The distinct unusual characteristics of papillary renal cell carcinoma (pRCC) contribute to its aggressive biological behavior, which is difficult to diagnose and treat. For this type of cancer, Protheragen provides full solutions for diagnostic and therapeutics development services.
Overview of Papillary Renal Cell Carcinoma (pRCC)
Papillary renal cell carcinoma (pRCC) is a well-defined subtype of kidney cancer, constituting about 15 to 20% of the total population of renal cell carcinoma (RCC) cases. It is marked by the pRCC's heterogeneous nature, possessing tumors with various molecular and histological features. The typical age cohort of patients is 50 to 70, and the prognosis is favorable when the disease is localized. However, metastatic pRCC is tied to poor prognosis owing to its resistance to standard treatment. The disease presents with two predominant histological types: Type 1 is generally less aggressive, more often multifocal, while Type 2 is more aggressive with higher malignancy and frequently diagnosed in advanced stages.
Fig.1 Presents molecular pathways involved in clear cell papillary renal cell carcinoma (ccpRCC). (Rysz J.,
et al., 2021)
Pathogenesis of Papillary Renal Cell Carcinoma (pRCC)
The development of pRCC is associated with intricate genetic and molecular changes which vary among its two main subtypes. In type 1 pRCC, changes in the MET gene are common, especially mutations or copy number increases that cause MET pathway dysregulation. MET receptors, which receive hepatocyte growth factor (HGF), signal cellular growth and survival. Thus, the MET pathway is tumorigenic when activated.
On the flip side, Type 2 pRCC is characterized by greater genetic interruption, with mutations in SETD2, BAP1, and PBRM1 genes and often involves chromatin remodeling along with tumor suppressor activities. Also, mutations in the FH gene, a critical gene in the tricarboxylic acid cycle, are associated with Type 2 pRCC, especially in the hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. These changes in genes cause changes in metabolism, increased oxidative stress, and disruption of the NRF2-antioxidant response element (ARE) signaling pathway, and are all factors that Type 2 tumors are aggressively phenotyped with.
Diagnostics Development for Papillary Renal Cell Carcinoma (pRCC)
In the case of pRCC, preclinical diagnostics focus on histology-based classification and molecular profiles. Type 1 and Type 2, the two main subtypes, can be differentiated by specific markers, MET mutation in Type 1 and SETD2 mutation in Type 2. With the rise of molecular diagnostics, next generation sequencing (NGS) is used to uncover fundamental mutations and aberrations on chromosomes crucial to the disease’s staging and prognosis. For instance, MET mutation identification in Type 1 pRCC can be used for targeted interventions. Moreover, CIMP can be used as a molecular marker for Type 2 pRCC and as a marker to separate subgroups with CIMP from those with worsening prognosis.
Therapeutics Development for Papillary Renal Cell Carcinoma (pRCC)
- Targeted Therapies
Especially therapies aimed at MET pathways, which are frequently changed in Type 1 pRCC, are showing promise for prcc-targeted therapies. Crizotinib and cabozantinib are MET inhibitors that have shown some success in clinical trials suppressing tumor growth. Moreover, sunitinib and axitinib, which are VEGF inhibitors, have shown activity in advanced pRCC, but their usefulness is frequently limited by the heterogeneity of the disease.
- Immunotherapy
The management of renal cell carcinoma has been transformed with the advent of ICIs or immune checkpoint therapies. pRCC is responsive to treatment with Pembrolizumab, which has been validated in the KEYNOTE-427 trial with an approximately 29% response rate in advanced disease. Moreover, the efficacy of ICIs is further potentiated through the co-administration of VEGF agents like lenvatinib, which results in better response rates and longer periods of progression-free survival.
Table 1. Notable trials in papillary renal cell carcinoma. (Chawla N. S., et al., 2023)
| Trial |
Inclusion Criteria |
Number of Patients (Papillary) |
Experimental Arm |
Control Arm |
Results |
| RAPTOR (NCT00688753) |
• Locally advanced or metastatic type 1 or type 2 papillary RCC.
• No previous systemic treatment |
88 (88) |
First-line everolimus 10 mg orally daily |
N/A |
OS (median): 21.4 months (95% CI 15.4–28.4)
>
PFS (median): 4.1 months (95% CI 3.6–5.5) |
| SUPAP (NCT00541008) |
• Locally advanced or metastatic type 1 or type 2 papillary RCC.
• No previous systemic treatment |
61 (61) |
Sunitinib 50 mg orally daily every 4 weeks followed by 2 weeks without treatment |
N/A |
OS (median): 17.8 months (95% CI, 5.7–26.1) (type 1 pRCC) and 12.4 months (95% CI, 8.2–14.3) (type 2 pRCC)
PFS (median): 6.6 months (95% CI, 2.8–14.8) (type 1 pRCC) and 5.5 months (95% CI, 3.8–7.1) (type 2 pRCC) |
| AXIPAP (NCT02489695) |
• Locally advanced or metastatic papillary RCC.
• No previous treatment with a tyrosine kinase inhibitor in the adjuvant setting |
44 (44) |
Axitinib 10 mg orally twice daily |
N/A |
24-week progression-free rate: 45.2% (95% CI, 32.6–+∞)
PFS (median): 6.6 months (95% CI, 5.5–9.2) |
| PAPMET (NCT02761057) |
• Locally advanced or metastatic papillary RCC.
• Up to one previous line of therapy is allowed (except for another VEGF-TKI) |
147 (147) |
Cabozantinib 60 mg orally daily, crizotinib 250 mg orally daily, savolitinib 600 mg orally daily, or sunitinib 50 mg orally daily (with 4 weeks on and 2 weeks off) |
N/A |
Cabozantinib vs. crizotinib vs. savolitinib vs. sunitinib
PFS (median): 9 vs. 2.8 vs. 3 vs. 5.6 months
OS (median): 20 vs. 19.9 vs. 11.7 vs. 16.4 months |
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 services for the development of diagnostics and therapeutics for papillary renal cell carcinoma (pRCC). Our services encompass molecular diagnostics, advanced imaging techniques, biomarker development, and therapeutics development.
Disease Models
- Type 1 PRCC Mouse Model with Activating-MetHY Mutation
- FLCN Gene Knock-Out Models
- ACHN (Papillary RCC) Cell Line-Derived Xenografts (CDX) Models
- Caki-2 (Clear Cell RCC) Cell Line-Derived Xenografts (CDX) Models
Protheragen specializes in preclinical research services for pRCC, including the development of targeted therapies, immunotherapy, and combination therapeutics. Our services are designed to support the discovery and validation of novel therapeutic agents through comprehensive preclinical studies. If you are interested in our services, please feel free to contact us.
References
- Rysz, Jacek, et al. "Characteristics of clear cell papillary renal cell carcinoma (ccpRCC)." International Journal of Molecular Sciences 23.1 (2021): 151.
- Chawla, Neal S., et al. "An update on the treatment of papillary renal cell carcinoma." Cancers 15.3 (2023): 565.
- Cancer Genome Atlas Research Network. "Comprehensive molecular characterization of papillary renal-cell carcinoma." New England Journal of Medicine 374.2 (2016): 135-145.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
