Peripheral 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.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/627065 |
| Date | 01 November 2017 |
| Creators | Islam, Shariful, Vick, Eric, Huber, Bryan, Morales, Carla, Spier, Catherine, Cooke, Laurence, Weterings, Eric, Mahadevan, Daruka |
| Contributors | Univ Arizona, Ctr Canc, Canc Biol GIDP, Univ Arizona, Dept Hematopathol, Univ Arizona, Ctr Canc, Dept Med, Univ Arizona, Dept Radiat Oncol |
| Publisher | IMPACT JOURNALS LLC |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| 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). |
| Relation | http://www.oncotarget.com/fulltext/22222 |
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