Antiangiogenic Therapy in Clear Cell Renal Carcinoma (CCRC): Pharmacological Basis and Clinical Results

Abstract

Angiogenesis has a direct stimulatory effect on tumor growth, duplication, invasion and metastatic development. A significant portion of conventional renal cell carcinomas are angiogenesis-dependent tumors and the pathways supporting this process have been thoroughly investigated over the last 20 years. As a consequence, many tyrosine kinase inhibitors (TKIs) (sunitinib, sorafenib, pazopanib, axitinib, and cabozantinib), one monoclonal antibody (bevacizumab), and two mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus) have been investigated and approved for the treatment of advanced or metastatic clear cell renal carcinoma (metastatic CCRC) in first-line, as well as second-line, therapy, with impressive results in progression-free survival and in the objective response rate compared with previously available therapies or placebo. Recently, a new type of drug has been approved for metastatic CCRC: immunomodulatory checkpoint inhibitors (ICIs), alone or in combination with TKIs. However, many questions and areas to be explored still remain with regard to clear cell renal carcinoma (CCRC) treatment: research on predictive biomarkers, the best patient selection, how to overcome the mechanisms of resistance, and the best sequence of therapies in daily clinical practice. This review focuses on the pharmacological properties and anticancer activities of these drugs. The toxicity profile and clinical limitations of these therapies are also discussed.

Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma

“…Various targets of CZ are associated with immunosuppression, thus allowing it to directly immunomodulate the tumor microenvironment, increase cytotoxic T cell activation/infiltration, and induce susceptibility of tumor cells to cytotoxic T cell-mediated tumor cell killing, differentiating itself from other VEGF-targeting TKIs [ 26 , 37 , 39 , 41 , 43 , 44 , 67 , 74 ]. In particular, TAM kinases such as AXL and MET promote immunosuppressive phenotypes in tumor-associated immunosuppressive cells (including regulatory T cells, myeloid-derived suppressor cells, and tumor-activated macrophages) [ 37 ], which in turn contribute to the resistance against immune checkpoint inhibitors [ 37 , 41 ].…”

“…RCC management has advanced significantly with the advent of newer generation TKIs, such as cabozantinib (CZ), that are effective in the first-line setting for intermediate- or poor-risk metastatic RCC, with significant clinical benefits in the progression-free survival and overall response rate [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. CZ is an oral, potent multi-target TKI that targets the VEGF receptor (VEGFR)-2 and several other receptor tyrosine kinases (RTKs), including the hepatocyte growth factor receptor (MET), the TAM (TYRO-3, AXL, and MER) family of receptor kinases, the ROS proto-oncogene 1, the c-kit proto-oncogene product, the Fms-related receptor tyrosine kinase 3, the tropomyosin receptor kinase B, the angiopoietin-1 receptor, and the RET proto-oncogene [ 34 , 35 , 39 , 41 , 42 , 44 ]. Compared to other pure anti-angiogenic TKIs, the concomitant inhibition of multiple clinically relevant RTKs with a greater potency provided by CZ interferes with tumor progression, metastasis, angiogenesis, and therapeutic resistance to VEGF inhibition through dual multi-facet effects on the tumor cells and their microenvironment [ 34 , 35 , 39 , 41 , 42 , 44 ].…”

“…CZ is an oral, potent multi-target TKI that targets the VEGF receptor (VEGFR)-2 and several other receptor tyrosine kinases (RTKs), including the hepatocyte growth factor receptor (MET), the TAM (TYRO-3, AXL, and MER) family of receptor kinases, the ROS proto-oncogene 1, the c-kit proto-oncogene product, the Fms-related receptor tyrosine kinase 3, the tropomyosin receptor kinase B, the angiopoietin-1 receptor, and the RET proto-oncogene [ 34 , 35 , 39 , 41 , 42 , 44 ]. Compared to other pure anti-angiogenic TKIs, the concomitant inhibition of multiple clinically relevant RTKs with a greater potency provided by CZ interferes with tumor progression, metastasis, angiogenesis, and therapeutic resistance to VEGF inhibition through dual multi-facet effects on the tumor cells and their microenvironment [ 34 , 35 , 39 , 41 , 42 , 44 ]. In particular, CZ has a unique anti-tumor immunomodulatory profile because several targets of CZ, including VEGFR2, MET, and the TAM kinases, play crucial roles in mediating the immunosuppressive tumor microenvironment in metastatic RCC.…”

Metastatic Clear Cell Renal Cell Carcinoma to Pancreas and Distant Organs 24 Years After Radical Nephrectomy: A Case Report and Literature Review

“…In the case of multiple organ metastases from CCRCC, the European strategy is more inclined to initiate a systemic treatment first. Next, whether a local treatment will be proposed depends on the response to systemic treatment ( 38 ). Nevertheless, our study suggests that systemic therapy following metastasectomy may be also safe and effective.…”

Downregulation of lncRNA APCDD1L-AS1 due to DNA hypermethylation and loss of VHL protein expression promotes the progression of clear cell renal cell carcinoma

“…HIF1α and HIF2α can regulate the transcription of many genes involved in angiogenesis, metabolism and chromatin remodeling, which are associated with the development of ccRCC 9 . Based on this biological property of ccRCC, several targeted drugs with antiangiogenic activity have been approved for the treatment of advanced RCC, including mammalian target of rapamycin inhibitors, monoclonal antibody that interferes with vascular endothelial growth factor and tyrosine kinase inhibitors 10 . Unfortunately, current drug treatments are not effective enough, have severe side effects, and are prone to developing drug resistance during the course of treatment.…”