CUL1: Novel Therapeutic Target in Myeloid Neoplasms Harboring -7/Del(7q)
| Autor: | Mikkael A. Sekeres, Torsten Haferlach, Anjali S. Advani, Kevin Fung, Vera Adema, Hetty E. Carraway, Christina Snider, Hassan Awada, Michael R. Savona, Sunisa Kongkiatkamon, Jennifer S. Carew, Stephan Hutter, Cassandra M Kerr, Jaroslaw P. Maciejewski, Jibran Durrani, Yogenthiran Saunthararajah, James G. Phillips, Manja Meggendorfer, Valeria Visconte, Kevin R. Kelly, Francesca Gould, Steffan T. Nawrocki |
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| Rok vydání: | 2019 |
| Předmět: |
education.field_of_study
medicine.medical_specialty Poor prognosis Myeloid Deletion mutant business.industry Immunology Population Cell Biology Hematology Biochemistry Myeloid neoplasia medicine.anatomical_structure Cytogenetic Abnormality Family medicine Investigational Drugs medicine In patient business education |
| Zdroj: | Blood. 134:1281-1281 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2019-129196 |
| Popis: | Lenalidomide (LEN) has established a new paradigm of targeted therapy in MDS. The mechanistic underpinnings of LEN efficacy are related to the synthetic lethality of this agent through its ability to bind cereblon (CRBN). LEN induces degradation of CK1α, which is encoded by the CSNK1A1 gene located on the del(5q) CDR, whereby haploinsufficient levels of this gene allow for selective toxicity to deletion mutants. Another common cytogenetic abnormality present in patients with myeloid neoplasia (MN) is -7/del(7q). To date no selective therapies exist for -7/del(7q), an urgent unfulfilled need, given the poor prognosis associated with this cytogenetic abnormality. We were interested to explore if this same notion of selective toxicity may be possible in del(7q) myeloid patients and sought to screen drugs for this focused population. From a large cohort of patients with MN (n=3,328), we found -7/del(7q) in 10% (n=316) of patients. We first identified a signature pattern of haploinsufficient genes on -7/del(7q) based on NGS. We then searched for haploinsufficient genes which, if targeted by investigational drugs, could provide a therapeutic window for selected MN subtypes in analogy to LEN in del(5q). For the purpose of our analysis, haploinsufficient expression was defined as 97) with sensitivity levels of KG-1 in the lower μM ranges. Our analysis also identified changes in death box-RNA-helicases (DDX41, DDX24,DDX54) and DNA binding proteins (CHD3), opening the possibility that MLN4924 might lead to degradation of key proteins implicated in the pathogenesis of MDS/ AML. The therapeutic index was confirmed by the absence of toxicity to normal CD34+ cells which were unresponsive to MLN4924 because they lack the expression of NEDD8-activating enzyme (NAE) (major target of MLN4924). In contrast to normal cells, NAE is highly expressed in myeloid cancer cells. In an ongoing dose-escalation study of MLN4924 plus AZA, 1 patient with -7 had stable disease after 6 cycles of therapy and 2 patients with del(7q) achieved complete and partial remissions. In sum, we propose that MN with -7/del(7q) abnormalities might represent a patient population genetically hypersensitive to synthetic lethality by neddylation inhibitors. Disclosures Hutter: MLL Munich Leukemia Laboratory: Employment. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Kelly:Novartis, Bayer, Janssen, Pharmacyclics, Celgene, Astrazeneca, Seattle Genetics: Honoraria, Speakers Bureau; Genentech, Verastem: Consultancy; Takeda: Research Funding. Saunthararajah:Novo Nordisk: Consultancy; EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Savona:AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. |
| Databáze: | OpenAIRE |
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