The role of PARP2 in inhibiting prostate cancer

The paper we presented last year in PNAS is mainly focussed on PARP2 but, as we know, PARP inhibitors have been very popular now especially in prostate cancer and two US FDA approved PARP inhibitors have been used in clinic right now. But those PARP inhibitors are mainly focussing on the DNA repair function of PARP1 and PARP2. But, as we know, the PARP family has 17 members and each of those proteins have different functions even beyond the DNA repair function. Some of the functions don’t even rely on the PARP enzymatic activity.

As we looked at all 17 members in prostate cancer clinical samples, what we found was that PARP2 particularly is highly expressed in prostate cancer, even higher in castration resistant prostate cancer. This was true in all publically available prostate cancer databases but also we have done tissue microarray using over a thousand clinical samples in-house and we found PARP2 protein levels are much higher in castrate resistant prostate cancer. A further study actually shows PARP2 is required for prostate cancer growth, specifically for CRPC prostate cancer cells.

Then we did a further analysis and what we found is PARP2 actually is very important for androgen receptor signalling. It’s involved with AR-mediated transcription through FOXA1. What we found in this paper is PARP2 actually interacts with FOXA1 which affects the androgen receptor recruitment to the chromatin and mediated transcription.

So targeting PARP2 through either genetic or pharmacologic means actually we can inhibit prostate cancer growth and shut down AR signalling. We think this is a somewhat unique function for PARP2 beyond DNA repair. So targeting PARP2 actually can be used potentially in future clinical work when AR-directed targeting fails. So this is an alternative therapeutic approach we think potentially can be of benefit for those lethal castration resistant prostate cancer. So this is the main discovery now in our papers.

Are there inhibitors being studied that specifically target PARP2?

Yes, there are a couple of selective PARP2 inhibitors in the literature and we tested those inhibitors. Actually they work very well in vitro, basically they inhibit AR signalling, also inhibit prostate cancer growth. But I still think those compounds are not potent enough to be used in vivo so we are currently developing more potent compounds based on those lead compounds and try to modify to get a better, a more potent and a more selective, PARP2 inhibitor.

An interesting thing is that current clinical use of those pan-PARP inhibitors do not work very well in terms of how they inhibit AR signalling and prostate cancer growth.

What are the differences between PARP1 and PARP2?

Basically PARP1 is the most studied PARP protein in the whole PARP family. Both PARP1 and PARP2 play a major role in DNA repair, especially those single strand breaks, but PARP1 accounts for 90% of PARP enzymatic activity in cells but PARP2 only accounts for around 5-10%. But PARP2 has some unique functions different from PARP1. For example, PARP2 has been shown to play a major role in some transcription regulations. That why in our studies we found this PARP2 but not PARP1 played a specific role in AR-mediated transcription and targeting PARP2 is very important and potentially can be a very important drug target for prostate cancer as we know androgen receptor signalling is a major target for prostate cancer.

What are your thoughts on the use of PARP inhibitors to treat metastatic prostate cancer?

So the current PARP2 are actually mainly based on the so-called synthetic lethality. In prostate cancer patients those cells contain BRCA1 and BRCA2 mutations or homologous recombination DNA repair defects and those cells are supersensitive to PARP inhibitors. But the problem is how can we identify patients who benefit from PARP inhibitor treatment? So the main issue is a biomarker – can we identify a biomarker so we can use this targeted therapy? Currently only BRCA1 and BRCA2 is a reliable biomarker. Of patients with those mutations about 60% patients will respond to a PARP inhibitor but we need to find a better biomarker. Also we need to understand the resistance mechanism because both de novo and acquired resistance to PARP inhibitors develop very quickly. So we need to better understand those mechanisms so we can use those PARP inhibitors to treat patients much better than we currently use.

How can you see them being used to treat prostate cancer in the future?

I think there’s a very bright future as it looks very promising. The only thing is, as I mentioned, we need to try and identify those patients most benefitting from those treatments. But, as we know, the PARP inhibitor is well tolerated in patients. Also, this kind of therapy can be used in combination with other therapies, for example immunotherapy or anti-androgen treatment. So there are a lot of combinations have been used in clinical trials by now. I think in the next couple of years we will see more positive results from those trials and we can actually use those PARP inhibitors in a broader range for more patients.

What research needs to be done in this area?

We need to understand better about all the PARP proteins because, as I mentioned, there are 17 members so each of those members they play a different role. As we looked at those protein expression levels in prostate cancer samples we found some of them highly expressed but some of them downregulated. Also a lot of those PARP proteins their function we still don’t quite understand. Current PARP inhibitors are mainly focussing on PARP1 and PARP2 but I think in the future we need to focus more on this whole family. There are a lot of things we need to understand.

Is there anything else you would like to add?

This field overall is booming, it’s a really exciting area. Actually I should mention PARP inhibitor targeted therapy actually is considered a true targeted therapy because the patients are selected. So it’s different from other treatments currently available for prostate cancer, those are unselected patients. This kind of direction for the future of prostate cancer treatment, we talk about precision medicine and personalised medicine. So we need to identify a better genetic functional biomarker for all kinds of different targeted therapies.