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

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

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

Adult Xp11.2 translocation renal cell carcinoma managed effectively with pazopanib

2021 ◽  
Vol 14 (6) ◽  
pp. e243058
Author(s):  
Cristian Solano ◽  
Shrinjaya Thapa ◽  
Mohammad Muhsin Chisti
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Stable Disease ◽  
Renal Cell ◽  
Systemic Treatment ◽  
Pulmonary Nodules ◽  
Progression Of Disease ◽  
Xp11.2 Translocation ◽  
Adrenal Nodule

Xp11.2 translocation renal cell carcinoma (TRCC) is a rare and aggressive variant of renal cell carcinoma (RCC) when presenting in adults. We report a case of a man in his early 40s who was diagnosed with stage III Xp11.2 TRCC and underwent radical nephrectomy. Seven months following the surgery, an adrenal nodule and bilateral pulmonary nodules were discovered. He underwent cryoablation of the adrenal nodule and systemic treatment with daily pazopanib. He displayed stable disease for approximately 6 years. Following this period, multiple hospitalisations interrupted daily pazopanib therapy resulting in progression of disease. His regimen was then changed to ipilimumab and nivolumab, followed by current daily therapy with axitinib. The patient now shows stable disease in his 10th year after diagnosis. This case study demonstrates the efficacy of pazopanib for metastatic Xp11.2 TRCC and warrants further investigation to supplement the guidelines regarding the use of targeted therapy for TRCC.

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

Clinical outcome of patients with metastatic renal cell carcinoma who interrupted VEGFR-TKI after achieving stable disease or better response.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 459-459
Author(s):  
Dong Hoe Koo ◽  
Inkeun Park ◽  
Jae-Lyun Lee ◽  
Jin-Hee Ahn ◽  
Dae Ho Lee ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Outcome ◽  
Cell Carcinoma ◽  
Disease Progression ◽  
Metastatic Renal Cell Carcinoma ◽  
Stable Disease ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Free Survival

459 Background: The purpose of the this study is to evaluate the clinical outcome of VEGFR-TKIs interruption in patients with metastatic renal cell carcinoma (mRCC) after achieving stable disease (SD) or better response. Methods: A retrospective analysis of medical records and imaging studies was performed on all patients with mRCC treated with VEGFR-TKIs between January 2008 and July 2014 (n=505). Patients who achieved SD or better response under VEGFR-TKI and later discontinued VEGFR-TKIs for any reason with the exception of disease progression were included in the analysis. Outcomes analyzed were progression free survival (PFS) after VEGFR-TKIs discontinuation, patterns of disease progression, time to subsequent therapy (TST), response to VEGFR-TKI resumption, and time to treatment failure (TTF) after TKI resumption. Results: We identified 32 patients (sunitinib=20, sorafenib=7, and pazopanib=5). The responses to VEGFR-TKIs were CR (n=4), PR (n=11), SD (n=15), and controlled but non-measurable (n=2). Median time to interruption from the initiation of VEGFR-TKI therapy was 16.6 months (95% CI, 12.8-20.3). The main causes of VEGFR-TKI interruption was toxicity (n=19, 59.4%), will to have treatment holiday (n=7, 21.8%), patient’s refusal (n=3, 9.4%), and others (n=3, 9.4%). At the time of analysis, 16 patients had disease progression and 1 patient was dead. With a median follow-up duration of 56.6 months (range, 12.6-167.4), median PFS from VEGFR-TKI interruption was 23.8 months (95% CI, 12.5-35.0), and the median TST was 26.2 months (95% CI, 15.9-36.6). The progression was observed in pre-existing lesions in 7 patients (43.7%) or new lesions developed in 9 (56.3%). Among 11 patients who received VEGFR-TKI resumption, 2 patients (18.2%) achieved a PR and the stable disease was observed in 9 (81.8%) with a median TTF of VEGFR-TKI resumption of 6.2 months (95% CI, 4.0-8.4). Conclusions: In patients with mRCC controlled with VEGFR-TKIs, VEGFR-TKI could be interrupted at least temporarily when clinically warranted.

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