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Updated: Mar 1, 2026
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Non-clear cell renal cell carcinomas: biological insights and therapeutic challenges and opportunities
Gabriel G Malouf1, Richard W Joseph2, Amishi Y Shah3
1Pitié-Salpêtrière Hospital, AP-HP, University Pierre and Marie Curie, Paris, France.
Abstract:
The non-clear cell renal cell carcinomas (nccRCCs) are a diverse group of rare-variant renal carcinomas. Each subtype harbors a distinct cell of origin and exhibits a distinct clinical behavior and response to therapy. The advent of next-generation sequencing has drastically advanced our understanding of key genetic and epigenetic drivers in these tumors, although mechanistic studies are needed to elucidate pathogenesis. The only 2 randomized clinical trials in nccRCC included patients with diverse histologic subtypes. Both of these trials compared everolimus with sunitinib and provided evidence suggesting that frontline sunitinib is superior to everolimus in terms of progression-free survival. Renal medullary and collecting duct carcinomas do not respond to targeted agents, supporting the use of platinum-based chemotherapy as frontline therapy. Clinical evidence is currently emerging on the efficacy of c-MET inhibitors in patients with papillary type 1 RCC harboring germline c-MET mutations. Data on the activity of immune checkpoint inhibitors in this setting are lacking; however, several trials are ongoing in this space. The management of patients with nccRCC likely will improve in the future with histology-driven trials, which may pave the way for personalized therapies based on the molecular characterization of these orphan kidney cancer subtypes. Efforts must also be made to establish in vitro and animal models for testing hypotheses generated through extensive genomic analysis. Ultimately, collaborative national and international studies are urgently needed to improve therapeutic strategies in patients with metastatic disease.
Insights
Non-clear cell renal cell carcinomas (nccRCCs) are rare kidney cancers with diverse subtypes. Frontline sunitinib shows superiority over everolimus, and platinum chemotherapy is recommended for specific subtypes.
Area of Science:
- Oncology
- Genetics
- Pathogenesis
Background:
- Non-clear cell renal cell carcinomas (nccRCCs) represent a heterogeneous group of rare kidney cancers.
- Each subtype originates from a distinct cell type, displaying unique clinical behaviors and therapeutic responses.
- Next-generation sequencing has significantly enhanced understanding of nccRCC genetic and epigenetic drivers, yet mechanistic studies are crucial for elucidating pathogenesis.
Purpose of the Study:
- To review the current understanding and therapeutic landscape of non-clear cell renal cell carcinomas.
- To highlight the need for histology-driven trials and molecular characterization for personalized therapies.
- To emphasize the importance of collaborative studies and model development for advancing nccRCC treatment.
Main Methods:
- Review of existing clinical trial data, including randomized trials comparing everolimus and sunitinib.
- Analysis of genetic and epigenetic drivers identified through next-generation sequencing.
- Discussion of emerging evidence for targeted agents and chemotherapy in specific nccRCC subtypes.
Main Results:
- Frontline sunitinib demonstrated superior progression-free survival compared to everolimus in diverse nccRCC subtypes.
- Renal medullary and collecting duct carcinomas show resistance to targeted agents, supporting platinum-based chemotherapy.
- Emerging data suggest efficacy of c-MET inhibitors for papillary type 1 RCC with germline c-MET mutations.
Conclusions:
- Histology-driven trials and molecular profiling are essential for advancing personalized therapies in nccRCC.
- Development of in vitro and animal models is needed to test genomic-derived hypotheses.
- International collaboration is critical for improving therapeutic strategies in metastatic nccRCC.
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