“Proteomics and Clinical Decisions”

anel Discussion) [#19] Michael Forster: Proteomics have the ability to monitor proteins and biology and cancer- related changes in real time. The biomarker information you derive in real time is closer to the therapeutic intervention, enabling you to gear therapies better to specific patients. 3.How should proteomics be integrated with other diagnostic tests to guide clinical decisions?

Karin Rodland: If I was doing an N-of-1 research experiment on Brian, I would take his RNA-seq data and the biological processes that had been implicated, and I would use Mandy's targeted proteomic assays, and I would verify which kinases in that pathway are actually upregulated and driving the abnormal behavior in the pathway. 4.What's next?

Kristina Beeler: Complex biological processes are characterized not by just one level of -omics. They need the multi-omics level and current status. Proteins provide essential functional information to understand the true phenotype. Karin Rodland: Looking at Brian as a research project, how do we make proteomics available to him as a research subject?

He has to find a physician and a precision oncology clinical trial to look at all these different molecular measurements and integrate them and get enrolled. Then we will need to address the question that Mandy is trying to focus on: “how do we turn that into the standard of care?

” Amanda Paulovich: You really need partners in large academic centers that are willing to go out on a limb, and centers that are legally adventurous enough and willing to go down that path with you. Unfortunately, it's just hard to do. As Karin said, you're pushing the envelope beyond what standard of care is. We need better diagnostics.

80% of healthcare decisions are based on diagnostic tests, but they account for less than 20% of healthcare costs. Somehow, diagnostics must be valued in the same way that blockbuster drugs are, and they're way way undervalued right now.

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“Proteomics and Clinical Decisions” (Panel Discussion) [#19] Meeting Notes SUMMARY KEYWORDS proteomics, proteins, technology, cancer, patient, question, mass spec, samples, mass spectrometry, genomics, clinical, diagnostics, clinical trial, liquid biopsies, data, oncology, fred hutch, reproducibility SPEAKERS Karin Rodland, Amanda (Mandy) Paulovich, Kristina Beeler, Saed Sayad, Michael Förster, Marlon Ruiz, Brian McCloskey, Sheeno Thyparambil, Brad Power

, samples, mass spectrometry, genomics, clinical, diagnostics, clinical trial, liquid biopsies, data, oncology, fred hutch, reproducibility SPEAKERS Karin Rodland, Amanda (Mandy) Paulovich, Kristina Beeler, Saed Sayad, Michael Förster, Marlon Ruiz, Brian McCloskey, Sheeno Thyparambil, Brad Power Brad Power 00:03 This is the Prostate Cancer Lab where we're learning about novel tests that can help personalize cancer treatment decisions.

Today we have a panel, which is the first time we've done this. I want to first introduce Karin Rodland, who introduced me to a number of the panel members, so she's really the network organizer and helped to bring the panel together today. I'll let each of the panelists introduce themselves.

Please provide your personal background, your organization and its role, and the topic you will cover including where you are in the evolution of this emerging technology. Karin, why don't you start, please, and then we'll move to Mandy, Kristina, and then Michael and Marlon.

I also have a joint appointment in Oregon Health Sciences University, which is a leader in precision oncology and SMART trials. Also, I do know a lot of people, and I tried to get them involved. Brad Power 01:54 Karin was featured in a previous session we had for which we have a recording, a transcript, and her slides. Amanda Paulovich 02:20 I'm from the Fred Hutch Cancer Center.

I'm a clinically trained medical oncologist with a PhD in genetics. Unfortunately, I've seen this disease of cancer from many sides. I've been a cancer patient, having been diagnosed with early-stage breast cancer at the age of 40, which I guess technically makes me a cancer survivor. I'm now a cancer researcher and a clinical oncologist.

As an oncologist treating patients, I was very struck by the variability that I saw from patient to patient. I saw patients with what looked like the same tumor would have very different responses to the same therapy, and very different profiles in terms of side effects as well. That led me to yearn for what we now call personalized, or precision oncology, which is what we're trying to achieve.

“Proteomics and Clinical Decisions” (Panel Discussion) [#19] genome sequence. That was a very critical start on our path to precision oncology, but it's not enough. Genes don't reliably predict response to treatment, and the gene mutations or expression in cells don't reliably predict the expression of proteins in our cancer cells. Since proteins are the targets of therapies, we have to be able to quantify proteins.

o precision oncology, but it's not enough. Genes don't reliably predict response to treatment, and the gene mutations or expression in cells don't reliably predict the expression of proteins in our cancer cells. Since proteins are the targets of therapies, we have to be able to quantify proteins.

When I got into this field 19 years ago, and still today, most studies on proteins use conventional technologies that are 50 years old and wholly inadequate to meet the needs of the post genomic community. In fact, there aren't good assays for measuring most human proteins in a clinical setting. This very critical human proteome, as it's called, remains clinically inaccessible.

In 2003, I joined Fred Hutch to set up a translational proteomic lab to try and leverage new technologies to solve this gap based on mass spec. Brad Power 04:33 I know you've been associated with something you've developed in your lab that's become commercially available recently. So I'd like to hear about that as well, please.

A couple of years later, we launched this NCI CPTAC program and spent five years and probably $30 million convincing the world that these conventional technologies that are 50 years old aren't the only way to measure proteins. We can use newer technology based on mass spec to make reliable measures of proteins.

That got us another five years of the program at NCI where we spent five years and another $30+ million proving, in my opinion, common sense, that measuring proteins adds value over just sequencing DNA.

That finally proved beyond a shadow of a doubt, even to the genomics-centric folks at the National Cancer Institute who are now on board, that there's value in combining proteomics and genomics - what we now call proteogenomics.

“Proteomics and Clinical Decisions” (Panel Discussion) [#19] groundwork for the clinical translation of mass spec-based proteomics. There's a lot of proteogenomic characterization centers looking at the gamut of human tumors trying to characterize them on a molecular level using mass spec-based technologies.

For the first time, we also introduced translational research centers to these technologies whose goals are to try and take them and push them into the clinic. In that phase, we saw the development of laboratory-developed tests.

In fact, my laboratory is now a CLIA-certified environment, and we have successfully translated this new mass spec-based measurement technology into clinical trials where we run patient samples for correlative studies in our CLIA environment. That's where we're really stuck right now.