HYPOTHESIS

NUDT5 is a key mediator of hormone signaling in BC and is a target for maintenance therapy following initial BC treatment.

Background & Significance

While the treatment of localized, hormone receptor positive BC is often successful, up to 25% of patients will develop disease recurrence within 15 y of successful initial treatment. Previous studies have identified that NUDT5 protein is critical factor in hormone receptor positive BC which mediates the genetic and proliferative response to hormone stimulation45. My group has since discovered first-in-class, small molecule NUDT5 inhibitors that induce the identical response as NUDT5 depletion in BC cells. These inhibitors have been thoroughly optimized within our medicinal chemistry program and we believe that they have promising applications as maintenance therapies in tertiary BC prevention46

Objectives

We will focus on the application of NUDT5 inhibitors as potential therapeutic agents for BC prevention. The ESR will join our NUDT5 inhibitor development team and will:

characterize the activity of novel NUDT5 inhibitors in state-of-the-art target engagement assays;

explore the impact of NUDT5 inhibition on hormone signaling and proliferation in hormone responsive cancers. The ESR will also

investigate the effects of NUDT5 inhibition in patient derived cell lines and

further the pre-clinical evaluation of lead inhibitors in vivo.

Enrolment in Doctoral degree(s):

  • Karolinska Institute