Exth-35. in Vivo 1h Mrs Detects Reduced 2hg Production in Idh1 Mutant Gliomas Treated With a Dual Pi3k/mtor Inhibitor
Year: 2018
Type: conference-abstract
Abstract: 70–90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase (IDH1mut). Mutant IDH produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis. Inhibitors of phosphoinositide-3-kinase (PI3K) pathway are currently under clinical investigation for IDH1mut gliomas with positive outcome results, but early response imaging biomarkers are missing. The goal of this study was to identify potential magnetic resonance (MR) detectable biomarkers of IDH1mut glioma response to the dual PI3K/mammalian target of rapamycin (mTOR) inhibitor XL765. We used two genetically-engineered IDH1mut models: a U87 glioblastoma-based model (U87IDHmut) and an immortalized normal human astrocyte-based model (NHAIDHmut), as well as a patient derived IDH1mut model (BT142). The reduction of PI3K/mTOR pathway signaling was validated with western blots of p4E-BP1 for all models. We then used MR spectroscopy (MRS) to investigate the impact of treatment on cell metabolism. Using 1H-MRS, we observed that XL765 induced a significant ~70% and ~50% reduction in steady-state levels of 2HG and glutamate in U87IDHmut while in NHAIDHmut the drop was ~90% and ~70% for 2HG and glutamate respectively. In the case of BT142 there was a ~35% drop in glutamate levels while 2HG was MRS undetectable in both groups. The translatability of our findings was evaluated in mice bearing orthotropic U87IDHmut xerographs treated with XL765 orally twice a day. XL765-treatment of mice led to an apparent slower tumor growth, which was associated with significantly increased animal survival. Importantly, in vivo 1H-MRS spectroscopy showed a significant reduction in 2HG levels. The results were verified by 1H-MRS of tumor extracts. Collectively, our results indicate that treatment with XL765 is associated with response in IDH1mut models. To our knowledge, this is the first time in vivo 1H-MRS detected reduction in 2HG in gliomas undergoing treatment with a non-IDH1mut-specific inhibitor. Thus, 2HG could potentially be used as a response biomarker.
Source: Neuro-Oncology
Institution: University of California, San Francisco
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2899882919