Editor’s note: A version of this article originally appeared on the Frederick National Laboratory website. Dr. Ventzi Hristova was unable to be recorded and is not included in the video footage of the event.
Frederick-area biotechnology professionals got an inside look at advances in mass spectrometry as part of the quarterly Biotech Connector Series at the Frederick National Laboratory for Cancer Research.
Mass spectrometry is an analytical technique that allows scientists to determine the mass, structure, and chemical properties of molecules. It is a powerful tool with broad applications, as showcased by the three speakers who each presented different approaches to leverage mass spectrometry and gain novel insights into human health.
“We are fortunate to have local investigators working in the mass spectrometry field,” said Lyuba Khavrutskii, organizer of the Biotech Connector and member of the Partnership Development Office team at the Frederick National Laboratory. “As the event speakers demonstrated, the technology supports research in multiple environments.”
Top-down Approach for RAS Proteoforms
Caroline DeHart, Ph.D., of the Frederick National Laboratory, discussed the use of mass spectrometry to examine proteoforms, distinct molecular forms of a protein that incorporate all relevant information about variations in the genetic sequence and post-translational modifications, which are changes after the protein has been produced. The focus of her research is on RAS proteoforms. RAS genes (HRAS, KRAS, NRAS) are among the most frequently mutated in human cancers, including pancreatic, colorectal, and lung cancer.
RAS proteins had a longstanding reputation of being “undruggable,” as decades-long efforts to design targeted inhibitors for specific mutant RAS proteins proved unsuccessful. The RAS Initiative at the Frederick National Laboratory is changing that outlook.
“Our goal is to learn as much as possible about the RAS proteoforms resulting from each mutation in each of these cancer types, so we can then design better targeted inhibitors,” DeHart said. “However, the RAS proteins are incredibly challenging to analyze by standard proteomic methods.”
To address the challenge, DeHart and team utilize an emerging mass spectrometry approach that she co-developed. This approach can directly visualize, precisely characterize, and easily distinguish between RAS proteoforms. It has yielded novel insights in mapping the KRAS proteoform landscape in colorectal cancer, while revealing how many RAS proteoforms remain to be discovered. Her team has optimized a new method to improve sensitivity and sequence coverage while analyzing RAS proteoforms to gain a better understanding of which may be engaged in different types of cancer.
Bottom-up Approach for Environmental Toxins
To begin his talk, Robert N. Cole, Ph.D., of Johns Hopkins School of Medicine asked, “If I could take a pinprick of your blood and tell you what environmental toxins you’ve been exposed to in the last three months, would you want to know?”
The room gave him a resounding “yes,” and he explained how he is using a novel method called Pan-Protein Adductomics to detect environmental toxins in human blood serum, thereby assessing a person’s exposure.
He explained, “When we incorporate toxins into our body, they or their metabolites will modify proteins and affect the functions of those proteins, so a good way of determining the amount of internal dose is looking at what is decorating your proteins.”
For this work, Cole’s team targets the protein albumin, the most abundant protein in blood plasma. In doing so, they were able to see changes over time and with exposure to increasing air pollution.
Clinical Applications
Ventzi Hristova, Ph.D., DABCC, of Amgen, presented on clinical applications in biopharmaceutical settings and, specifically, mass spectrometry for proteomics, which is the study of proteins and how they interact.
“We’re using clinical proteomics data to try and identify biomarkers that will enable early disease detection and also that enable us to monitor disease progression in patients,” Hristova said.
She presented a study on chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease that is frequently not diagnosed until later stages—creating a need for early biomarkers. Her team identified proteins that were found both in the bronchoalveolar lavage fluid collected from the lungs and blood as potential biomarkers for patient evaluation.
“Additionally, seeing these proteins in [blood] gave us additional insight into the mechanisms of COPD,” Hristova said. “We knew that at least, to some degree, there was tissue damage that was causing leakage and release of these proteins in circulation.”
Get Connected
The quarterly Biotech Connector is held in collaboration with the Frederick Country Chamber of Commerce as a way to support the Frederick biotechnology community. The next event will be held on February 22 at 8 a.m.
Victoria Brun is a partnership project manager in the Frederick National Laboratory Center for Innovation and Strategic Partnerships, where she provides project management support across the office’s broad portfolio of collaborative projects. Among its functions, CISP establishes the partnerships and collaborations among Frederick National Laboratory scientists and external researchers in government, academia, industry, and the nonprofit research sector.