2014 PCRP Investigator Vignette

Title: Global Characterization of Protein-Altering Mutations in Prostate Cancer

Investigator: Peter Nelson, MD; Fred Hutchinson Cancer Research Center

So the current funding grants from the CDMRP have focused in two ways. One of them was really designed to take advantage of the newest technologies in genome sequencing. The proposal was designed to identify all of the mutations or alterations in the genetic alphabet of a prostate cancer cell or a prostate tumor. Primarily, we focused on those prostate cancers that had spread or metastasized to distant sites like the bone and lymph nodes.

So it's been a joint project with Jay Shendure at the University of Washington, who was one of the pioneers in this next generation sequencing. So, the idea was to take advantage of this to comprehensively look in prostate cancers to identify the mutations—those changes in DNA that were responsible for activating cancer genes or oncogenes, or inactivating tumor suppressor genes. And we had the opportunity to look both at localized prostate cancer and, importantly, metastatic prostate cancers through what was called a rapid autopsy program at the University of Washington.

The preliminary data that emerges is that prostate cancers seem to have a far fewer number of mutations than many other cancers that we deal with. But, interestingly, we found a subset of these prostate cancers that were hyper-mutated; they had about 10 times as many mutations as the average prostate cancer. It looks like there's a genomic mechanism that leads to this instability. There are several genes that are sort of gatekeepers, if you will, for correcting mutations and not letting them happen. And so what we found is that these genes are disrupted in these hyper-mutated prostate cancers. So we have a clear mechanism for why it happens, but again we don't yet know, clinically, what the importance of it is going to be. We may be able to exploit that because you might anticipate that these genomes are unstable and might be susceptible to certain types of chemotherapy. And so that's what we're now starting to study.

So we did find in this project that there were mutations not unexpectedly in the androgen receptor and other genes in the androgen receptor pathway. And so that overlapped or segued with the other proposal that's been funded by the CDMRP, and this one is designed to understand how prostate cancers can eventually bypass the need for this very strong molecular engine, the androgen receptor, anticipating that the field will eventually effectively eliminate the androgen receptor but won't still cure prostate cancer. And so we want to understand what those drivers are, and we've identified several that we hope can be exploited in the future as therapeutics for those prostate cancers that eventually progress on the newest androgen receptor targeting agents.

So we think it's going to be a problem. It's not yet a problem, because right now we still need to focus on the androgen receptor because we haven't completely ablated it, but we're anticipating that the field collectively will ablate the pathway, will successfully block this engine, and we want to be ready with the next wave of therapeutics designed to eliminate the bypass. So that's what the second project has been about.

The CDMRP, the DoD Prostate Program has a special place, and I think having an emphasis on innovation and being willing to take a risk is very important, and that attitude is embodied in the grant reviewers. So certainly, those of us that sit at the table, reviewing these grants, put that at a very high level. We don't want to just look at the next incremental advance. And so when we're reviewing these proposals, that's at the forefront of the thinking. So we'd rather take a risk on something that really may not work but has the potential that if it does work, it's going to change people's thinking or catalyze a more rapid advancement rather than something that just looks like it's going to be a small step forward.