Current and emerging therapies for first line treatment of metastatic clear cell renal cell carcinoma

Serzan, Michael T.; Atkins, Michael B.

doi:10.20517/2394-4722.2021.76

Cited by 26 publications

(26 citation statements)

References 75 publications

(134 reference statements)

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“…However, no recommendation has been made regarding the use of sunitinib versus pazopanib in first-line settings. Furthermore, the treatment paradigm for metastatic RCC has recently changed with the introduction of immune checkpoint inhibitors (ICI) in combination with VEGFR-TKIs [ 4 , 13 , 14 ], but the percentage of patients responding to this novel therapeutic strategy remains unsatisfactory (~10%) [ 15 , 16 , 17 ]. There are still no optimized guidelines for TKIs selection in these combination regimens to achieve the optimal response with minimum toxicity [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Sunitinib versus Pazopanib Dilemma in Renal Cell Carcinoma: New Insights into the In Vitro Metabolic Impact, Efficacy, and Safety

Amaro

Pisoeiro

Valente

et al. 2022

IJMS

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Sunitinib and pazopanib are tyrosine kinase inhibitors (TKIs) used as first-line therapy for metastatic renal cell carcinoma (RCC). Although these TKIs are associated with similar survival outcomes, some differences have been reported in their safety profiles. In this work, traditional toxicological endpoints (cell viability and growth, oxidative stress, and nuclear morphology) and 1H NMR spectroscopy-based metabolomics analysis were used to provide new insights into the cytotoxicity and metabolic mechanisms underlying sunitinib and pazopanib treatments. Tumoral (Caki-1) and non-tumoral (HK-2) human renal cells were exposed to clinically relevant concentrations of sunitinib (2 µM) or pazopanib (50 µM). Sunitinib showed selectivity for cancer cells, inhibiting proliferation, and inducing apoptotic death of Caki-1 cells, whereas pazopanib had a similar cytotoxic effect in both tumoral and non-tumoral cells. 1H-NMR metabolomics unveiled a higher impact of sunitinib on the levels of intracellular metabolites of Caki-1 cells (seven dysregulated metabolites), suggesting dysregulations on amino acid, glutathione and glycerophospholipid metabolisms. In contrast, pazopanib had a higher impact on the levels of extracellular metabolites of Caki-1 cells (seven dysregulated metabolites in culture medium), unveiling alterations on amino acid and energetic metabolisms. In HK-2 cells, sunitinib caused only a minor increase in intracellular isoleucine levels, whereas pazopanib induced several alterations on the intracellular (three dysregulated metabolites) and extracellular (three dysregulated metabolites) compartments suggesting changes on amino acid, glycerophospholipid, and energy metabolisms. Our results demonstrate that these TKIs elicit distinct cellular and metabolic responses, with sunitinib showing better in vitro efficacy against target RCC cells and lesser nephrotoxic potential than pazopanib.

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Section: Introductionmentioning

confidence: 99%

Sunitinib versus Pazopanib Dilemma in Renal Cell Carcinoma: New Insights into the In Vitro Metabolic Impact, Efficacy, and Safety

Amaro

Pisoeiro

Valente

et al. 2022

IJMS

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“…everolimis), and HIF2α inhibitors (e.g. belzutifan) [49]. However metastatic ccRCC continues to carry a 5 year survival rate of 13% [49].…”

Section: Discussionmentioning

confidence: 99%

Oncometabolite L-2-Hydroxyglutarate Promotes Oncogenesis of Renal Cell Carcinomas by Down-Regulating Differentiation

Taub¹

2023

Renal Cell Carcinoma - Recent Advances, New Perspectives and Applications

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L-2-Hydroxyglutarate (L2HG) overproducing Renal Cell Carcinomas (RCCs) arise in the kidney due to the genetic loss of L-2HG Dehydrogenase (L2HGDH), the enzyme responsible for the metabolism of L2HG. The overproduced 2-Hydroxyglutarate (2HG) promotes tumorigenesis by inhibiting α-ketoglutarate (αKG)-dependent dioxygenases, including Ten-eleven-Translocation 5-methylcytosine (5mC) dioxygenase (TET) enzymes as well as histone demethylases. The resulting epigenetic changes alter the phenotype of renal proximal tubule (RPT) cells, the cells of origin of RCCs. This report describes the consequences of increased L2HG on the differentiation of RPT cells, one of the initial steps in promoting tumorigenesis. Presumably, similar alterations promote the expansion of renal cancer stem-cells and tumorigenesis.

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“…Currently, the mechanism underlying the tumorigenesis of ccRCC remains elusive, and management for ccRCC patients with metastatic disease limited to tyrosine kinase inhibitor (TKI) therapies and immune checkpoint inhibitors therapies [15]. TKI therapies show an amazing antitumor effect, which has been approved as the rst-line therapy for advanced ccRCC patients [16].…”

Section: Discussionmentioning

confidence: 99%

CDCA5 is a potent therapeutic target of clear cell renal cell carcinoma

Wang

Liu

et al. 2022

Preprint

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Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer in adult, and patients with advanced ccRCC are facing limited treatment options. Cell division cycle associated 5 (CDCA5), a key regulator for segregating sister chromatids in cell cycle, has been increasingly reported for a potential therapeutic target in multiple human cancers. However, the functional roles of CDCA5 in ccRCC remain uncertain. Here we identified that CDCA5 expression was frequently upregulated in ccRCC tumors and significantly associated with poor prognosis of ccRCC patients. To investigate the role of CDCA5 in ccRCC progression, loss function cell models were established. Knockdown of CDCA5 remarkably suppressed ccRCC cell proliferation and migration ability, and also induced cell apoptosis in vitro. In addition, the significance of CDCA5 in ccRCC was further demonstrated in a mouse xenograft model. Silencing of CDCA5 drastically inhibited in vivo tumorigenicity of ccRCC cells. Mechanically, we identified CDCA5 may cooperate with EEF1A1 to promote the tumorigenic phenotype of ccRCC. Overall, our results revealed the significant functional role of CDCA5 in ccRCC progression, which may pave a way for the development of new treatment strategies for ccRCC treatment.

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Current and emerging therapies for first line treatment of metastatic clear cell renal cell carcinoma

Cited by 26 publications

References 75 publications

Sunitinib versus Pazopanib Dilemma in Renal Cell Carcinoma: New Insights into the In Vitro Metabolic Impact, Efficacy, and Safety

Sunitinib versus Pazopanib Dilemma in Renal Cell Carcinoma: New Insights into the In Vitro Metabolic Impact, Efficacy, and Safety

Oncometabolite L-2-Hydroxyglutarate Promotes Oncogenesis of Renal Cell Carcinomas by Down-Regulating Differentiation

CDCA5 is a potent therapeutic target of clear cell renal cell carcinoma

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