Our findings indicate that increased glutaminase expression is associated with an immune-suppressive tumor microenvironment, poor clinicopathologic features, and worse long-term outcomes in patients with endometrial cancer.

The GLS inhibitor IN-3 may be a potent anti-cancer agent in prostate cancer by demonstrating its differential effect between cancer and normal cells. Further studies are warranted to elucidate its drug potential in prostate cancer.

The investigations led to imply that L-glutaminase may have the potential to be an effective antimicrobial agent for preventing and inhibiting bacterial growth, as well as inhibiting the biofilm formation in the P. aeruginosa-originated vaginosis. The observations may be of promising value for future clinical use.

The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax. Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML.

P1/2, N=29, Completed, Vanderbilt-Ingram Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Dec 2023

Our findings elucidate YAP1-mediated glutamine metabolism as a crucial bypass mechanism against DFMO, following the inhibition of polyamine metabolism. Our study provides valuable insights into the potential role of DFMO in an "One-two Punch" therapy of metastatic and recurrent osteosarcoma.

Targeting glutaminase and glutamic acid may overcome the osimertinib-resistant EGFR-mutant lung cancer.

Combining panobinostat with CB-839 resulted in enhanced cytotoxicity and increased caspase 3/7 activity. Glutaminolysis contributes to the viability of MM cells, and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition. These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.

Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared to either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for HNSCC patients, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease.

Furthermore, we show that combining chemical inhibition of GLS with ELAVL1 silencing synergistically decreases breast cancer cell growth and invasion. These findings suggest that dual inhibition of GLS and HuR offers a therapeutic strategy for breast cancer treatment.

Inhibition of glutaminase aggravates oxidative stress by reducing glutathione level, thus leading to apoptotic-mediated cell death in cancer cells Therefore, inhibiting the glutaminase activity using glutaminase inhibitors such as BPTES, DON, JHU-083, CB-839, compound 968, etc. may answer many intriguing questions behind the uncontrolled proliferation of cancer cells and serve as a prophylactic treatment for cancer. Earlier reports neither discuss nor provide perspectives on exact signaling gene or pathway. Hence, the present review highlights the plausible role of glutaminase in cancer and the current therapeutic approaches and clinical trials to target and inhibit glutaminase enzymes for better cancer treatment.

P1; Recruiting --> Active, not recruiting

P1; Trial completion date: Sep 2024 --> Jun 2025 | Trial primary completion date: Sep 2024 --> Jun 2025

Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.

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

P1/2, N=28, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

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.