Exploring the "Dark Matter" in Prostate Cancer Genomics

Mark A. Rubin, MD

OncLive: What are the implications of genomic studies in prostate cancer for the development of new therapies?

Mark A. Rubin, MD, is an expert in prostate cancer genomics and pathology who has led key discoveries in the distinction between indolent and aggressive types of the malignancy. He is the Homer T. Hirst III Professor of Oncology in Pathology and a professor of Pathology in Urology at Weill Cornell Medical College. He is also founding director of the Englander Institute for Precision Medicine.Rubin: The focus has long been on the androgen receptor, so obviously there are a lot of drugs that have been developed for the androgen receptor and they are incrementally improving in their ability to bind to the ligand to actively target androgen receptors.

So that continues, but now the emerging alterations are defining other strategies. One of those would be that, if you know whether somebody has a DNA repair mutation, those patients may be more amenable to PARP inhibition.

PARP inhibition creates a synthetic lethal situation because you have a defect in homologous DNA repair and now you give them a drug that prevents non-homologous endjoining, so you’ve hit both aspects of DNA repair, leading to cell death. A clinical trial recently showed a benefit of PARP inhibitors in patients who tend to have DNA repair mutations in this advanced setting.

There also are novel agents targeting Wnt signaling, which has been used in colorectal cancers that are known to have alterations in this pathway. Now we have identified a subset in prostate cancer patients with these defects.

Another area that's really in early development would be a subset of patients who develop a type of advanced cancer that’s no longer responsive to the androgen receptor and that’s called neuroendocrine prostate cancer.

What are the main unanswered questions and obstacles to understanding the prostate cancer genome?

Our group and others are targeting some of the driving factors in this type of prostate cancer, including n-MYC (not c-MYC) and the aurora kinase. So I think we are starting to see small fractions of prostate cancer with very specific drivers, and drugs are being developed against those.The prostate cancer genome is complicated because, unlike some other cancers, most of the alterations are not point mutations, but are in the structural rearrangement of the genome. We showed that in the first whole-genome sequencing study that we did a few years ago.

How has our understanding of prostate cancer evolved from these genome sequencing studies?

Understanding prostate cancer genomics requires understanding whole-genome sequencing of those tumors, which is much more complicated and is really not part of clinical care at this point. That would give some additional insight, we believe, into the noncoding alterations that are potentially affecting prostate cancer progression. That’s been referred to as “dark matter” that may, in fact, play a role in disease risk and also in disease progression.Some of the alterations were known prior to these studies. For example, the common ETS rearrangements were known before the advent of next-generation sequencing and it was known that PTEN loss was common.

But I think the whole-genome sequencing now has provided us with a snapshot of the landscape of mutations in localized disease and, more recently with the Stand Up to Cancer study, we now have a good picture of what prostate cancer looks like when it has been treated. I think continuation of these studies will just flesh out some of the less common alterations, but we have a good idea of what the main alterations are.

Now I think we’ll need to learn more about some of the other components, such as the structural changes you see in whole-genome sequencing, and then also changes in the epigenome, so looking at the epigenetic changes through methylation and other alterations.

What can we learn from how patients fail or respond to certain drugs?

In the context of precision medicine, as patients are treated we anticipate finding new sets of mutations and alterations that confer resistance to drugs. That will be very important, and I think that’s sort of the next area we’ll be focusing on.I’m interested in particular in neuroendocrine tumors. We have an ongoing clinical trial where we’ve targeted patients with this type of disease. I think we’re learning that only a small percentage respond and we’re trying to understand the mechanism for why those patients respond and how to identify those patients early on. In those who don’t respond, obviously we want to find other therapies for them.