Induction of Oncogenic mircoRNA by rapamycin: Role in TSC Therapy



 DESCRIPTION (provided by applicant): The TSC/mTORC1 signaling axis is dysregulated in tuberous sclerosis complex (TSC). Everolimus, a rapamycin analog that partially inhibits mTORC1, is approved for the treatment of renal angiomyolipomas in TSC patients, but responses are not complete and regrowth begins after treatment discontinuation. microRNA (miRNA, miRs), which post-transcriptionally repress gene expression, have been shown to play a critical role in numerous disease processes; however, the role of miRNA in TSC and TSC therapeutic responses represents a key knowledge gap. In recently published work, we discovered a set of rapamycin-dependent miRNA, or "Rapa-miRs." The unexpected finding that rapamycin upregulates pro-survival oncogenic miRNA, particularly miR-21, underlies our central hypothesis: inhibition of miRNA-dependent survival networks will enhance effectiveness of mTORC1 inhibition in angiomyolipoma therapy, leading to more complete and durable clinical responses. This hypothesis will be tested in three Specific Aims: Aim 1: To identify the regulatory mechanisms that lead to induction of miRNA by rapamycin. Aim 2: To identify biologically active rapamycin-dependent target genes of miR-21 in TSC2- deficient cells. Aim 3: To determine how the induction of miR-21 by rapamycin impacts the growth and survival of TSC2-deficient cells.