Abstract 6660: Fasting-mimicking diet and starvation escape inhibition as novel low-toxic treatments for kidney cancer

Abstract Fasting, or fasting-mimicking diet (FMD), can delay tumor growth and promote tumor regression by making cancer cells more vulnerable to conventional therapies, while promoting protection and resistance in normal cells. FMD, which imitates the beneficial effects of fasting while being more tolerated by patients, activates peculiar survival/growth pathways in different cancer types, which can be identified and inhibited leading to tumor regression with low-toxicity. In the present study, we exploited the beneficial effects of FMD in the treatment of kidney cancer, which remains a major challenge despite the significant therapeutic progress of the past years. We developed a protocol that recapitulates in vitro the main molecular effects of FMD, in which cancer cells are exposed to reduced levels of glucose and serum factors. We observed that renal cancer cells subjected to in vitro FMD up-regulate specific starvation escape pathways, including the ERK-MAPK and the mTOR-S6K signalling. We developed a treatment based on FMD and selective inhibitors of these pathways, which induced cell death in a wide range of renal tumor lines, but not in normal cells, through the impairment of the purine metabolism ultimately leading to oxidative stress. We confirmed that the treatment is very effective in delaying tumor growth and in promoting tumor regression in different kidney cancer subcutaneous xenograft mouse models, attesting its safety and low toxicity on mice. The treatment also reduced metastasis formation upon intravenous injection of renal cancer cells in a syngeneic mouse model. We believe that this study represents a promising start to develop innovative and feasible treatments for kidney cancer, which could potentially also be extended to other cancer types. Citation Format: Samuel Lazzeri, Anastasiya Shmahala, Olga Blazevits, Valter D. Longo. Fasting-mimicking diet and starvation escape inhibition as novel low-toxic treatments for kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6660.