Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models

Wicker, Christina A.; Hunt, Brian G.; Krishnan, Sunil; Aziz, Kathryn E.; Parajuli, Shobha; Palackdharry, Sarah; Elaban, William R.; Wise‐Draper, Trisha M.; Mills, Gordon B.; Waltz, Susan E.; Takiar, Vinita

doi:10.1016/j.canlet.2020.12.038

Cited by 51 publications

(32 citation statements)

References 26 publications

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“…Clonogenic cell survival assays with FaDu (pharynx), HN5 (tongue), and CAL-27 (tongue) cell lines treated with radiation and Telaglenastat demonstrated significantly diminished proliferation compared to radiation or Telaglenastat treatment alone. These findings were confirmed using xenograft models in which combination therapy was superior to monotherapy (147). Similar results have been reported in lung cancer radiosensitization where treatment with Telaglenastat increased efficacy of RT by 30% in multiple cell lines and in H460-derived tumor xenografts (146).…”

Section: Rational Combinations Of Radiation and Targeted Therapy In The Preclinical Settingsupporting

confidence: 81%

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

et al. 2021

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In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ‘‘one size fits all’’ paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.

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Section: Rational Combinations Of Radiation and Targeted Therapy In The Preclinical Settingsupporting

confidence: 81%

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

et al. 2021

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“…In fact, there are both in vivo and in vitro studies previously conducted that demonstrate the importance of glutamine for cancer cells [ 53 ]. In this regard, the enzyme glutaminase (GLS1), which catalyzes the first step of glutamine metabolism, is highly expressed in colon cancer and linked to significantly reduced survival [ 54 , 55 ]. Besides, recent epidemiological studies correlate low serum glutamine levels (indicative of higher glutamine consumption) with poorer overall survival in colorectal cancer patients [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…Even though many studies have been conducted to unveil the metabolism of glutamine in tumors, there is much yet to be explored. Additionally, several clinical studies with GLS1 inhibitors (Phase I/II clinical trial: telaglenastat, CB-839) [ 55 ] for the treatment of different types of cancer, including colorectal cancer, showed promising results. Moreover, recent studies suggest targeting glutamine mitochondrial transporters as a new cancer starvation strategy for controlling tumor growth [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Glutamine Modulates Expression and Function of Glucose 6-Phosphate Dehydrogenase via NRF2 in Colon Cancer Cells

et al. 2021

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Nucleotide pools need to be constantly replenished in cancer cells to support cell proliferation. The synthesis of nucleotides requires glutamine and 5-phosphoribosyl-1-pyrophosphate produced from ribose-5-phosphate via the oxidative branch of the pentose phosphate pathway (ox-PPP). Both PPP and glutamine also play a key role in maintaining the redox status of cancer cells. Enhanced glutamine metabolism and increased glucose 6-phosphate dehydrogenase (G6PD) expression have been related to a malignant phenotype in tumors. However, the association between G6PD overexpression and glutamine consumption in cancer cell proliferation is still incompletely understood. In this study, we demonstrated that both inhibition of G6PD and glutamine deprivation decrease the proliferation of colon cancer cells and induce cell cycle arrest and apoptosis. Moreover, we unveiled that glutamine deprivation induce an increase of G6PD expression that is mediated through the activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2). This crosstalk between G6PD and glutamine points out the potential of combined therapies targeting oxidative PPP enzymes and glutamine catabolism to combat colon cancer.

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“…Previous studies have also demonstrated that ferroptosis plays important roles in OSCC. Several drugs (such as telaglenastat (CB-839) [16] and histone deacetylase inhibitor quisinostat [17]) and new materials such as zero-valent iron nanoparticles [18] have been shown to enhance the anti-OSCC response in part through ferroptosis. Moreover, both non-thermal plasma and photodynamic therapy(PDT) can effectively eliminate OSCC cells by inducing ferroptosis [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis-related gene signature predicts the prognosis in Oral squamous cell carcinoma patients

Zhang

Chen

et al. 2021

BMC Cancer

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Background The prognosis of oral squamous cell carcinoma (OSCC) patients is difficult to predict or describe due to its high-level heterogeneity and complex aetiologic factors. Ferroptosis is a novel form of iron-dependent cell death that is closely related to tumour growth and progression. This study aims to clarify the predictive value of ferroptosis-related genes (FRGs) on the overall survival(OS) of OSCC patients. Methods The mRNA expression profile of FRGs and clinical information of patients with OSCC were collected from the TCGA database. Candidate differentially expressed ferroptosis-related genes (DE-FRGs) were identified by analysing differences between OSCC and adjacent normal tissues. A gene signature of prognosis-related DE-FRGs was established by univariate Cox analysis and LASSO analysis in the training set. Patients were then divided into high- and low-risk groups according to the cut-off value of risk scores, A nomogram was constructed to quantify the contributions of gene signature and clinical parameters to OS. Then several bioinformatics analyses were used to verify the reliability and accuracy of the model in the validation set. Finally, single-sample gene set enrichment analysis (ssGSEA) was also performed to reveal the underlying differences in immune status between different risk groups. Results A prognostic model was constructed based on 10 ferroptosis-related genes. Patients in high-risk group had a significantly worse OS (p < 0.001). The gene signature was verified as an independent predictor for the OS of OSCC patients (HR > 1, p < 0.001). The receiver operating characteristic curve displayed the favour predictive performance of the risk model. The prediction nomogram successfully quantified each indicator’s contribution to survival and the concordance index and calibration plots showed its superior predictive capacity. Finally, ssGSEA preliminarily indicated that the poor prognosis in the high-risk group might result from the dysregulation of immune status. Conclusion This study established a 10-ferroptosis-releated gene signature and nomogram that can be used to predict the prognosis of OSCC patients, which provides new insight for future anticancer therapies based on potential FRG targets.

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Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models

Cited by 51 publications

References 26 publications

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

Glutamine Modulates Expression and Function of Glucose 6-Phosphate Dehydrogenase via NRF2 in Colon Cancer Cells

Ferroptosis-related gene signature predicts the prognosis in Oral squamous cell carcinoma patients

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