A variety of approaches to measure the efficacy of PARP inhibitors

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Published: 25 Apr 2018
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Dr Elisabetta Leo - AstraZeneca, Cambridge, UK

Dr Leo speaks with ecancer at AACR 2018 about results from a head-to-head comparison of five PARP inhibitors using a novel proteomic assay.

Having compared the approvals, mechanisms and doses of olaparib, veliparib, rucaparib, niraparib and talazoparib, Dr Leo highlights the potential for predicting responses and assessing novel PARP inhibitors.

For more on PARP inhibitors, watch our interview with Dr Mark O’Connor here.

I worked on DNA repair and DNA replication. I started working on the PARP inhibitor mechanisms of action when it was in ? lab, and then I moved to the MD Anderson Cancer Center within a biotech company that is embedded in the cancer centre.

Tell me about your recent research?

I am really proud to say that I developed a novel PARP trapping assay to be able to quantify and measure in a much more accurate way the ability of PARP inhibitors to trap PARP on the DNA on the chromatin. This is in cell lines.

What is the novel proteomics approach?

This is something that was done by my colleagues and it’s a proteomic approach that is based on chromatography and it’s a new chemical proteomics that is able to measure the ability of one PARP inhibitor to bind to different PARPs. Because we know that the major anti-cancer effect is given by inhibiting PARP1 but PARP is composed of a family of seventeen PARP members and we wanted to profile the number of PARPs within the family that are bound to each PARP inhibitor.

Tell me about the secondary pharmacology aspect?

Absolutely. There are other cytotoxicities, other general toxicities in the clinic that we observe specifically for, for example, niraparib or rucaparib. We did a screening to check whether there were some off-target effects not within the PARP family, so whether these PARP inhibitors targeted other components in the body, other proteins that are present in the body. What we saw, strikingly, is that niraparib in particular has a very high affinity for a transporter of serotonin, dopamine and other neurological signalling proteins. Although at the moment this is really a biochemical test it’s not unreasonable to think that this could be correlated to effects like insomnia that are specific for these PARP inhibitors and not for others.

You observed the bone marrow to look for toxicity, how did this work?

What we measured is basically the fact that in the clinic we observe certain toxicities and the preliminary toxicity is the haematological one. So we noticed that several PARP inhibitors are more toxic than olaparib but in an in vitro assay we couldn’t see these differences. So we wanted to check, in vivo whether there was a reason for this clinical observation. What we did was we tried to test if the compounds, the different PARP inhibitors, had a different way of distributing inside the rat body, the body of the rat. Basically what we saw is that olaparib does not go into the bone marrow so the accumulation in the bone marrow is very limited compared to the plasma distribution whereas the other PARP inhibitors, in particular talazoparib, niraparib and also rucaparib to some extent, they accumulate into the bone marrow and we believe that this is the reason for the increased cytotoxicity specific for the haematological component.

Why is there such an important multidisciplinary aspect?

I have to say that although I’m very proud to report this I am actually just a spokesman and this work was done by a team that is global because basically we are based in Cambridge, UK, but part of the team is based in Boston, in Gatehouse Park in Waltham actually, in the US. Most of the time we have virtual meetings and we really feel that every component, every person from this multidisciplinary approach team brought to this virtual table their possible best and this is why this is really a team work that is multidisciplinary and multi-global.