The C. elegans lin-28 gene encodes an evolutionarily conserved RNA- binding protein that functions in pathways involving let-7-family microRNAs to control transitions from more proliferative to less proliferative behavior for progenitor cells. Similarly, mammalian LIN-28 regulates the biogenesis of let-7- family microRNAs and also promotes stem cell pluripotency and proliferative behavior. LIN-28 also functions downstream of Myc oncogenic signaling in human cancer cells, in part by inhibiting tumor suppressor microRNAs. Thus, LIN-28 represents a viable target for development of anti-cancer therapeutics. The conservation between C. elegans and humans of the roles for LIN-28 in proliferation and pluripotency prompts us to propose to use C. elegans as an efficient and inexpensive system to screen for small molecule inhibitors of LIN- 28. We will take advantage of the striking developmental phenotypes associated with LIN-28 gain of function in C. elegans to identify compounds that can inhibit LIN-28 activity and suppress those phenotypes. We will leverage the well- developed genetics of the C. elegans lin-28 pathway to triage our drugs for those that directly affect the LIN-28 protein in worms, and hence are most likely to function similarly in human cells. Our main goal is to establish the feasibility of the C. elegans system for chemical genetics of LIN-28. At the same time, we will further maximize the potential payoff from the project by incorporating into our strategy measures that facilitate the rapid transition of LIN-28-targeting drugs in the clinic. Accordingly, using mammalian cancer cell line models, we will perform follow-up tests of candidate LIN-28 inhibitors that we initially identify in C. elegans to establish their efficacy in mammalian cells. Most importantly, our screens on worms will utilize libraries of FDA-approved drugs, and therefore there is the prospect of almost immediate clinical application against human cancer of anti-LIN-28 drugs identified in C. elegans.
LIN-28 plays a major role in regulating the biogenesis of the tumor suppressor miRNAs of the let-7 family and does so downstream of Myc oncogene signaling. LIN-28 therefore represents a potential druggable target in the context of human cancer. We propose to utilize the nematode C. elegans as an in vivo system to efficiently screen for small molecule drugs that can inhibit LIN-28 activity. The chemical compounds the we identify by their inhibition of LIN-28 function in C. elegans will form the basis for further testing of their ability to inhibit LIN-28 in mammalian cancer lines. Since we will include in our screens libraries of FDA-approved drugs, there is the prospect of almost immediate clinical application of anti-LIN-28 drugs that we will identify.
| Ambros, Victor (2011) MicroRNAs and developmental timing. Curr Opin Genet Dev 21:511-7 |
| Karp, Xantha; Ambros, Victor (2011) The developmental timing regulator HBL-1 modulates the dauer formation decision in Caenorhabditis elegans. Genetics 187:345-53 |
| Hammell, Christopher M; Karp, Xantha; Ambros, Victor (2009) A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans. Proc Natl Acad Sci U S A 106:18668-73 |
