The following commentary is provided courtesy of Dr. Oren J. Becher.
Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models
Tammy Hennika , Guo Hu , Nagore G. Olaciregui, Kelly L. Barton, Anahid Ehteda, Arjanna Chitranjan, Cecilia Chang, Andrew J. Gifford, Maria Tsoli, David S. Ziegler, Angel M. Carcaboso, Oren J. Becher
Published: January 4, 2017 in PLOS ONE. http://dx.doi.org/10.1371/journal.pone.0169485
This collaborative pre-clinical study that originated in discussions held at the recent Pediatric Infiltrating Glioma meeting in London, 2016 confirms and extends previous observations by Monje and colleagues regarding the efficacy of panobinostat in DIPG in additional models. We observe that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro (when the DIPG cells are grown in isolation in a dish) and in short-term in vivo efficacy studies in mice (when we measure the effect of panobinostat on tumor cell growth after delivering only a few doses of drug to DIPG-bearing mice). Importantly, we observed that panobinostat does not significantly prolong the survival of mice bearing H3.3-K27M-mutant DIPGs when it is administered systemically. The lack of survival benefit observed with panobinostat is likely related to toxicity observed associated with systemic administration of panobinostat that necessitated dose de-escalation.
This study is important because it highlights the challenge of identifying an effective drug for DIPG. We are looking for a drug that can be administered to children at a dose so that sufficient drug can reach the tumor cells in the brainstem to induce their death while at the same time, the drug cannot be too toxic to the normal cells both near and afar. As panobinostat is being evaluated in children with DIPG, it will be important to determine how much drug can reach the tumor cells of a child with DIPG without causing excessive toxicity to all the normal cells of the child. Furthermore, an added complexity is the intratumoral heterogeneity (tumor cells are different within a single DIPG tumor) and intertumoral heterogeneity (tumor cells are different between different DIPG tumors) of the human disease, which is why it is important to test a large number of preclinical models. It is likely that only therapies that prolong survival dramatically (not just by a few days in mouse models) at an intratumoral drug level that can also be safely achieved in children, have a good chance of prolonging survival in children with DIPG.