When an aggressive cancer launches an invasion on the human body, anything that can be done to slow down or better understand that fast-paced assault is going to be a bonus.
Researchers at the Department of Energy’s Oak Ridge National Laboratory are now using a cutting-edge “drug design” approach. They are focusing on metabolic pathways that scientists in the future may be able to use to target highly aggressive tumor-forming cancers. These include lung, colon, breast, pancreatic and prostate cancers. A metabolic pathway is the series of interconnected chemical reactions that occur within a cell. These reactions allow the cell to consume or generate nutrients necessary for the cell to stay alive and divide.
In their latest research, the scientific team used neutrons and X-rays to draw a roadmap of every single atom, chemical bond, and electrical charge inside a key enzyme that belongs to a metabolic pathway. Cancer cells dramatically overuse this pathway to reproduce.
Identifying every single part of that key enzyme paves the way for designing new drugs. These drugs can act as roadblocks along the metabolic pathway to cut off the supply of vital resources to cancer cells. The research, published in August 2023 and in August 2024, is ongoing.
Interestingly, the molecules the team is planning to design belong to the class of metabolic anticancer drugs. These were some of the very first drugs used to treat cancer, such as methotrexate that targets a different enzyme.
Over the years, cancer researchers moved in different directions.
Today, however, there is a recognition of the need to return to the metabolic drugs. A multitude of intervention options, sometimes aligned to occur at the same time in a treatment plan, can often be the best approach to beating cancer.
“The 1C metabolism pathway is ‘hijacked’ by many types of cancer. If you think of this pathway as a highway, the enzyme we are studying (called SHMT) is the on-ramp cancer takes to hijack traffic,” said postdoctoral researcher Victoria Drago, the study’s lead author. “Blocking the enzyme with inhibitors or ‘roadblocks’ prevents cancer cells from using the highway, effectively cutting off their fuel supply, thereby preventing them from spreading.”
Designing a drug requires a detailed understanding of the enzyme structure and how the structure underpins its function at the atomic level. Neutrons and X-rays provide a wealth of information, such as the positions or arrangements of light and heavy elements.
To do this research, highly specialized user facilities are needed. In this instance, the research team utilized the High Flux Isotope Reactor and the Spallation Neutron Source at Oak Ridge National Laboratory and the Advanced Photon Source at DOE’s Argonne National Laboratory. These facilities are among the 28 user facilities the DOE Office of Science manages in the United States. User facilities provide state-of-the-art tools and instrumentation to researchers to advance scientific discovery.
This work represents a significant first step on the way to realizing a novel drug treatment. The next steps in the research campaign involve studying the enzyme in different reaction stages and understanding the details of its interactions with existing inhibitors.
“With more than 200 types, cancer continues to be a devastating disease,” said ORNL distinguished R&D scientist Andrey Kovalevsky. “That means, if we’re ever going to beat the disease, it’s going to require exploring every option and studying every aspect of the disease at every level — from tumors, cells, and molecules down to individual atoms.”
