Targeting metabolic and epigenetic reprogramming in metastatic fumarate hydratase-deficient renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Fumarate hydratase-deficient renal cell carcinoma (FHdRCC) is a rare but aggressive malignancy.
• It has a high metastatic potential and poor prognosis, necessitating novel therapeutic strategies.
• The 2022 WHO classification now categorizes FHdRCC as a molecularly defined subtype of renal cell carcinoma.

Purpose of the Study:

• To review ongoing clinical trials for advanced/metastatic FHdRCC.
• To highlight the underlying molecular mechanisms including metabolic and epigenetic reprogramming, and pro-oncogenic signaling.
• To discuss emerging targeted treatment strategies for FHdRCC.

Main Methods:

• Review of current phase 2 clinical trials evaluating targeted therapy combinations.
• Analysis of treatment outcomes, including objective response rates (ORR).
• Discussion of the molecular underpinnings of FHdRCC targeted by novel therapies.

Main Results:

• Several targeted therapy combinations are under investigation, including immune checkpoint inhibitors, multi-tyrosine kinase inhibitors, and PARP inhibitors.
• Promising combinations show high objective response rates: nivolumab/cabozantinib (100%), lenvatinib/tislelizumab (93.3%), bevacizumab/erlotinib (72%), and sintilimab/axitinib (63.1%).
• These results underscore the potential of targeted agents in managing advanced FHdRCC.

Conclusions:

• Targeted therapies, particularly combinations, demonstrate significant efficacy in advanced FHdRCC.
• Understanding metabolic and epigenetic reprogramming is crucial for developing novel treatment strategies.
• Personalized medicine approaches targeting specific signaling pathways hold promise for improving outcomes in metastatic FHdRCC.