Hyunsung Woo Bailey West Mariah C. Antopia Zanshe Thompson Karen Reddy Jung-Hyun Kim Leslie Cope Raajit Rampal Richard Koche Alison R. Moliterno Jerry L. Spivak Division of Hematology Departments of Medicine Oncology & Pathology The Johns Hopkins University School of Medicine Baltimore MD Johns Hopkins University School of Medicine Baltimore MD Cellular and Molecular Medicine Graduate Program Johns Hopkins University School of Medicine Baltimore MD Doctoral Diversity Program Johns Hopkins University School of Medicine Baltimore MD Department of Medicine Division of Hematology Johns Hopkins University School of Medicine Baltimore MD Whiting School of Engineering The Johns Hopkins University Baltimore MD Pathobiology Graduate Program Johns Hopkins University School of Medicine Baltimore MD The Institute for Basic Biomedical Sciences Johns Hopkins University School of Medicine Baltimore MD Division of Hematology The Johns Hopkins University School of Medicine Owings Mills MD The Johns Hopkins University School of Medicine Baltimore MD Memorial Sloan Kettering Cancer Center New York NY Center for Epigenetics Research Memorial Sloan Kettering Cancer Center New York NY Human Oncology and Pathogenesis Program Leukemia Service Department of Medicine Center for Epigenetics Memorial Sloan Kettering Cancer Center New York NY Division of Hematology Department of Medicine Johns Hopkins University/Fda Silver Spring MD Department of Oncology Johns Hopkins University School of Medicine Baltimore MD

Introduction: Myeloproliferative neoplasms (MPN) are clonal blood disorders with hyperactive JAK/STAT signaling and an increased risk of transformation to acute myeloid leukemia (AML). Importantly, AML in MPN is almos...

Introduction: Myeloproliferative neoplasms (MPN) are clonal blood disorders with hyperactive JAK/STAT signaling and an increased risk of transformation to acute myeloid leukemia (AML). Importantly, AML in MPN is almost universally fatal and targetable mechanisms remain elusive. We discovered that High Mobility Group A1 (HMGA1) chromatin regulators are required for MPN progression and leukemic transformation in JAK2 V617F mouse models (Li et al, Blood 2022). Immune escape is a fundamental mechanism of tumor progression in solid tumors, although its role in MPN is unknown. We therefore sought to test the hypotheses that: 1) HMGA1 drives MPN progression by activating gene networks involved in immune evasion, 2) Targeting HMGA1 networks with therapy in advanced MPN will trigger an anti-tumor immune attack. Methods: To dissect mechanisms underlying HMGA1, we performed multiomic sequencing (seq) approaches, including RNAseq, chromatin immunoprecipitation (ChIPseq), and assays of chromatin accessibility (ATACseq) in JAK2 V617F mutant AML cell lines (DAMI, SET-2, UKE-1). HMGA1 was inactivated via CRISPR or short hairpin RNA (shRNA). To examine three dimensional (3D) genome architecture, we employed chromatin conformation capture (3C). ChIP was used to detect chromatin binding of repressive histones and CCCTC-binding factor (CTCF) complexes. To define pathways relevant to MPN patients, we assessed bulk and single cell (sc) RNAseq of peripheral blood mononuclear cells (PBMCs) and CD34 + cells. Artificial intelligence (AI) was used to identify drugs targeting HMGA1. Results: To elucidate transcriptional networks governed by HMGA1 in MPN, we integrated multiomic approaches (RNA/ChIP/ATACseq) in JAK2 V617F mutant AML cells, which revealed that HMGA1 represses gene networks involved in interferon γ signaling and antigen presentation (AP), including genes encoding major histocompatibility complex (MHC) class I and II proteins. HMGA1 also represses the CD74 gene, which encodes the

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Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity

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Cancer cell 2025年

作者： Andrew W Daman Anthony C Antonelli Gil Redelman-Sidi Lucinda Paddock Shireen Khayat Mythili Ketavarapu Jin Gyu Cheong Leonardo F Jurado Anna Benjamin Song Jiang Dughan Ahimovic Victoria R Lawless Michael J Bale Oleg Loutochin Victor A McPherson Maziar Divangahi Rachel E Niec Dana Pe'er Eugene Pietzak Steven Z Josefowicz Michael S Glickman Immunology and Microbial Pathogenesis Program Graduate School of Medical Sciences Weill Cornell Medicine New York NY USA Department of Pathology and Laboratory Medicine Division of Cell and Cancer Pathobiology Weill Cornell Medicine New York NY USA. Immunology Program Sloan Kettering Institute New York NY USA. Infectious Diseases Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Department of Pathology and Laboratory Medicine Division of Cell and Cancer Pathobiology Weill Cornell Medicine New York NY USA Howard Hughes Medical Institute Chevy Chase MD USA Computational and Systems Biology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. Pharmacology Program Weill Cornell Medicine Graduate School of Medical Sciences New York NY USA. Immunology and Microbial Pathogenesis Program Graduate School of Medical Sciences Weill Cornell Medicine New York NY USA. Department of Medicine Department of Pathology Department of Microbiology & Immunology McGill University Health Centre McGill International TB Centre Meakins-Christie Laboratories McGill University Montreal QC Canada. Urology Service Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA. Department of Urology Jewish General Hospital McGill University Montreal QC Canada. Human Oncology and Pathogenesis Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York NY USA. Department of Pathology and Laboratory Medicine Division of Cell and Cancer Pathobiology Weill Cornell Medicine New York NY USA. Electronic address: szj2001@med.cornell.edu. Immunology Program Sloan Kettering Institute New York NY USA Infectious Diseases Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Electronic address: glickmam@***.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and p... 详细信息

