Benjamin W. Purow
Primary AppointmentAssociate Professor, Neurology
- BA, Chemistry and Physics, Harvard University-Cambridge, MA
- MD, Medicine, Johns Hopkins University-Baltimore, MD
Examination of the molecule called microRNA-7, which may have therapeutic potential for gliomas.
Glioma is the most common brain tumor and has been calculated to cause more lost years of life than any other cancer. Median survival of patients with glioblastoma, the highest-grade glioma, is roughly one year, fueling an aggressive search for new therapies targeting the proteins and pathways underlying these cancers. Our laboratory is focused on discovering new genes and microRNAs underlying glioma pathogenesis and incorporating these findings into novel therapies. Our goal is to develop therapies active not only against the bulk of glioma cells but also against stem cell-like glioma cells, a recently-discovered subpopulation that is only a small fraction of the glioma cells but is more therapy-resistant and able to regenerate the cancer. We showed in a previous publication that Notch, a central pathway in stem cell maintenance and cell fate determination, is a potential therapeutic target in glioma. In another report, we demonstrated that other prominent cancer pathways are inhibited by a microRNA down-regulated in glioblastoma, microRNA-7. microRNAs are a newly-discovered class of non-coding RNAs that block expression of numerous target mRNAs upon binding the 3’-untranslated region. Several microRNAs have been found to be up- or down-regulated in cancers, but little has been published on their functions relative to key oncogenic pathways. Our previous studies in gliomas with microRNA and with Notch led us to investigate whether there might be Notch-interacting microRNAs with important roles in these tumors. We have now identified microRNAs both upstream and downstream of Notch, and delivery of these microRNAs has therapeutic potential. We are pursuing these exciting findings through the following projects:
1) Investigation of microRNA-7 as a potential tumor suppressor in gliomas and as a therapy. We showed previously that expression of microRNA-7 is down-regulated in glioblastomas, likely through a processing defect. Our results demonstrated that this microRNA inhibits expression of both the EGF receptor and of upstream drivers of the Akt pathway, both important in gliomas. More recently, we have shown that microRNA-7 also targets members of the Notch pathway and inhibits Notch activity. Delivery of this microRNA inhibits glioma cell viability and invasiveness, for both established cell lines and tumor stem cell lines. We are now further exploring the biological relevance of microRNA-7 and testing its potential as a therapy in preclinical models.
2) Investigation of other microRNAs down-regulating Notch. We have also identified other microRNAs that diminish Notch activity, and one in particular shows promise as a Notch inhibitor and glioma therapy. Interestingly, Notch suppresses expression of this microRNA, suggesting a feedback loop. Like microRNA-7, expression of this microRNA is down-regulated in human glioblastoma samples relative to normal brain. Delivery of this microRNA is very effective versus glioma cells in vitro, and we will test its in vivo use.
3) MicroRNAs downstream of Notch. We have performed microRNA microarrays to investigate microRNAs regulated by Notch that may act as potential mediators. The results not only promise to shed light on the biology of the Notch pathway, but are also revealing other microRNAs with therapeutic potential according to our initial experiments.
4) Application of an alpha-secretase inhibitor as a novel Notch inhibitor and glioma therapy. Notch activation requires two enzymatic cleavages, one by an alpha-secretase and one by a gamma-secretase. Gamma-secretase inhibitors have been explored as Notch inhibitors, but alpha-secretase inhibitors have not. In this work we are developing an alpha-secretase inhibitor, INCB3619 (Incyte Corp., DE), as a novel Notch inhibitor and anti-glioma agent.