Glutamate-cysteine ligase catalytic subunit as a therapeutic target in acute myeloid leukemia and solid tumors.

Acute myeloid leukemia (AML) is a highly heterogenous and aggressive disease with a poor prognosis, necessitating further improvements in treatment therapies. Recently, several targeted therapies have become available for specific AML populations. To identify potential new therapeutic targets for AML, we analyzed published genome wide CRISPR-based screens to generate a gene essentiality dataset across a panel of 14 human AML cell lines while eliminating common essential genes through integration analysis with core fitness genes among 324 human cancer cell lines and DepMap databases.

Combination of Ibrutinib and ABT-199 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton tyrosine kinase (BTK)-mediated B-cell receptor signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance.

The role of PIM1 in the ibrutinib-resistant ABC subtype of diffuse large B-cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous lymphoma and the most common subtype of non-Hodgkin lymphoma, accounting for roughly 30% of newly diagnosed cases in the United States. DLBCL can be separated into the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, with distinct gene expression profiles, oncogenic aberrations, and clinical outcomes. ABC-DLBCL is characterized by chronically active B-cell receptor (BCR) signaling that can be modulated by Bruton's tyrosine kinase (BTK) activity.

A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma.

Purpose: Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N = 55) with single-agent abexinostat in relapsed/refractory lymphoma.

Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma.

Background: It has been demonstrated that several inhibitors of histone deacetylase (HDAC) can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models. The authors sought to determine the maximum tolerated dose, pharmacokinetics/pharmacodynamics, safety, and toxicity of the HDAC inhibitor abexinostat (PCI-24781) when administered with doxorubicin to patients with metastatic sarcomas.

Methods: Participants were enrolled in a standard, phase 1, 3 + 3, dose-escalation study design.