In their previous work, Pacey and Dev have assessed the effects of giving an approved potent inhibitor of PARP enzymes, to patients for two weeks prior to prostatectomy. Half of these participants were also randomly allocated to an anti-androgen hormone treatment, which lowers testosterone levels. Analysis of biopsy and prostatectomy samples showed that inhibiting PARP enzymes contributes to a significant impact on the cancer cells even in some patients with no known gene mutations such as BRCA2.

The researchers found molecular evidence of drug effect in prostate cancer cells. The study also revealed several unique effects of combination treatment that were not as strongly observed with the PARP enzyme inhibitor alone, or in a separate study involving anti-androgen therapy. This includes changes in the expression of various pathways, including those involved in cell turnover and inflammation; these could help to explain why the combination treatment may be effective in a wider group of patients.

Crucially, both experimental treatments were well tolerated by all participants and had no impact on their planned operations or subsequent recovery.

NICE (the National Institute for Health and Care Excellence) recently approved the utilisation of the PARP enzyme inhibitor with drugs that block testosterone effects in patients with metastatic prostate cancer. Dev and Pacey want to understand this better and to see if the treatment could be repurposed at earlier stages of prostate cancer, to help many more men.

“Why would individuals without those DNA repair gene defects benefit from a therapy that works entirely through that mechanism? That’s what our lab is working on.”

^{Harvey Dev}

“We’re interrogating the genetic drivers that underpin these processes and we've identified a few candidates that we think are important. We’re looking into novel markers which could be unrelated to the cascade of functions that BRCA is involved with but which we think are functionally relevant to how these drugs cooperate.”

The androgen receptor, the main hormone driver in cancer cells, is somehow contributing to the DNA repair process and it is through the combination of targeting that pathway and boosting the sensitivity of cancer cells to treatments that Dev and Pacey believe a breakthrough could be made.

Dev says: “As we start to validate our findings, we can go back to patients and look for those markers and see whether we've now identified another group of individuals who would benefit from combination treatment.”

Pacey says: “For clinical trials to work best, you need collaboration with a translational lab like Harvey’s, critically supported by patients who wish to take part. Working with Harvey focuses the mind. We all have a shared interest in DNA repair and we’re looking for opportunities to convert discoveries in this area into developing effective treatments.

“We’re in a great place on this campus. It is quite unique that we can bring together surgery, radiotherapy, oncology, pathology and radiology experts to develop treatments for earlier onset patients to help them live much longer. And we’re right next to the biopharma company, AstraZeneca, which is world class at developing PARP inhibitors and DNA repair inhibitors.”

Pacey focuses his efforts on drugs in early development because, he says, they “offer a sweet spot to do something impactful in the lab and make a difference down the line for patients. I like what I do because the small scale of the studies makes it agile.”

Both Dev and Pacey can’t emphasise enough the importance of collaborating with trial participants like Andrew Pickering.

“We currently don't have great models for prostate cancer. The best model is human cancer itself."

^{Simon Pacey}

"So we rely on these pre-surgical, window-of-opportunity studies. We rely on our patients giving us their time completely altruistically. My job is then to design a study to answer key questions while minimising the risk of side effects. I can’t get that risk down to zero but that’s what I’m aiming for so that men can undergo their planned surgery on time.

“We've got a really good track record in Cambridge of recruiting men to take part in these window studies, which is no small feat because the team might have to approach 200 men to recruit just 20.”

Andrew says: “During the trial you are monitored very closely. Even if the trial drugs had side effects or were found to be harmful in any way at all, I'm certain that it would be picked up very quickly and addressed. Having that attention is really reassuring. The care given by the doctors and nurses, who are working as part of the trial team, is second to none.”

Dev adds: “Most of what we do wouldn't be achievable without patients volunteering for the benefit of others in the future. It hits me with every patient interaction that we need to work fast to make a clinical impact now, rather than in 20 years’ time. This motivation really feeds into the very DNA of our new Early Cancer Institute. Physicists, engineers and mathematicians continue to make critical contributions to our research but we are also heavily and unapologetically clinical, and extremely aware of the need to accelerate our research efforts to help the very patients that we see every day.”