scholarly journals The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259241
Author(s):  
Ethan Emberley ◽  
Alison Pan ◽  
Jason Chen ◽  
Rosalyn Dang ◽  
Matt Gross ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tca Cycle ◽  
Strongly Correlated ◽  
Signal Transduction Inhibitors ◽  
Glutamine Consumption ◽  
Orally Bioavailable ◽  
Anti Tumor Activity

Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.

Signal Transduction Inhibitors in Renal Cell Carcinoma

2008 ◽  
pp. 399-413
Author(s):  
Ellen A. Ronnen ◽  
Saby George ◽  
Ronald M. Bukowski ◽  
Robert J. Motzer
Keyword(s):  
Signal Transduction ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Signal Transduction Inhibitors

Stable Disease in Renal Cell Carcinoma After Using Signal Transduction Inhibitors

2010 ◽  
Vol 999 (999) ◽  
pp. 1-14
Author(s):  
Saby George ◽  
Shetal N Shah ◽  
Ronald M Bukowski ◽  
/snm ◽  
>
Keyword(s):  
Signal Transduction ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Stable Disease ◽  
Renal Cell ◽  
Signal Transduction Inhibitors

Comorbidity and other predictors of survival in veterans with metastatic renal cell carcinoma (RCC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15561-e15561
Author(s):  
Michael Cho ◽  
Trent P Wang ◽  
Melanie L. Gonzalez ◽  
Victor T Chang ◽  
Fengming Zhong ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Co Morbidity ◽  
Signal Transduction Inhibitors ◽  
History Of ◽  
Ecog Ps

e15561 Background: Comorbidity as a prognostic marker has been reported in several solid tumors. We examined whether co-morbidity indices predict survival in Veterans with metastatic renal cell carcinoma (RCC) who were treated with signal transduction inhibitors. Methods: In an IRB-approved protocol, we reviewed the records of patients (Pts) diagnosed with RCC at a VA Medical Center from 1/1/2000 to 12/31/2011. Age, ECOG Performance Status (ECOG PS), Hemoglobin (Hgb), Albumin (Alb), Corrected Calcium (CCa), history of Nephrectomy, and histology (clear cell (CC) vs. non clear cell (NCC)) were abstracted. Co-morbidity was assessed with Charlson Comorbidity Index (CCI), and the Kaplan-Feinstein Index (KFI). We developed a survival model with age, ECOG PS, Hgb, Alb, CCa, history of nephrectomy, and histology. Co-morbidity indices were tested by determining if they were independent predictors of survival after inclusion in this model. Cox regression analyses were performed with SAS V9.2. Results: There were 24 Pts;6 (25%) are alive. The Median (M) age when seen at VA was 64 years (54-85). The M Hgb level was 12.1g/dL (6.7-16.5), Alb was 4.1g/dL (2.8-5.0), and CCa was 9.19mg/dL (7.9-12.5). The M CCI was 4.2 (1.4-12.0) and KFI was 2.0 (1-3). The M Survival was 823 days (24-3482). 17(68%) pts had clear cell carcinoma and 18(72%) had nephrectomies Median ECOG PS was one range(0-4). The median number of treatments was 2, range 1-7. Results of univariate analyses with co-morbidity indices were significant for age (p < ,029) and history of nephrectomy p< .068). There were no multivariate predictors of survival. Conclusions: In the univariate analysis, ECOG PS as well as Nephrectomy status were significant predictors for M survival. CCI and KFI did not predict M survival. In distinction to other solid tumor histologies where chemotherapy is used, KFI and CCI in RCC may not be associated with overall survival due to either RCC histology or use of signal transduction inhibitors as treatment. Confirmatory studies should be done in larger populations. This was supported by the New Jersey Commission for Cancer Research.

Signal-transduction inhibitors in renal cell carcinoma

2007 ◽  
Vol 99 (5b) ◽  
pp. 1289-1295 ◽  
Author(s):  
Nicholas J. Vogelzang ◽  
Cora N. Sternberg
Keyword(s):  
Signal Transduction ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Signal Transduction Inhibitors

scholarly journals Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma

Metabolites ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 1
Author(s):  
Tomonori Sato ◽  
Yoshihide Kawasaki ◽  
Masamitsu Maekawa ◽  
Shinya Takasaki ◽  
Kento Morozumi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Energy Metabolism ◽  
Cell Carcinoma ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Progression ◽  
Renal Cell ◽  
Treatment Resistance ◽  
Tca Cycle ◽  
Glutamine Uptake

Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.

Impaired Signal Transduction in Tumor Infiltrating T Cells from Patients with Renal Cell Carcinoma

1995 ◽  
pp. 72-83
Author(s):  
James Finke ◽  
Seiji Kudoh ◽  
Jill Stanley ◽  
Xiaoli Li ◽  
Qiu Wang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell

Efficacy of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4504-4504 ◽  
Author(s):  
Toni K. Choueiri ◽  
Sumanta Kumar Pal ◽  
David F. McDermott ◽  
David A. Ramies ◽  
Stephanie Morrissey ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Regression ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Primary Objective ◽  
Heavily Pretreated ◽  
Cell Components ◽  
Anti Tumor Activity

4504 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). Anti-tumor activity was also evaluated. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Cabo was given daily at a dose of 140 mg free base (equivalent to 175 mg salt form) starting at Day 2. Rosi (4 mg) was given Day 1 and Day 22 to complete PK assessment for DDI. Cabo was continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: Enrollment is complete at 25 RCC pts; 17/25 (64%) RCC pts had received ≥ 2 prior agents; 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. The majority of pts were in an intermediate (21/25) or poor (3/25) prognostic category (1/25 in favorable category) per Heng et al (JCO, 2009, v27, p5794). ORR by mRECIST: 7/25 (28%). Disease control rate (PR + SD): 72% at 16 weeks; 19/21 (90%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 - 63% reduction in measurements). 10/25 (36%) pts remain on cabo. Median PFS is 14.7 months (95% CI: 7.3, upper limit not reached) with a median follow-up of 7.7 months. AEs ≥ Grade 3 severity: hypophosphatemia (36%), hyponatremia (20%), and fatigue (16%). PK data suggest that clinically relevant doses of cabo do not alter the Cmax or AUC0-24h of rosi, consistent with no inhibition of CYP2C8. Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated RCC pts with a toxicity profile similar to that of other VEGFR TKIs. PK data suggest no DDI between cabo and rosi (CYP2C8 substrate).

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