The mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in several paediatric hematologic and solid tumour malignancies. First generation mTOR inhibitors were poorly tolerated, and therefore had limited clinical utility. While the second-generation mTOR inhibitors demonstrated important clinical benefits the success of single-agent therapy was limited and primarily resulted in disease stabilization rather than regression.
mTOR signalling impacts many cellular processes. The aim of this project is to identify specific mTOR functions required for malignancy and to facilitate selective synthetic lethal targeting while sparing other mTOR functions required for healthy cell survival. Specifically, we identified a novel mTOR-regulated pathway that is activated when DNA replication is hindered in cancer cells. This pathway is essential for nuclear structure and DNA integrity in mTOR-driven cancers and thus, presents an opportunistic synthetic lethal target.
Started: 1 January 2020
Ending: 31 December 2021
