FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2532482854> ?p ?o ?g. }

• W2532482854 endingPage "4682" @default.
• W2532482854 startingPage "4682" @default.
• W2532482854 abstract "Abstract Background: The Ikaros family zinc finger transcription factor, Aiolos, is upregulated in more than 80% of CLL patients with data suggesting that it may be an important driver of CLL survival and hence a bona fide target for therapeutic intervention. To date, transcription factors such as Aiolos have not been amenable to drug therapy. We and others have shown that the IMiDs™ immunomodulatory drugs such as Lenalidomide (LEN) bind Cereblon (CRBN), a substrate receptor of the cullin ring E3 ubiquitin ligase complex (CRL4CRBN) and promote ubiquitination and subsequent proteosomal degradation of lymphoid transcription factors Ikaros and Aiolos. Such insights have been critical for the design and development of next generation IMiD analogues. CC-122 is a novel non-phthalimide, first-in-class, PPM™ pleiotropic pathway modifier drug with anti-proliferative, anti-angiogenic, and immunomodulatory properties. CC-122 specifically targets CRBN and promotes degradation of Aiolos and Ikaros. We have now investigated the effects of LEN and CC-122 on CLL proliferation, and Aiolos and Ikaros degradation, in a cohort of primary CLL cases using an in vitro co-culture system based on CD154 expressing mouse fibroblasts and exogenous IL-21 that recapitulates the in vivo CLL microenvironment. Results: Forty CLL primary patient PBMC samples, selected to represent diverse prognostic subgroups, were cultured in media supplemented with LEN, CC-122, or control and assessed in a BrdU incorporation assay. Among these analyzed samples, four distinct ‘response’ subsets were identified. In subset 1 (n=10, 25% of cases), we found that CC-122 is superior to LEN in inhibiting proliferation (mean IC50: LEN 5.7µM; CC-122 1.2µM). Subset 2 (n=23; 57% of cases) was sensitive to CC-122, but unresponsive to LEN. In these cases, CC-122 inhibited proliferation by at least 50% at a concentration of ≤3µM despite the failure of LEN (IC50: >10 µM) to inhibit proliferation, highlighting a qualitative difference between the two agents. In subset 3, the anti-proliferative activities of CC-122 and LEN were comparable (n=2, 5% of cases). Finally, both CC-122 and LEN were inactive (up to 10µM) in a 4th subset (n=5; 12% of cases). We subsequently explored associations between CC-122 activity and known CLL prognostic risk factors in these samples. In 5 out of 6 cases with 17p deletion CC-122 inhibited proliferation (IC50: <0.3-0.8 mM). Similarly, in 4 out 6 cases harbouring an 11q- defect CC-122 was active (IC50: 0.8-3 µM). In general, the efficacy of either drug at inhibiting CLL cell proliferation did not segregate with established prognostic variables (e.g. IgVH mutation status, cytogenetic abnormalities, etc.), or previous treatment exposure (e.g. chlorambucil, fludarabine, alemtuzumab, etc.). Preliminary investigations of the CLL cells demonstrate wide variation in baseline Ikaros, Aiolos, and CRBN levels between individual cases as measured by either flow cytometry and/or western blot. We show that treatment of CLL cells with CC-122 or LEN results in variable degradation of Ikaros (LEN 0-100%; CC-122 55-100%) and Aiolos (LEN 72-100%; CC-122 97-100%) compared to untreated controls. Of note, CC-122 was consistently superior to LEN in promoting Aiolos and Ikaros degradation. In contrast, levels of CRBN, the molecular target of CC-122 and LEN, were unaffected by either compound. The predictive value of baseline Aiolos, Ikaros and CRBN expression, as well as their degradation, by CC-122 in relation to cellular response is currently being assessed. Conclusions: Taken together, these data demonstrate that CC-122 has robust anti-proliferative activity in primary CLL cells through a unique mechanism of selective degradation of Aiolos and Ikaros transcription factors. CC-122 is superior to LEN and is active across several prognostic backgrounds. Furthermore, we show significant activity of CC-122 even in cases that are non-responsive to LEN suggesting that CC-122 targets a novel pathway in CLL. These data suggest that further evaluations of CC-122 in pre-clinical and clinical studies, as a single agent or in combination with established or novel compounds (such as Btk and PI3Kd inhibitors), are warranted. Disclosures Blocksidge: Celgene: Research Funding. Glenn:Celgene: Research Funding. Gandhi:Celgene Corp: Employment, Equity Ownership. Klippel:Celgene: Employment, Equity Ownership. Pourdehnad:Celgene: Employment, Equity Ownership. Chopra:Celgene Corp: Employment, Equity Ownership. Kalakonda:Celgene: Research Funding." @default.
• W2532482854 created "2016-10-28" @default.
• W2532482854 creator A5014125875 @default.
• W2532482854 creator A5014243449 @default.
