A novel immunomodulatory molecularly targeted strategy for refractory Hodgkin's lymphoma (original) (raw)
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ENGAGE- 501: Phase 2 study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma
Haematologica, 2016
Classical Hodgkin lymphoma treatment is evolving rapidly with high responses from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response therefore development of novel therapies is warranted to improve patient outcomes. In this phase 2 study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled; 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week), 16 patients on Schedule B (15 mg oral entinostat once weekly in three of four weeks). Patients received a median of 3 prior treatments (range 1-10) with 80% of the patients receiving a prior stem-cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention to treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease be...
Oncogene, 2018
The dysregulation of PI3K signaling has been implicated as an underlying mechanism associated with resistance to Bruton's tyrosine kinase inhibition by ibrutinib in both chronic lymphocytic leukemia and mantle cell lymphoma (MCL). Ibrutinib resistance has become a major unmet clinical need, and the development of therapeutics to overcome ibrutinib resistance will greatly improve the poor outcomes of ibrutinib-exposed MCL patients. CUDC-907 inhibits both PI3K and HDAC functionality to exert synergistic or additive effects. Therefore, the activity of CUDC-907 was examined in MCL cell lines and patient primary cells, including ibrutinib-resistant MCL cells. The efficacy of CUDC-907 was further examined in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model. The molecular mechanisms by which CUDC-907 dually inhibits PI3K and histone deacetylation were assessed using reverse protein array, immunoblotting, and chromatin immunoprecipitation (ChIP) coupled with sequen...
Oncotarget, 2017
Phosphoinositide 3-kinase (PI3K) and Myc are known to cooperate in promoting the survival and growth of a variety of B-cell lymphomas. While currently there are no small molecule inhibitors of Myc protein, histone deacetylase (HDAC) inhibitors have been shown to reduce levels of Myc protein by suppressing its transcription. We assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin. CUDC-907 treatment down-regulated the phosphorylation of PI3K downstream targets, including AKT, PRAS40, S6, and 4EBP1, increased histone 3 acetylation, and decreased Myc protein levels. SILAC-based quantitative mass spectrometry demonstrated that CUDC-907 treatment decreased the protein levels of several components of the B cell receptor (BCR) and Toll like receptor (TLR) pathways, incl...
Haematologica, 2017
Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concentrations required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between October 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and advers...