Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 .

Chemotherapy-Induced Cognitive Impairment Is Associated with Increased Inflammation and Oxidative Damage in the Hippocampus.

Increasing evidence indicates that chemotherapy results in long-term effects on cognitive dysfunction in some cancer survivors. While many studies have established the domains of cognition and corresponding regions in the brain most affected, little is revealed about the potential molecular mechanisms that mediate these adverse changes after treatment. The effects of chemotherapy on the brain are likely attributed to various mechanisms, including oxidative stress and immune dysregulation, features that are also reminiscent of cognitive aging. We have investigated the cognitive effects of a cocktail composed of doxorubicin and cyclophosphamide (AC-chemo) in a surgical ovariectomized rodent model. In this study, we address whether the levels of pro-inflammatory cytokines and oxidative stress-responsive gene markers are altered in the CNS of rats treated with systemic AC-chemo. We further evaluated the levels of nucleic acids modified by oxidative stress in the hippocampus using both immunohistochemical and Northern blotting techniques with a monoclonal antibody against 8-hydroxyguanosine (8-OHG) and 8-OHdG base lesions. We demonstrate that ERK 1/2 and JNK/SAPK signaling activities are elevated in the hippocampus of AC-chemo rats. The levels of pro-inflammatory, oxidative stress-responsive, and RNA/DNA damage markers were also higher in drug-injected animals relative to saline controls. The results indicate that the effects of AC chemotherapy are associated with oxidative damage and a global stress response in the hippocampus. These alterations in the molecular signature of the brain may underlie the processes that contribute to cognitive impairment after treatment.