1st - 5th Apr 2017
Dr Bindra speaks with ecancer at AACR 2017 about the determination of PARP inhibitor sensitivity in brain tumour cells with IDH mutations
He describes how, from screening of a CRISPR-Cas9 model of mutant IDH cells, synthetic lethality with PARP inhibitory therapy was uncovered.
Dr Bindra highlights the current approval of PARP inhibitors in other indications, and outlines upcoming trials to further explore treatment options.
This story is actually a wonderful example of academia and the beautiful enterprise of being able to pursue anything you want. This was an NIH funded study, especially important in this climate these days, we couldn’t have done this without NIH research. Essentially we had a student that created one of the first CRISPR-Cas models for IDH wildtype mutant cells. We created this model and did a high throughput screen and it was an unbiased screen. We simply asked the question with really no preconceived notions what molecules in the DNA repair and damage space would specifically target IDH mutations.
We came into this really not knowing what we would expect and to our surprise we hit a marked synthetic lethal interaction with PARP inhibitors. From there the story really took off because we realised that this PARP inhibitor sensitivity was actually a signal that the IDH mutations induced an HR defect, essentially BRCAness. So these were no different than BRCA deficient tumours which really was coming out of left field; really many people were in disbelief when we reported this story. It took quite a time for people to really understand that this is truly what’s happening with oncometabolites.
Does this open up a new potential area of treatment?
Exactly, so this is opening up not only a new area of treatment, and that’s because we have FDA approved PARP inhibitors that we can possibly test; this work is all in vivo and in vitro and we’re going to be beginning a trial soon which we’ll be speaking about at this conference here. But not only that but it calls into question one of the main treatment paradigms in place for these mutations. Our study specifically shows that oncometabolites actually drive this DNA repair defect and that when you reverse them with many of the small molecule inhibitors of IDH1 and IDH2 you actually reverse the sensitivity.
We also will be presenting unpublished data today that the IDH1 and IDH2 inhibitors, at least in the laboratory setting in our hands and the hands of many of our collaborators, do not have the effects that have been described previously. So we really call into question the current clinical paradigm and we really ask whether we need to actually consider exploiting the phenotype rather than suppressing it.