Project B20

Exploiting ferroptosis-based strategies in cancers of the adrenal

Adrenocortical carcinomas (ACC) and neuroblastoma (NB) exhibit pronounced sensitivity to ferroptosis due to their distinctive metabolic requirements. We previously found that many ACC and NB cell lines depend on selenium supplementation for growth, reflecting a reliance on selenoprotein biosynthesis to maintain redox homeostasis and suppress ferroptotic cell death. However, the mechanisms of selenium uptake in these cancers remained undefined. To address this gap, we performed an SLC-focused CRISPR knock-out screen in selenium-auxotrophic cancer models and identified a novel selenite transporter as essential for inorganic selenium uptake and ferroptosis resistance. A subsequent small-molecule screen yielded a selective inhibitor for this transporter, establishing it as a novel regulator of selenium metabolism and a potential therapeutic target.

In the current funding period, we will pursue three aims to define the functional and translational relevance of the selenite transporter. 

Aims

(I)will determine how genetic or pharmacological inhibition affects selenite uptake, selenoprotein synthesis, and ferroptosis sensitivity in ACC and NB models. 

(II) will optimize the initial inhibitor through structure–activity relationship studies and elucidate its mechanism using purified transporter reconstituted in liposomes. 

(III) will evaluate the therapeutic potential of the transporter inhibition in orthotopic ACC mouse models, alone and in combination with standard therapies. Together, these studies will establish whether targeting selenium uptake can be exploited to selectively induce ferroptosis in ACC and NB, opening new avenues for treatment of these aggressive cancers.

© SFB/TRR205