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dc.contributor.authorIslam, Shariful
dc.contributor.authorVick, Eric
dc.contributor.authorHuber, Bryan
dc.contributor.authorMorales, Carla
dc.contributor.authorSpier, Catherine
dc.contributor.authorCooke, Laurence
dc.contributor.authorWeterings, Eric
dc.contributor.authorMahadevan, Daruka
dc.date.accessioned2018-03-15T23:26:18Z
dc.date.available2018-03-15T23:26:18Z
dc.date.issued2017-11-01
dc.identifier.citationCo-targeting aurora kinase with PD-L1 and PI3K abrogates immune checkpoint mediated proliferation in peripheral T-cell lymphoma: a novel therapeutic strategy 2017, 8 (59) Oncotargeten
dc.identifier.issn1949-2553
dc.identifier.pmid29245981
dc.identifier.doi10.18632/oncotarget.22222
dc.identifier.urihttp://hdl.handle.net/10150/627065
dc.description.abstractPeripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate similar to 30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4(+)/CD8(+) cells, we hypothesized that Program Death Ligand-1 (PDL1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3K alpha (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells. Expression of PD-L1 relative to PD-1 is high in PTCL biopsies (similar to 9-fold higher) and cell lines. Combination of alisertib with pan-PI3K inhibition or VCR significantly reduced PD-L1, NF-kappa B expression and inhibited phosphorylation of AKT, ERK1/2 and AK with enhanced apoptosis. In a SCID PTCL xenograft mouse model, alisertib displayed high synergism with MLN1117. In a syngeneic PTCL mouse xenograft model alisertib demonstrated tumor growth inhibition (TGI) similar to 30%, whilst anti-PD-L1 therapy alone was ineffective. Alisertib + anti-PD-L1 resulted in TGI > 90% indicative of a synthetic lethal interaction. PF-04691502 + alisertib + anti-PD-L1 + VCR resulted in TGI 100%. Overall, mice tolerated the treatments well. Co-targeting AK, PI3K and PD-L1 is a rational and novel therapeutic strategy for PTCL.
dc.description.sponsorshipThe Hope Foundation Impact Award (SWOG); Lymphoma SPORE; West Cancer Center/UTHSC; WCC/UTHSCen
dc.language.isoenen
dc.publisherIMPACT JOURNALS LLCen
dc.relation.urlhttp://www.oncotarget.com/fulltext/22222en
dc.rights© Islam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).en
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/
dc.subjectT-cell lymphomaen
dc.subjectimmune checkpointen
dc.subjectaurora kinasesen
dc.subjectanti-PD-L1en
dc.subjectPI3K isoformsen
dc.titleCo-targeting aurora kinase with PD-L1 and PI3K abrogates immune checkpoint mediated proliferation in peripheral T-cell lymphoma: a novel therapeutic strategyen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Ctr Canc, Canc Biol GIDPen
dc.contributor.departmentUniv Arizona, Dept Hematopatholen
dc.contributor.departmentUniv Arizona, Ctr Canc, Dept Meden
dc.contributor.departmentUniv Arizona, Dept Radiat Oncolen
dc.identifier.journalOncotargeten
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-06-24T13:28:19Z
html.description.abstractPeripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate similar to 30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4(+)/CD8(+) cells, we hypothesized that Program Death Ligand-1 (PDL1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3K alpha (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells. Expression of PD-L1 relative to PD-1 is high in PTCL biopsies (similar to 9-fold higher) and cell lines. Combination of alisertib with pan-PI3K inhibition or VCR significantly reduced PD-L1, NF-kappa B expression and inhibited phosphorylation of AKT, ERK1/2 and AK with enhanced apoptosis. In a SCID PTCL xenograft mouse model, alisertib displayed high synergism with MLN1117. In a syngeneic PTCL mouse xenograft model alisertib demonstrated tumor growth inhibition (TGI) similar to 30%, whilst anti-PD-L1 therapy alone was ineffective. Alisertib + anti-PD-L1 resulted in TGI > 90% indicative of a synthetic lethal interaction. PF-04691502 + alisertib + anti-PD-L1 + VCR resulted in TGI 100%. Overall, mice tolerated the treatments well. Co-targeting AK, PI3K and PD-L1 is a rational and novel therapeutic strategy for PTCL.


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© Islam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).
Except where otherwise noted, this item's license is described as © Islam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).