CPC-GENE: Targeting prostate cancer

How can we find better ways to combat prostate cancer? Five years ago a multi-disciplinary, multi-institutional team came together to find out. Their collaborative research has changed the understanding of prostate cancer and identified new ways to better diagnose and manage the disease.

Two decades ago researchers at Princess Margaret Hospital (now the Princess Margaret Cancer Centre) began banking prostate cancer tumour samples from consenting patients about to receive radiotherapy. They suspected the samples could be useful in the future when there was a better understanding of the underlying biology of the disease. What they didn’t realize was that they were building the foundations for the largest prostate cancer genomics research project in the world: The Canadian Prostate Cancer Genome Project, or CPC-GENE.

OICR and Prostate Cancer Canada created CPC-GENE in 2011 (with funds from the Movember Foundation), bringing together a multidisciplinary, multi-institutional, pan-Canadian team to use these samples to find genomic biomarkers that could more accurately diagnose men with prostate cancer. The goal of these markers was to better identify those men with aggressive disease who need intensified treatments beyond just surgery or radiotherapy in order to get better.

... many men could be spared that harmful side effects of radiation and surgery, and men with aggressive cancers can receive the right treatment faster...

Prostate cancer provides a unique challenge for researchers and clinicians. It is the most common cancer in Canadian in men, and the third leading cause of death, but not all prostate cancers are equal. Some are slow growing and will take years before they become lethal (if ever). Others are aggressive and need immediate and drastic treatment. Unfortunately, the tools to define with precision whether a cancer is aggressive or not are still lacking and many men end up receiving sub-optimal treatment. New and more accurate tests are necessary to better direct the right treatment to the right patient.

The CPC-GENE project came to an end in December 2016 and the results have been outstanding. In five years of operation the group sequenced 429 tumour samples from 386 patients and used the findings to better understand prostate cancer and how it develops. Discoveries published in prestigious journals like Nature and The Lancet Oncology have helped the research community better understand the genetic origins of the disease. The group shared their sequencing data with researchers around the world through CPC-GENE’s participation in the International Cancer Genome Consortium.

Most importantly, the team fulfilled their stated mission to develop genomic biomarkers that will help to better diagnose prostate cancer, with two signatures that outperform all the published and clinically approved tests for aggressive prostate cancer.

These signatures are now being tested and improved to enter the clinic, where they could provide a clearer answer of how aggressive a man’s prostate cancer is, and help to guide treatment decisions. The result is that many men could be spared the harmful side effects of radiation and surgery, and men with aggressive cancers can receive the right treatment faster.

We spoke with Drs. Robert Bristow and Paul Boutros, CPC-GENE Co-leaders, and Dr. Michael Fraser, CPC-GENE Associate Director, about the project’s evolution, challenges and successes, and the integral role multi-disciplinary collaboration played in the project’s success.

Paul Boutros, Robert Bristow, and Michael Fraser

What were the biggest challenges of a project this size?

Paul Boutros: Team formation and how new the science was that underlay it. There wasn’t a prostate genomics program in place here in Toronto that this was being built on top of. We were really building it from scratch. We had to reach across disciplines, through bio-banking, computation and genomics. We had to bring together researchers and clinicians.

Michael Fraser: I think getting everyone to pull on the same rope, and all want the same thing, was the most difficult part in the early days of the project, because we were working with very independent researchers but we also needed that unity of vision.

PB: I would actually say the single thing we had to learn the most was trust.

Robert Bristow: And patience.

PB: That interpersonal stuff is more important than anything else.

RB: You have to believe that each component of the team is doing well and the quality of what they are doing is exactly right. Everything that came out from each part of the team had to be high quality and high speed and the team had to put all these bits together.

What was the initial reaction from the research community to your work?

MF: I think it took a while for us to get on the map in the international sphere.

RB: One of the first turning points was getting the reviews back on our first paper and people realizing it was really novel and no one had been able to do it before.

PB: Our first paper to Nature Medicine was actually rejected, with review.

RB: The funny thing is, it also got rejected from Lancet Oncology and we pushed back with a long letter. They asked if the research was really important. I wrote a very strong letter on behalf of the team to ask them to reconsider and say that this really matters and could change patient care.

PB: (Laughing) We have a track record of discussing our work passionately with editors to help them recognize the deep clinical value it brings.

RB: It’s true. But once we got that Lancet Oncology paper there was more awareness of our team and work in the next round of submissions. And that led to far more collaborations with other international teams.

What were the group’s biggest accomplishments?

MF: At the time we started, virtually no one was doing clinical outcome-driven cancer genomics. We knew that we were doing something unique. And now, we can see the next iteration of large cancer genomics consortia like ICGCmed, which is going to do precisely what we’ve done on a much larger scale.

We’ve created a genomic and clinical dataset that has the potential to drive discovery for decades. I can’t tell you the number of times we’ve thrown around novel research questions for CPC-GENE - Dr. Michael Fraser

RB: For me, it’s the fact that we really did the job we said we would do and we did it well. We brought together a team that hadn’t worked together before, and then created a product that could be used in the clinic. Everyone recognizes that the true payback for the investment is a good clinical test that is being used for the problem that we addressed. There are very few scientists or clinicians who get to be involved in something like this and then see it through to the very end – clinical use. It’s almost like the holy grail of doing science.

PB: I am just so proud of the flexibility of the team that we were working with. If you look at us on day one we each had our own skills and beliefs and biases, but over time we just jumped seamlessly into new things. There was a willingness to do whatever it took to answer an important question. It didn’t matter what it was, but once it was decided that it needed to be done everyone pulled together to make it happen.

Why do you think this group in particular was able to work so well together?

MF: Certainly there was good leadership, vision and consensus around why this mattered.

PB: It was always clear that we were doing something important and so people believed in it. But also hiring people who were smart and motivated and would have done well whatever they were doing. And certainly being in a well resourced, collaborative environment like OICR mattered.

RB: Once people see a well-functioning team and you’re able to produce then you become a collaborative choice. We were. We’ve asked for collaborations with other groups and they’ve been very open with giving us data. These are groups that could have worked with anyone, but they chose to work with us.

There are very few scientists or clinicians who get to be involved in something like this and then see it through to the very end – clinical use. It’s almost like the holy grail of doing science. - Dr. Robert Bristow

Looking ahead, what excites you most about CPC-GENE’s legacy?

MF: We’ve created a genomic and clinical dataset that has the potential to drive discovery for decades. Important questions remain, and the dataset to answer them – in time – remains. So not only have we generated exciting data, with huge potential ramifications for the clinic, but we’ve also produced a resource greater brains than ours can interrogate for years to come. What more can you ask from a program?

PB: I’m so excited to see all the CPC-GENE trainees and where they are taking their careers. They are going to be looking into questions that are different from, but related to and inspired by the work that we’ve done, and I think that’s a legacy that we’re going to see for decades. Also, the work that we’ve done has been focused on the intermediate disease risk setting, but I think there are exciting opportunities to see how they are going to apply in other clinical scenarios in prostate cancer. Most importantly, I’m excited about bringing our existing tests into the clinic.

RB: We also now have a worldwide prostate group in which the genomes sequenced in Toronto will be added to those in Germany, Australia and the US. So now we’re going to be able to ask big questions that we couldn’t ask with a smaller cohort. That’s going to lead to even more collaborations and, I believe, to more breakthroughs for patients and more improvements in their treatment.