GLS1 expression in CRC plays important roles in tumor progression. CB-839 has inhibitory effects on cancer proliferation and the tumor microenvironment.

Glutaminase-1 inhibitor CB-839 reversed the effects of SLC38A1 overexpression...In conclusion, METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer progression. SLC38A1 inhibition is a potential therapeutic strategy for cervical cancer.

Here, we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent (TPE-BBT) and a glutaminase inhibitor (CB-839)...The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity. This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy, and provides novel recurrence-resistant radiotherapy without adverse side effects.

GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.

P2, N=42, Not yet recruiting, Washington University School of Medicine | Trial completion date: Apr 2030 --> Jul 2030 | Trial primary completion date: Apr 2030 --> Jul 2030

P1, N=36, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

CB-839 attenuated the interaction of GLS and PDK1 in ESCC cells by suppressing PDK1 expression, which further evoked the downregulation of p-PDHA1 (s293), however, GLS overexpression markedly enhanced the level of p-PDHA1 (s293). These findings suggest that interaction of GLS with PDK1 accelerates the glycolysis of ESCC cells by inactivating PDH enzyme, and thus targeting GLS may be a novel therapeutic approach for ESCC patients.

These effects were more pronounced when CB-839 was combined with the JAK1/2 inhibitor ruxolitinib or the glycolysis inhibitor 3PO, indicating possible synergies when co-targeting different metabolic and oncogenic pathways. In line with the effects shown in mice, proliferation of CD34+ hematopoietic stem and progenitor cells from PV patients was inhibited by CB-839 at nanomolar concentrations. These data suggest that inhibiting glutaminase alone or in combination with inhibitors of glycolysis or JAK2 inhibitors represents an attractive new therapeutic approach to MPN.

In this review, we describe the essential functions and regulatory mechanisms of human GLS2 and the cellular compartments in which GLS2 has been localized. Furthermore, we present the context-dependent oncogenic and tumor-suppressor properties of GLS2, and delve into the mechanisms underlying these phenomena.

P1, N=40, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Trial completion date: Dec 2023 --> Dec 2024

P2, N=42, Not yet recruiting, Washington University School of Medicine | Trial completion date: Jan 2030 --> Apr 2030 | Trial primary completion date: Jan 2030 --> Apr 2030

OSCC cells were treated with specified concentration of PL alone or with ferroptosis inhibitor Ferrostatin-1 (Fer-1) and antioxidant N-Acetylcysteine (NAC) to assess their effects on biological characteristics such as cell proliferation, cell death and intracellular ferroptosis related pathways. Our study suggested that the nature product PL can induce the ferroptotic death of OSCC cells, which is further enhanced when combined with CB-839. The synergistic anticancer effect of these two may prove new strategy for OSCC treatment.

It was validated that GLS1 was a sensitive and specific biomarker for pathological diagnosis of HCC and had prognostic value, thus having practical value for clinical application.

Supplementation of DLBCL cells with α-ketoglutarate or with the antioxidant α-tocopherol mitigated oxidative stress and abrogated cell death upon GLS1 inhibition, indicating an essential role of glutaminolysis in the protection from oxidative stress. Furthermore, the combination of the GLS1 inhibitor CB-839 with the therapeutic BCL2 inhibitor ABT-199 not only induced massive ROS production, but also exhibited highly synergistic cytotoxicity, suggesting that simultaneous targeting of GLS1 and BCL2 could represent a novel therapeutic strategy for DLBCL patients.

Likewise, the glutamine uptake inhibitor V9302 and glutaminase-1 inhibitor CB839 induced oxidative stress in PDAC cells, along with cell death and cell cycle arrest that were again compensated by MCT1 upregulation and forced lactate uptake. Our findings show a novel mechanism by which PDAC cells adapt their metabolism to glutamine scarcity and by which they develop resistance against anticancer treatments based on glutamine uptake/metabolism inhibition.

P1, N=54, Recruiting, M.D. Anderson Cancer Center | N=84 --> 54

The first innovative proof is that GLS promotes cell proliferation by regulating CCND2 via PI3K/AKT/mTOR pathway in NPC, and GLS inhibitor CB-839 may serve as a new potential therapeutic target for NPC treatment.

P1; Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

Finally, we demonstrated that the PTBP1-promoted CDDP resistance of HCC cells was through modulating the GLS-glutamine metabolism axis. Summarily, our findings uncovered a PTBP1-mediated CDDP resistance pathway in HCC, suggesting that PTBP1 is a promisingly therapeutic target to overcome chemoresistance of HCC.

Low-dose gemcitabine-induced senescence and increased GLS1 expression were observed in PDAC cells. Cellular senescence may contribute to treatment resistance of PDAC, hence targeting GLS1 in iSnCa cells may improve the therapeutic effect.

GLS1 expression is highest in TNBC and basal breast cancer, supporting ongoing clinical investigation of GLS1 inhibition in TNBC. GLS1 may have prognostic implications but further research is needed to validate this finding. GLS1 had significant positive gene correlations with immune genes, which may have implications for potential combinations of glutaminase inhibition and immunotherapy.

P2, N=108, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2023 --> Aug 2024 | Trial primary completion date: Aug 2023 --> Aug 2024

No abstract available

In conclusion, GLS outperforms CA-125 in distinguishing between benign and malignant ovarian tumors. The combination of GLS and CA-125 had better accuracy in distinguishing benign and malignant ovarian tumor when compared to using CA-125 alone.

Rescue experiments demonstrated that restoration of miR-181a-5p in PVT1-overexpressing CDDP-resistant ESCA cells successfully overcame the PVT1-promoted cisplatin resistance through targeting GLS. Summarily, our study revealed molecular mechanisms of the lncRNA PVT1-promoted cisplatin resistance in ESCA by modulating the miR-181a-5p-GLS axis.

P1/2, N=53, Active, not recruiting, David Bajor | Trial completion date: Jun 2023 --> Dec 2023

P2, N=42, Not yet recruiting, Washington University School of Medicine | Trial completion date: Aug 2029 --> Nov 2029 | Initiation date: May 2023 --> Aug 2023 | Trial primary completion date: Aug 2029 --> Nov 2029

No abstract available

P1/2, N=53, Active, not recruiting, David Bajor | Trial completion date: Jan 2023 --> Jun 2023

The produced L-ASNase exhibits maximal activity at 37 °C and pH 7.0 and is highly stable under physiological conditions. In addition, M. guilliermondii L-ASNase has no associated glutaminase or urease activities, demonstrating its potential as a promising antineoplastic agent.

P1/2, N=33, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

Glutaminase 1 (GLS1) inhibition, alone and in combination with metformin, disrupts the bioenergetic demands of tumor progression and metastasis, showing promise for clinical translation. [F]FDG may be useful in detecting telaglenastat's impact on glycolysis. Exploration of kinetic tracer uptake protocols is needed to define clinically relevant patterns of [F]GLN uptake in patients receiving telaglenastat.

In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed. Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.