GLS1 With BCL-2 Presents New Treatment Potential in DLBCL

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Simultaneously targeting glutaminase-1 (GLS1) and BCL-2 could be a potential therapy strategy for patients with diffuse large B-cell lymphoma (DLBCL), according to a recent study.¹

Administering the GLS1 inhibitor CB-839 (Telaglenastat) demonstrated a reduction of levels of intermediates in the tricarboxylic acid cycle as well as a strong mitochondrial accumulation of reactive oxygen species (ROS).

Further, combining CB-839 with the BCL-2 inhibitorvenetoclax (Venclexta)also demonstrated significant induction of ROS production and synergistic cytotoxicityby enhancing ROS accumulation.

“Since various cancer cells utilize glutaminolysis to satisfy their increased demand for energy, non-essential amino acids, nucleotides, and fatty acids, pharmacological targeting of GLS1 has been proposed as a promising strategy for anti-cancer treatment and is currently tested in clinical trials,” authors of the study published in Blood Advances wrote.

Investigators analyzed GLS1 protein expression in a set of 42 human DLBCL biopsies. Approximately 43% (n = 18) of the samples had GLS1 expression. To assess GLS1 activity in the survival of the cells, the DLBCL cells were treated for 6 days with CB-839.

Investigators found that the DLBCL cell lines were sensitive to CB-839 but the agent did not affect primary B cells. While CB-839 somewhat affected the DLBCL cell cycle, it notably induced death in those cell lines.

ROS induction in DLBCL cell lines was enhanced when CB-839 and venetoclax were combined. The combination demonstrated synergistic cytotoxicity, which led investigators to postulate that it may have potential for treating DLBCL.

Previous studies have found that CB-839 showed an acceptable safety profile. A 2015 study (NCT02071862) of CB-839 in solid tumors observed that grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 20% of patients (n = 7). The TRAEs included increases in alanine transaminase, aspartate aminotransferase, creatinine, and gamma-glutamyl transferase, and alkaline phosphatase, as well as lymphopenia and hypoglycemia.² 

Other studies have similarly found the effectiveness of targeting GLS1 in cancer—and specifically lymphoma—treatment. Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl (BPTES) is a GLS1 inhibitor that spares GLS2 and shows antitumor potential against lymphoma B cells in vitro and murine models. The agent has also showed suppression effects on platinum-resistant colorectal and ovarian cancer cells.³ Additionally, a 2022 study showed that CB-839 and venetoclax could be effective in overcoming ibrutinib (Imbruvica) resistance in patients with mantle cell lymphoma.⁴

“Indeed, we found that combination of CB-839 with ABT-199, a BCL2 inhibitor currently approved and used for the treatment of different hematological malignancies, strongly enhanced the induction of cell death in DLBCL…[The] combinatorial treatment of DLBCL cells with ABT-199 and CB-839 resulted in synergistic ROS formation and cytotoxicity,” study authors added.¹

REFERENCES:

1. Gomez Solsona B, Horn H, Schmitt A, et al. Inhibition of glutaminase-1 in DLBCL potentiates venetoclax-induced antitumor activity by promoting oxidative stress. Blood Adv. Published online November 7, 2023. doi:10.1182/bloodadvances.2023010964

2. Harding JJ, Telli ML, Munster PN, et al. Safety and tolerability of increasing doses of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase, in solid tumors. JClinical Oncology. 2015;33(15_suppl 15):2512-2512. doi:10.120/jco.2015.33.15_suppl.2512

3. Jin J, Byun J-K, Choi Y-K, Park K-G. Targeting glutamine metabolism as a therapeutic strategy for cancer. Exp Mol Med. 2023;55(4):706-715. doi:10.1038/s12276-023-00971-9

4. Li L, Nie L, Jordan A, et al. Targeting glutaminase is therapeutically effective in ibrutinib-resistant mantle cell lymphoma. Haematologica. 2023;108(6):1616-1627. Published 2023 Jun 1. doi:10.3324/haematol.2022.281538