Role of MicroRNA in the Pathogenesis and Treatment of TSC
Abstract
The 2006 Nobel Prize was awarded for the discovery of microRNA (miRNA or miRs), small molecules that negatively regulate protein expression by binding to complementary messenger RNA (mRNA). miRNA have been implicated in numerous developmental and disease processes, including cancers. miRNA have been studied as biomarkers of cancer prognosis. Most excitingly, in 2013 successful miRNA targeted therapy for Hepatitis C was reported in the New England Journal of Medicine. miRNA therapeutics represents a rapidly advancing field; however, relatively little is known about miRNA in tuberous sclerosis complex (TSC), highlighting an important knowledge gap. TSC is caused by hyperactivation of mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1), which results in excessive cell growth and proliferation. mTORC1 inhibitors, such as Rapamycin and Everolimus (Rapalogs) induce tumor regression; however, tumors regrow upon treatment cessation. This finding suggests that Rapalogs prevent excessive cell growth and cell division, but do not kill the hyperproliferative cells. Therapies that elicit durable clinical responses and obviate the need for long-term Rapalog treatment represent an unmet clinical need. In recently published work, we identified a number of miRNA that are induced by Rapamycin, which we refer to as "Rapa-miRs." Among the most highly upregulated Rapa-miRs were pro-survival miRNA, including miR-24, -29b, and -221, which decrease the expression of proteins that prevent tumor formation (tumor suppressors). This surprising finding highlights a previously unknown mechanism that may limit the efficacy of mTORC1 inhibitors. We hypothesize that elucidating the mechanisms through which Rapamycin regulates miRNA-24, -29b, and -221, understanding the targets and functions of miR-24, -29b and -221 both in vitro and in vivo, and identifying circulating serum miRNA candidate biomarkers in patients with TSC will catalyze the development of strategies to treat TSC-associated tumors and lymphangioleiomyomatosis. In summary, these studies will identify novel therapeutic targets and candidate biomarkers, which we expect to have a profound impact on the clinical care of adults and children living with TSC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510263
Entities
People
- Elizabeth P Henske
Organizations
- United States Army