David Bowtell, Ph.D.; Peter MacCallum Cancer Centre, Melbourne, Australia, Australian Ovarian Cancer Study

Our study started off by creating a bioresource in a strand of Ovarian Cancer Study. This was kicked off by an OCRP program grant in 2001, and that allowed us to recruit women with ovarian cancer. We had promised that we would recruit 1,000 women, and in the end, we recruited 2,500 women with ovarian cancer, either benign, borderline, or invasive cancers.

Over the last nearly 10 years, we've followed those women in terms of how they've progressed with their disease. Some have been cured, and some, sadly, have died. What we have done is use that study as a foundation resource to really try to address three main areas of ovarian cancer research broadly. One is to look at environmental risk factors. The second is to look at new genetic risk factors, so identifying new genes that are involved in ovarian cancer risk. The third, which I'm particularly involved in, is to understand molecular changes that occur in a cancer cell that really determine how it grows and how it responds to therapy. We've made some, I think, very important discoveries in each of those three areas. One of the most significant findings, I think, for us is that we've found that serous ovarian cancer, which is the most common histotype, account for more than two-thirds of the invasive cancers. Not just one disease-there are in fact two main subtypes. The most common subtype, called Type 2, splits into four different molecular subtypes, each with different clinical outcomes. So what we are trying to do at the moment for those four subtypes is understand what drives them, what makes them respond differently to chemotherapy, and why do some woman with some of these subtypes have the disease progress rapidly while others have a indolent course of the disease and a longer period of disease-free survival and overall survival.

We want to know why it is that there are 20% or 30% of woman who when they're treated with first-line treatment relapse very quickly after that treatment is finished. So that's primary resistance. We also want to understand in the majority of women who have a good response to therapy originally, why when the disease returns, or if it returns, do they start to develop a resistance to chemotherapy and no longer respond to it. This is acquired resistance.

Another area we are very interested in is looking at the DNA copy number changes that occur in ovarian cancer, and these are very profound, particularly in serous cancers. We found one locus in particular, one region on one chromosome, that when it's amplified women fail primary treatment. So we have now just recently shown that involves a cell cycle gene called CyclinE, and what we are trying to do is understand how that determines primary treatment failure. If we can understand that better, the idea then is that when women present for treatment, if we find that they carry this gene amplification, we may decide then to direct them to a more specific molecularly targeted therapy given their very high likelihood that they are going to fail for first-line treatment.

So OCRP was absolutely pivotal to establishing the strain of Ovarian Cancer Study. They funded us with a program grant back in 2000, and that really created the funding to build this wonderful biospecimen and clinical data resource, and that can be accessed by anyone, anywhere in the world through a structured application. So it's an enabling resource, a unique, enabling resource for research worldwide. That's the first thing. The second thing is, as we generate our data, we're putting that data in public domain. We created the largest gene expression data set funded by OCRP back a couple of years ago, and that led to the work on molecular subtypes. That data is now in the public domain and is probably one of the best data sets for gene expression in ovarian cancer. We've done the same thing with our copy number data that now is in the public domain.

I think what was so impressive about the OCRP was that although the investigators, including myself, had very strong track records as researchers, we didn't have such a strong track record in ovarian cancer. So OCRP was willing to back our proposal and our track record and see whether we would deliver. Happily, we delivered in spades. Their willingness to take a bet on us, I think, was very important. Just like the OCRP, we find the best research wherever it lies, and we develop partnerships. It's the fun thing about doing research is to have these international linkages and move the research along quickly.