FASTING-MIMICKING DIET AND STARVATION ESCAPE INHIBITION AS NOVEL LOW-TOXIC TREATMENT FOR RENAL CELL CARCINOMA

Renal cell carcinoma (RCC) remains a major therapeutic challenge despite significant therapeutic progress in recent years. Current treatments prolong survival but are often undermined by resistance and systemic toxicity, underscoring the need for integrative approaches with improved efficacy and tolerability. Fasting-mimicking diets (FMD) have emerged as promising interventions that sensitize tumor cells while protecting normal tissues. In this project, I investigated the potential of combining FMD with the identification and pharmacological inhibition of starvation escape pathways (SEPs) in the context of RCC. Transcriptomic and metabolomic profiling revealed that under nutrient restriction, RCC cells become highly dependent on ERK-MAPK and mTOR-S6K signaling. Building on this observation, I developed a treatment strategy combining FMD with selective inhibition of these pathways. This regimen consistently induced cancer cell death in vitro across multiple RCC lines while sparing normal cells and proved effective in vivo in syngeneic and xenograft models by delaying tumor growth, promoting regression, and reducing metastatic spread. Not only the treatment was well tolerated, but it reduced the toxicity of the drugs administered. Mechanistically, my data point to a nucleotide-centered vulnerability: by simultaneously restricting extracellular nucleotides through FMD and impairing de novo synthesis via ERK-MAPK and mTOR-S6K inhibition, the treatment collapses intracellular dNTP pools, triggers redox imbalance, and leads to cell death. Although the precise chain of events remains to be fully elucidated, the convergence of transcriptomic, metabolomic, and functional evidence strongly supports this model. The results presented here are highly promising and provide a strong rationale for the development of novel therapeutic approaches in RCC. These may ultimately contribute to new stand-alone treatments, even though are more likely to serve as complementary platforms to be integrated with current standard therapies, with the potential to enhance efficacy while preserving a favorable safety profile. Moreover, the mechanisms uncovered in this work reveal differential metabolic vulnerabilities that are not unique to RCC and may extend to other malignancies. Altogether, these findings lay the foundation for innovative and reduced toxicity therapy that warrant further investigation and careful translation into clinical practice.