Exth-39. Preclinical Testing of Dietary Histone Deacetylase Inhibitors on Fresh Fig-ros1 Positive Human Glioblastoma Tissue in Ex-vivo Models
Year: 2016
Type: conference-abstract
Abstract: Experimental evidence has shown the primary reason for treatment failure in glioblastoma (GBM) is signal redundancy due to co-activation of several functionally linked receptor tyrosine kinases (RTKs), oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GBM)-ROS1 and also histone dacetylase (HDAC) activity. Therefore, targeting these functionally linked kinases and HDACs could be useful for GBM therapy. The study consisted of 10 tissue samples from 10 patients who underwent neurosurgical resection of GBM at the Medical University of South Carolina. We established GBM slice cultures (obtained from GBM patients), which can be kept in vitro for at least 10 days. Upon treatment with dietary HDAC inhibitors such as Alliin, Allicin, dially disulfite (DATS), methyl allyl trisulfide (MATS), L-Deoxyalliin (S-allyl cysteine), S-methyl L-cysteine), slices were collected for biochemical analysis. Our ex vivo models demonstrated that 72 hr treatments with 25 µM of 6 HDAC inhibitors induce antitumor activity on FIG-ROS1-positive and elevated levels of lysine 9-acetylated histone H3 GBM cells. Our western blot and activity assay results also demonstrate that combination blockade of HDAC activity and expression of FIG, p-ROS1, p-ALK, and p-Met protein levels augment apoptosis in ex vivo FIG-ROS1+ GBM slices obtained from GBM patients, which mechanistically involves activation of caspase-3. Interestingly, it is important to note that we did not see significant effect of HDAC inhibitors on FIG-ROS1-negative GB cells. Administration of HDAC inhibitors induce antitumor activity in FIG-ROS1-positive GBM cells in an ex-vivo model. Further studies in different animal models of are warranted to determine useful therapies for the management of human GBMs.
Source: Neuro-Oncology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2588959629