Aberrant epigenetic alterations are important mechanisms in the development of human cancers. The misregulation of histone deacetylases (HDAC), which often leads to the silencing of gene expression, is linked to cancer progression and research in recent years has focused on reversing these changes in gene expression through inhibition of HDACs. Clinical use of several HDAC inhibitors (HDACi) shows promise towards treatment of a variety of cancers, but these agents are less effective as monotherapies in solid tumors, highlighting the need to find rational combinations of chemotherapeutic agents for the treatment of these tumors. The objective of this application is to identify an effective therapy for glioblastoma, a particularly aggressive type of brain tumor with poor prognosis, that targets a combination of histone modifying enzymes and understand the mechanism(s) by which inhibition of these enzymes enhances tumor cell death. Based upon our preliminary data which demonstrate that combined inhibition of HDACs and LSD1 in glioblastoma cell lines leads to enhanced apoptotic cell death, we hypothesize that LSD1 and HDACs regulate the expression genes involved in apoptosis and inhibition of LSD1 and HDACs leads to changes in gene expression to enhance tumor cell death in vitro and in vivo. The hypothesis will be tested by pursuing two specific aims: 1) Determine the mechanism(s) by which inhibition of LSD1, by knockdown and pharmacological inhibitors, in combination with HDACi promotes apoptotic cell death and, 2) Evaluate the therapeutic effects of the combination of LSD1 inhibitors and HDACi in a glioblastoma mouse model. For the completion of Aim I, targeted array-based qPCR will be used to identify changes in pro- and anti-apoptotic genes that are regulated by LSD1 and HDACs. The involvement of the identified genes in the apoptosis induced by HDAC and LSD1 inhibition and how HDACs and LSD1 regulate these genes will be assessed.
For Aim II, we will use an intracranial xenograft model of glioblastoma to evaluate the efficacy of combined HDAC and LSD1 inhibition in vivo and evaluate the mechanism(s) of apoptosis as defined by Aim I. These studies will provide a greater understanding of how apoptosis is regulated in glioblastoma which will enable us to develop more effective therapies for the treatment of this deadly disease.
The proposed studies address a research area that has largely been unstudied and focuses targeting the epigenetic modifying enzymes LSD1 and HDACs in glioblastoma, a particularly malignant brain tumor. This research is relevant to public health because understanding the fundamental mechanisms underlying the function of pharmacological inhibitors of chromatin modifying enzymes will enhance our ability to better clinically treat glioblastoma and possibly extend the life expectancy of patients diagnosed with this deadly disease.
|Singh, Melissa M; Johnson, Blake; Venkatarayan, Avinashnarayan et al. (2015) Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. Neuro Oncol 17:1463-73|
|Singh, Melissa M; Howard, Adrienne; Irwin, Mary E et al. (2012) Expression and activity of Fyn mediate proliferation and blastic features of chronic myelogenous leukemia. PLoS One 7:e51611|
|Singh, Melissa M; Manton, Christa A; Bhat, Krishna P et al. (2011) Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol 13:894-903|