Photo by Bo Jungmayer / Fred Hutch
[Editor's note: This is an update of a February 2017 Q&A with Dr. Amanda Paulovich.]
Proteomics expert Dr. Amanda Paulovich of Fred Hutchinson Cancer Research Center is speaking Wednesday at the annual meeting of the American Association for Cancer Research about her team's work to make the genome actionable for cancer patients using targeted proteomics.
Earlier this year, Paulovich was tapped by federal agencies to create a panel of tests to measure key proteins that can serve as markers for tumors. Part of former Vice President Joe Biden’s Cancer Moonshot initiative, the effort could ultimately lead to treatments that are more specifically targeted to a patient’s distinct type of cancer.
We asked Paulovich six questions about proteomics: Why we should care, what she’s working on, and what she’s excited about.
I think most people are unfamiliar with the word proteomics. What does that mean?
Our genes ― or DNA ― provide a blueprint that our cells use to manufacture proteins, which carry out most of the biological functions of our cells and bodies, and which are commonly targeted by cancer drugs. Proteomics is simply the study of proteins. There’s a great sports analogy from Joe Biden to describe this. He said that genes are the roster of who’s on your team, and the proteins are the players from the roster that are the starting lineup.
So it’s advantageous to be able to directly measure the amount of a protein that a patient’s cancer has in it, because it’s that protein that’s going to interact with drugs that we treat the tumor with, most of the time.
You’re an oncologist by training. How did you get into proteomics?
When I was treating cancer patients and writing orders for therapy, the variation in clinical response amongst my patients was dramatic. One patient would respond [to the chemotherapy], and the next patient ― with what looked like the same tumor ― wouldn’t respond, and might have a lot of toxicity caused by the treatment. So it became an ethical dilemma: You’re a physician, you’ve taken an oath to do no harm. And the best thing to do is to make an educated guess, based on average patient responses, about what treatment the patient’s tumor is going to respond to when you’re ordering potentially toxic chemotherapy.
I did a postdoctoral fellowship in genomics. … The idea was, this genomic revolution was occurring, this is great, you should be able to use genomic methodology to solve this … It turned out that there was no good signal at [that] level for what I was trying to look at, but there was a good signal at the protein level. … I knew I needed to be studying proteins, and then I looked around and I was shocked to realize that the 50-year-old technologies widely used to measure proteins just don’t work very well! As a result, the proteome’s not clinically accessible! And someone had to do something about it.
At the same time, … the National Cancer Institute was saying, we need standardized methods [for proteomics] and to figure out what is and isn’t reproducible. I had the good fortune to come to the Hutch right when that was happening, fortunate enough to become part of that NCI program in 2003.
You mentioned that the proteins in the human body are “not clinically accessible.” Can you explain that?
The vast majority of human proteins have no reliable standardized way to measure them. You can’t study how a drug works and which patients it works in if you can’t reliably detect the protein that the drug binds to and its effects on the tumor cells. And so it makes it difficult or impossible: Difficult if you’re going to try to start from scratch and build an assay ― and most people use these 50-year-old technologies that are very messy and not very reliable. Also, many don’t have the time, funding and/or expertise even to go build an assay. Lots of exciting biology is not pursued due to a lack of tools like assays. The proteome is full of dark matter that can’t be easily studied. You’re just stuck. You can’t study this. So that’s what I mean by inaccessible.
This sounds like a big problem. How have you worked on solving it?
What we’ve done is to develop a [proteomics] technology that is enabling. We’re developing community resources of standardized reagents and methods for detecting and measuring cancer-relevant proteins that should help to alleviate that problem. They’ll actually enable people to look directly at the targets of the drugs and not try to infer what those protein targets are doing based on a DNA sequence.
This new Cancer Moonshot project you’re part of is called the Applied Proteogenomics Organizational Learning and Outcomes, or APOLLO, Network. What for you is the most exciting thing about APOLLO?
APOLLO is one of the first opportunities to move the technology out of the preclinical space and into clinical trials. That’s a major inflection point that we’re just about to embark on over the next year.
In the preclinical space, you’re helping to get treatments developed, and in the clinical space, you’re hoping to better match patients to treatment. As we’ve rolled out the tools to solve this [proteomics] problem in the preclinical space, we’ve had success: We’re getting better data, better characterization of drugs before they move into clinical trials. But of course, if we can get even closer to the patients, that’s all the more rewarding. That’s what we’re going to find out.
Once you solve this problem, will you go back to treating patients as an oncologist? Because you won’t have that ethical dilemma anymore.
I think that’s kind of far down the line. I don’t know the answer to that.
I miss patient care a lot. I really loved patient care, and in fact it was up there as one of the two hardest decisions in my life to finally have to give that up. I didn’t feel comfortable taking care of sick patients part-time, while trying to develop a disruptive technology and run a competitive research program at that level. … If you’re taking care of the walking well … something where you see patients half a day per week at the clinic for follow-ups, that’s fine, but taking care of sick patients, giving them chemotherapy, I didn’t want to do that that part time.
But it’s exciting to me to partner with folks doing clinical trials, both in pharma and in academia, to try to help out with advancing precision oncology by providing a platform to measure proteins. … There’s a lot of really smart people writing and running clinical trials; there aren’t a lot of oncologists who are experts in measuring proteins. So I think there’s something unique that I have to offer there.
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Susan Keown is a staff writer at Fred Hutchinson Cancer Research Center. Before joining Fred Hutch in 2014, Susan wrote about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at firstname.lastname@example.org or follow her on Twitter at @sejkeown.
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