• W2532482854 creator A5014267088 @default.
• W2532482854 creator A5043395223 @default.
• W2532482854 creator A5045237544 @default.
• W2532482854 creator A5057353098 @default.
• W2532482854 creator A5072971421 @default.
• W2532482854 date "2014-12-06" @default.
• W2532482854 modified "2023-09-28" @default.
• W2532482854 title "CC-122 Has Robust Anti-Proliferative Activity in a Primary Chronic Lymphocytic Leukemia (CLL) Co-Culture Model and Is Superior to Lenalidomide" @default.
• W2532482854 doi "https://doi.org/10.1182/blood.v124.21.4682.4682" @default.
• W2532482854 hasPublicationYear "2014" @default.
• W2532482854 type Work @default.
• W2532482854 sameAs 2532482854 @default.
• W2532482854 citedByCount "7" @default.
• W2532482854 countsByYear W25324828542015 @default.
• W2532482854 countsByYear W25324828542017 @default.
• W2532482854 countsByYear W25324828542020 @default.
• W2532482854 countsByYear W25324828542021 @default.
• W2532482854 countsByYear W25324828542022 @default.
• W2532482854 crossrefType "journal-article" @default.
• W2532482854 hasAuthorship W2532482854A5014125875 @default.
• W2532482854 hasAuthorship W2532482854A5014243449 @default.
• W2532482854 hasAuthorship W2532482854A5014267088 @default.
• W2532482854 hasAuthorship W2532482854A5043395223 @default.
• W2532482854 hasAuthorship W2532482854A5045237544 @default.
• W2532482854 hasAuthorship W2532482854A5057353098 @default.
• W2532482854 hasAuthorship W2532482854A5072971421 @default.
• W2532482854 hasBestOaLocation W25324828541 @default.
• W2532482854 hasConcept C104317684 @default.
• W2532482854 hasConcept C134459356 @default.
• W2532482854 hasConcept C203014093 @default.
• W2532482854 hasConcept C25602115 @default.
• W2532482854 hasConcept C2776063141 @default.
• W2532482854 hasConcept C2776364478 @default.
• W2532482854 hasConcept C2777583451 @default.
• W2532482854 hasConcept C2777938653 @default.
• W2532482854 hasConcept C2778461978 @default.
• W2532482854 hasConcept C2778540781 @default.
• W2532482854 hasConcept C2778729363 @default.
• W2532482854 hasConcept C2779536868 @default.
• W2532482854 hasConcept C502942594 @default.
• W2532482854 hasConcept C55493867 @default.
• W2532482854 hasConcept C71924100 @default.
• W2532482854 hasConcept C86803240 @default.
• W2532482854 hasConceptScore W2532482854C104317684 @default.
• W2532482854 hasConceptScore W2532482854C134459356 @default.
• W2532482854 hasConceptScore W2532482854C203014093 @default.
• W2532482854 hasConceptScore W2532482854C25602115 @default.
• W2532482854 hasConceptScore W2532482854C2776063141 @default.
• W2532482854 hasConceptScore W2532482854C2776364478 @default.
• W2532482854 hasConceptScore W2532482854C2777583451 @default.
• W2532482854 hasConceptScore W2532482854C2777938653 @default.
• W2532482854 hasConceptScore W2532482854C2778461978 @default.
• W2532482854 hasConceptScore W2532482854C2778540781 @default.
• W2532482854 hasConceptScore W2532482854C2778729363 @default.
• W2532482854 hasConceptScore W2532482854C2779536868 @default.
• W2532482854 hasConceptScore W2532482854C502942594 @default.
• W2532482854 hasConceptScore W2532482854C55493867 @default.
• W2532482854 hasConceptScore W2532482854C71924100 @default.
• W2532482854 hasConceptScore W2532482854C86803240 @default.
• W2532482854 hasIssue "21" @default.
• W2532482854 hasLocation W25324828541 @default.
• W2532482854 hasOpenAccess W2532482854 @default.
• W2532482854 hasPrimaryLocation W25324828541 @default.
• W2532482854 hasRelatedWork W1950630419 @default.
• W2532482854 hasRelatedWork W1970372405 @default.
• W2532482854 hasRelatedWork W2025965695 @default.
• W2532482854 hasRelatedWork W2032200822 @default.
• W2532482854 hasRelatedWork W2060916625 @default.
• W2532482854 hasRelatedWork W2125722196 @default.
• W2532482854 hasRelatedWork W2162794727 @default.
• W2532482854 hasRelatedWork W2465418624 @default.
• W2532482854 hasRelatedWork W2526442120 @default.
• W2532482854 hasRelatedWork W2532482854 @default.
• W2532482854 hasVolume "124" @default.
• W2532482854 isParatext "false" @default.
• W2532482854 isRetracted "false" @default.
• W2532482854 magId "2532482854" @default.
• W2532482854 workType "article" @default.