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Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents: a single-centre, single-arm, phase 2 trial

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The Lancet Haematology 2020年第8期7卷 e566-e574页

作者： Taylor, Justin Mi, Xiaoli Penson, Alexander V Paffenholz, Stella V Alvarez, Kelsey Sigler, Allison Chung, Stephen S Rampal, Raajit K Park, Jae H Stein, Eytan M Tallman, Martin S Sen, Filiz Gönen, Mithat Abdel-Wahab, Omar Klimek, Virginia M Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY United States Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY United States Department of Pathology Memorial Sloan Kettering Cancer Center New York NY United States Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY United States Division of Hematology Department of Medicine University of Miami Miller School of Medicine Miami FL United States

Background: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclin...

Background: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Methods: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative oncology Group performance status score of 0–2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ***, NCT02228525. Findings: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1–12·2). Two patients did not meet the full eligibility criteria after baseline assessment;therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10–48) in six patients with marro

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A Multi-Site Break through Cancer Trial: Phase II Study Investigating Dual Inhibition of BCL2 and Menin in AML MRD Using the Combination of Venetoclax and Revumenib (Trial In Progress)

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Blood 2024年 144卷 4265.2-4265.2页

作者： Ghayas C. Issa Alexander J. Ambinder Wenbin Xiao Scott Manalis Alex K Shalek Lukasz P. Gondek Alex Kentsis Nicholas J. Short Naval Daver Jing Ning Lianchun Xiao Michael Hemann Ken Chen Keyur P. Patel Pavan Bachireddy Andrew A. Lane Marina Konopleva Omar Abdel-Wahab Jeffrey J. Molldrem Ross L Levine Jacqueline S. Garcia Department of Leukemia The University of Texas MD Anderson Cancer Center Houston TX Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD Department of Pathology and Laboratory Medicine Hematopathology Service Memorial Sloan Kettering Cancer Center New York NY Massachusetts Institute of Technology Cambridge MA Institute for Medical Engineering & Science and Department of Chemistry Massachusetts Institute of Technology Cambridge MA Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD Tow Center for Developmental Oncology Department of Pediatrics Memorial Sloan Kettering Cancer Center New York NY MD Anderson Cancer Center Houston TX The University of Texas M.D. Anderson Cancer Center Houston TX Department of Biostatistics University of Texas MD Anderson Cancer Center Houston David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge MA Department of Bioinformatics and Computational Biology The University of Texas MD Anderson Cancer Center Houston TX Department of Hematopathology The University of Texas MD Anderson Cancer Center Houston TX Department of Hematopoietic Biology & Malignancy The University of Texas M.D. Anderson Cancer Center Houston TX Department of Medical Oncology Dana-Farber Cancer Institute Boston MA Albert Einstein College of Medicine Bronx NY Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Departments of Hematopoietic Biology and Malignancy The University of Texas MD Anderson Cancer Center Houston TX Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY

Background and Significance: Measurable residual disease (MRD) represents the fundamental driver of relapse and mortality in acute myeloid leukemia (AML). However, there are currently no established approaches to addr...

Background and Significance: Measurable residual disease (MRD) represents the fundamental driver of relapse and mortality in acute myeloid leukemia (AML). However, there are currently no established approaches to address this unmet need. Our central hypothesis is that targeting vulnerabilities associated with specific leukemia genotypes will eradicate MRD and prevent disease relapse. Break Through Cancer is a collaboration between our centers aimed at making progress in the deadliest cancers by stimulating radical clinical and laboratory research collaboration. The menin-KMT2A interaction is a critical dependency in acute leukemias caused by rearrangement of the Lysine methyl transferase ( KMT2Ar ) or Nucleoporin 98 ( NUP98r ) genes, or mutation of the Nucleophosmin 1 gene ( NPM1mt ). Revumenib (previously SNDX-5613), is a potent, oral, selective inhibitor of this interaction with an established safety and efficacy in refractory leukemias with these genotypes (Issa GC, Nature 2023). Additionally, KMT2Ar or NPM1mt leukemias can undergo BCL2-dependent apoptosis, and dual Bcl-2 and menin inhibition led to synergistic activity in KMT2Ar or NPM1mt leukemia models (Carter BZ, Blood 2021; Fiskus W, BCJ 2022). Therefore, we designed this study investigating the combination of revumenib and venetoclax to eradicate MRD in these AML subtypes (NCT06284486). Study Design and Methods: This is a single arm, open label, multicenter, phase I/II investigator-initiated study. Patients (pts) age ≥ 12 years with weight ≥ 45Kg, and known history of NPM1mt , or KMT2Ar , or NUP98r AML with MRD ≥ 0.1% identified by multiparameter flow cytometry (MFC) using central testing would be eligible; no morphologic evidence of AML (blasts <5%) in first remission following high intensity therapy or at least 2 cycles of low intensity therapy, or in second remission following any therapy. Up to 12 pts will be enrolled on the phase I, using 3+3, with escalating doses of revumenib and a target dose of 163

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