Therapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade

Abstract

Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010–2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.

MPP7 is a potential prognostic marker and is associated with cancer metabolism and immune infiltration in clear cell renal cell carcinoma: a bioinformatics analysis based on the TCGA database

“…Owing to the lack of typical clinical symptoms, approximately 25–30% of patients with ccRCC have already developed distant metastases upon diagnosis ( 2 , 3 ). In addition, improvement via surgical nephrectomy achieves a good prognosis for early-stage ccRCC patients; however, the 5-year survival rate of patients with advanced ccRCC is still less than 10% ( 4 ). Novel therapeutics such as antiangiogenic therapy, immune checkpoint inhibitors, tyrosine kinase inhibitors, and mammalian target of rapamycin (mTOR) inhibitors have brought hope to advanced ccRCC patients.…”

Silver Nanoparticles (AgNPs) as Enhancers of Everolimus and Radiotherapy Sensitivity on Clear Cell Renal Cell Carcinoma

“…Due to its hypoxic nature, RCC is commonly resistant to both chemo-and radiotherapy. Thus, the management of metastatic disease highly depends on targeted therapies, such as anti-vascular endothelial growth factor (VEGF) antibodies, VEGF receptor tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) pathways inhibitors and immune checkpoint inhibitors [6]. Nevertheless, patients end up developing resistance to these agents, and a quarter of patients do not seem to show any clinical benefit.…”