Clear Cell Renal Cell Carcinoma (CCRCC) is the most common and often aggressive type of kidney cancer, comprising almost 75% of all renal cell carcinoma (RCC) cases. Protheragen stands as a leading partner in the intricate landscape of Clear Cell Renal Cell Carcinoma research and development, offering comprehensive services for both diagnostics and therapeutics.
Overview of Clear Cell Renal Cell Carcinoma (CCRCC)
Clear Cell Renal Cell Carcinoma (CCRCC) is also the most frequent type of renal cell carcinoma (RCC), comprising nearly 75% of all RCC cases. It arises from renal tubular epithelium, and CCRCC is defined by the overexpression of hypoxia-inducible factors (HIFs) because of mutations in the Von Hippel-Lindau (VHL) gene. This alteration of the gene increases many angiogenic factors like VEGF (vascular endothelial growth factor), which leads to augment tumor angiogenesis, proliferation, and survivability of cells. Most CCRCC cases are diagnosed incidentally with imaging modalities, and most of the cases are at the localized stage. However, nearly one-third of the cases have regional or distant metastasis, which significantly worsens their prognosis.
Fig.1 Timeline of FDA-approved agents and combination therapeutics for metastatic renal cell carcinoma. (Kase A. M.,
et al., 2023)
Pathogenesis of Clear Cell Renal Cell Carcinoma (CCRCC)
The CCRCC pathogenesis is precisely orchestrated by changes in the VHL gene (3p25), with its unique hereditary dominant traits. The VHL gene is a tumor suppressor; hence, its inactivation leads to the equilibrium of HIFs which, in turn, control more than 1000 target genes, outs of which, VEGF is one of the most important. In standard conditions, the VHL genius protein ensures the HIFs controlled by cell growth are turned off. CCRCC witnesses the loss of control of VHL ability, which drives HIFs constantly which is a booster for tumor growth and spread. Several genetic and epigenetic alteration pathways additionally fuel the CCRCC development and progression such as PBRM1 and BAP1 gene mutations.
Diagnostics Development for Clear Cell Renal Cell Carcinoma (CCRCC)
Molecular Diagnostics
Molecular diagnostics pertaining to CCRCC concentrate on the particular modifications and changes of genes relevant to the disease. Next-generation sequencing (NGS) is now considered indispensable in the finding of VHL mutations and other pertinent genomic alterations. For instance, identifying VHL mutations with NGS aids in the early diagnosis and stratification of cases. Furthermore, the presence of ctDNA in blood samples enables non-invasive surveillance of disease progression and therapeutic effectiveness.
Biomarker Development
The goal of biomarker studies is the identification of therapeutic response predictors, prognostic value, and relevant proteins, genetic markers, and other molecules. For example, the expression levels of two transcription factors, HIF-1α and HIF-2α, were associated with the degree of tumor aggressiveness and the response to anti-angiogenic therapies. Also, the advancement of liquid biopsy methods facilitates the identification of CTCs and ctDNA, providing dynamic information regarding the tumor.
Therapeutics Development for Clear Cell Renal Cell Carcinoma (CCRCC)
- Targeted Therapies
The CCRCC targeted therapies revolve around the inhibition of the VEGF pathway. There TKIs, including sunitinib, sorafenib, and pazopanib, have shown clinically meaningful improvements in PFS and OS. The phase III trial of sunitinib, for example, demonstrated a median PFS of 11 months with sunitinib compared to 5 months with interferon therapy. In addition, everolimus and temsirolimus, mTOR inhibitors, have also received approval for use in CCRCC because of their inhibitory effects on HIF activation.
- Immunotherapies
The use of immune checkpoint inhibitors targeting PD-1, such as nivolumab and pembrolizumab, alongside CTLA-4 inhibitors like ipilimumab has changed the therapeutic paradigm of CCRCC. In the CheckMate 214 trial, the combination of nivolumab and ipilimumab resulted in a median OS of 47 months, as opposed to 26.6 months with sunitinib. These therapies enable the case's immune system to identify and destroy the cancerous cells, consequently, this led to better survival rates and durable responses.
Table 1. FDA-approved agents for advanced RCC targeting the VEGF axis. (Kase A. M., et al., 2023)
| VEGFR TKI |
Receptor |
Trial |
Efficacy |
| Sorafenib |
Raf-1, B-Raf, B-Raf (V599E), VEGFR, PDGFR, c-Kit, RET |
Phase III RCT, sorafenib vs. placebo, previously untreated |
PFS 5.5 months vs. 2.8 months (HR 0.44, 95% CI 0.35–0.55, p < 0.01) |
| Lenvatinib (combined with everolimus) |
PDGFRα, PDGFRβ, FGFR1 |
Phase II RCT, lenvatinib + everolimus vs. everolimus, previously treated |
PFS 14.6 months vs. 5.5 months (HR 0.4, 95% CI 0.24–0.68; p = 0.0005) |
| Sunitinib |
c-Kit, FLT3, PDGFRβ |
Phase III RCT, sunitinib vs. interferon, previously untreated |
PFS 11 months vs. 5 months (HR 0.42, 95% CI 0.32–0.54; p < 0.001) |
| Cabozantinib |
c-MET, AXL, RET, KIT, FLT3, TRKB, Tie-2 |
Phase III RCT, cabozantinib vs. everolimus, previously treated |
PFS 7.4 months vs. 3.8 months (HR 0.58; 95% CI 0.45–0.75, p < 0.001) |
| Pazopanib |
PDGFR, FGFR, c-Kit |
Phase III RCT, pazopanib vs. placebo, previously untreated and cytokine pre-treated |
PFS 9.2 months vs. 4.2 months (HR 0.46, 95% CI 0.34–0.62, p < 0.001) |
| Axitinib |
PDGFRα, PDGFRβ, Kit, BCR-ABL1 |
Phase III RCT, axitinib vs. sorafenib, previously treated |
PFS 6.7 months vs. 4.7 months (HR 0.665, 95% CI 0.544–0.812, p < 0.0001) |
| Tivozanib |
Predominantly VEGFR 1–3 |
Phase III, RCT, tivozanib vs. sorafenib, previously treated |
PFS 5.6 months vs. 3.9 months (HR 0.73, 95% CI 0.56–0.93, p = 0.016) |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers comprehensive diagnostics and therapeutics development services for CCRCC. Our services leverage cutting-edge technologies and expertise in molecular biology, genomics, immunology, and pharmacology to accelerate the discovery and development of novel diagnostic tools and therapeutic agents for CCRCC.
Disease Models
- 786-O Cell Line Models
- A-498 Cell Line Models
- ACHN Cell Line Models
- Patient-Derived Xenografts (PDX) Models
- Syngeneic Models
Protheragen's preclinical research services for CCRCC include in vitro and in vivo models, pharmacokinetic and pharmacodynamic studies, and biomarker discovery and validation. If you are interested in our services, please feel free to contact us.
References
- Kase, Adam M., Daniel J. George, and Sundhar Ramalingam. "Clear cell renal cell carcinoma: from biology to treatment." Cancers 15.3 (2023): 665.
- Bahadoram, Sara, et al. "Renal cell carcinoma: an overview of the epidemiology, diagnosis, and treatment." G Ital Nefrol 39.3 (2022): 2022.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
