Dipg-61. Histone Deacetylase Inhibitor Panobinostat Synergizes With Dual Mtor Inhibitor Tak228 to Potentiate Killing of Dipg Cells
Year: 2018
Type: conference-abstract
Abstract: We have previously identified activity of the brain-penetrating dual TORC1/2 kinase inhibitor TAK228 (MLN0128) in DIPG. Currently, HDAC inhibitor Panobinostat is in clinical trials in patients with DIPG and is also known to synergize with mTOR inhibition in other cancer types. We hypothesized that TAK228 and Panobinostat would synergize to increase killing of DIPG cells. We found that each drug was effective at low nanomolar doses in JHH-DIPG1, SF7761, SU-DIPG-13 and JHH-DIPG16A. SF7761 and JHH-DIPG16A are derived from pre-treatment biopsies while SUDIPG13 and JHH-DIPG1 are derived from autopsy samples. Panobinostat increased H3KAc27 in all cell lines at low nanomolar doses. TAK228 also inhibited both TORC1 (pS6) and TORC2 (pAKT) at low nanomolar doses. Combination therapy caused a fivefold increase in cleaved PARP as measured by western blot within 24 hours of incubation in all cell lines. We used immunofluorescence to measure cleaved caspase 3 and found 40 percent increase in this marker of apoptosis as well (p<0.01 by ANOVA). Because both agents have a short half-life in mice, we hypothesize that an altered dosing scheme may be feasible to take advantage of the rapid induction of apoptotic synergy caused by dual treatment. Due to the promising synergistic effects in multiple DIPG cell lines in vitro, tests of efficacy in vivo using DIPG cell lines are currently underway.
Source: Neuro-Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2809027888