Proteogenomics reveals new target for beating drug resistance in acute myeloid leukemia

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Doctors have nearly a dozen new targeted drugs to treat patients with acute myeloid leukemia, or AML, yet three out of four die within five years. Despite a battery of drugs used to treat aggressive blood disorders, in which blood cells do not develop properly, some patients die within just a month or two.

A new study draws on a field of science known as proteogenomics to try to improve the view. In a paper published in January, 16 in Cell Report MedicineScientists report new findings about how drug resistance develops in some AML patients and how doctors can stop or slow the process.

The research comes from a team of researchers at the Department of Energy’s Pacific Northwest National Laboratory and Oregon Health and Science University. For nearly a decade, OHSU and PNNL researchers have worked together to fill an important gap in our knowledge of how cancer and other diseases develop. At one end of the spectrum, genes in our bodies can go awry, creating mutations that can be harmful or fatal. At the other end of the spectrum is a real person whose life is affected or even ended as a result.

What happens between genes and a person’s health?

Answer: There are a staggering number of complex molecular processes that scientists are trying to understand. At the center are proteins in the body and a field of study known as proteogenomics.

Sorting data with machine learning

The PNNL-OHSU team is studying thousands of proteins that may play a role in AML. Proteins are the body’s molecular workhorses, ferrying nutrients and other supplies between cells, turning genes on or off, and maintaining dozens of basic body processes. Although genes get the glory, they don’t do anything directly to keep our bodies going. That’s the job of proteins. For nearly 20 years, study author Karin Rodland of OHSU, formerly of PNNL, a pioneer in exploring the role of proteins in health and disease, has developed a program with OHSU and PNNL colleagues to study AML.

In the latest study, a team led by PNNL data scientist and computational biologist Sara Gosline conducted a comprehensive study of protein activity in 210 patients with AML. In all, the team measured the levels of nearly half a million pieces of protein from more than 9,000 proteins in the patients’ blood samples. The team combined these findings with a wide range of information already known about the disease – including the genes and mutations involved, molecular messengers that indicate which genes are active, and the effects of 46 drugs on AML patients, as well as information about how the disease progresses. patients

We were able to look at drug response patterns in hundreds of people by incorporating protein and gene measurements together, and this gave us a level of detail that was not possible in previous studies. This is a great example where we are able to put our growing knowledge of protein signaling and machine learning models to benefit patients in the future.”

Sara Gosline, Data Scientist and Computational Biologist at PNNL

Gosline and colleagues, including PNNL first author James Pino, deployed artificial intelligence, using several machine learning algorithms to make sense of the data.

Beating drug resistance

While research has yielded a wealth of information about what happens in the body of an AML patient, one finding has emerged that points to a possible way to avoid or delay drug resistance in some patients.

The team showed that treatment with quezartinib, approved last year to treat AML, can change how cancer cells respond to other drugs often used to treat patients.

Specifically, the team found that when patients on quizertinib stop responding to venetoclax, doctors may consider switching to another drug, panobinostat. This is an example of how proteogenomic information can change the roadmap that doctors use to navigate which drugs patients take at different stages of the disease.

“The problem is that the cancer continues to evolve,” Gosline said. “You hit the tumor with a drug and the tumor changes. This happens when patients develop drug resistance and the drugs stop working. Our study helps us understand how this happens and what can be done in response. Which drug Best tour?”

AML poses a special challenge, said study author Christina Tognon at OHSU.

“When you treat a tumor with a drug, you’re stressing the cells because they’re trying to figure out a way to escape that stress. That’s a big problem in AML patients. What’s even more difficult is that in AML, the tumor has many mutations at work. ; the disease doesn’t just come in one flavor,” said Tognon, who is an associate research professor and scientific director of the Drucker Laboratory at OHSU.

Ultimately, the team focused on 147 proteins and specific molecular locations known as phosphosites that play a critical role in determining which proteins are turned on and which are off.

Using only the protein data, the team sorted the samples into four distinct groups that predicted how the patients behaved. Patients whose samples were placed in one group had a better prognosis than the others, surviving longer than five years. Doctors hope that this kind of information will eventually become available in the clinic. This would allow some patients who do not need aggressive therapy with serious side effects to be avoided and assure that patients with the worst prognosis are treated as aggressively as possible.

“This work has the potential to lead to clinical applications, for example, diagnostics, such as protein biomarkers to predict responses to therapy and the design of new drug combinations that may outperform current ones,” said OHSU’s Jeff Tyner, professor of medicine at the OHSU School of Medicine and Knight Cancer Institute. .

The work is the latest of more than 200 studies that have looked at the protein’s activity in a variety of cancers, including colon, brain, endometrial, brain, blood and ovarian cancers. An OHSU-PNNL team

A recent article in the Annual Review of Pharmacology and Toxicology discusses the emerging role of proteins in treating patients with precision medicine. Increasingly, scientists are using proteomics-; Study of protein-; To bridge the gap between genomics (study of genes) to phenomics (phenotypes or observable traits).

PMedIC: an OHSU-PNNL collaboration

OHSU and PNNL scientists collaborate on many projects. OHSU brings outstanding clinical expertise as well as extensive laboratory knowledge of the disease and is a world-class center for new treatments for leukemia. PNNL offers an unparalleled ability to measure small amounts of important molecules in great detail. Much of this work occurs through the Pacific Northwest Biomedical Innovation Collaboratory, or PMedIC, a joint research collaboration between the two organizations. Through PMedIC and other collaborations, the institutions have made discoveries about several diseases, including Alzheimer’s disease, COVID-19 and the Zika virus.

At PNNL, additional authors include Camilo Poso, Michael Nestor, Jamie Moon, Joshua Hansen, Chelsea Hutchinson-Bunch, Marina Gritsenko, Carl Weitz, Jason McDermott, Tao Liu, and Paul Pihosky. Other authors from OHSU include Sunil Joshi, Kevin Watanabe-Smith, Nicola Long, Brian Drucker, Anupriya Aggarwal and Eli Treyer.

This work was supported by the National Cancer Institute’s Office of Cancer Clinical Proteomics Research (CPTAC U01CA271412), the ARCS Scholar Foundation, a Paul and Daisy Soros Fellowship, the National Cancer Institute (F30CA239335, R01 CA229875-01A1), the American Cancer Society. RSG-17-187-01-LIB), National Heart, Lung, and Blood Institute (R01 HL155426-01), Alex’s Lemonade Stand Foundation/RUNX1 Research Program, and the EvansMDS Foundation.


Journal Reference:

Pino, J.C., etc. (2024). Proteogenomic landscape mapping enables prediction of drug response in acute myeloid leukemia. Cell Report Medicine.

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