Researchers explore new metabolic pathway to fight cancer

When an aggressive cancer attacks the human body, anything that can be done to slow down or better understand this rapid attack is beneficial.

Researchers at the Department of Energy's Oak Ridge National Laboratory are currently using a cutting-edge “drug development” approach. They are focusing on metabolic pathways that may allow scientists to target highly aggressive tumor-forming cancers in the future. These include lung, colon, breast, pancreatic and prostate cancers. A metabolic pathway is the series of interconnected chemical reactions that take place within a cell. These reactions allow the cell to take in or create nutrients it needs to survive and divide.

In their latest research, the team of scientists used neutrons and X-rays to create a map of every single atom, chemical bond and electrical charge in a key enzyme belonging to a metabolic pathway that cancer cells dramatically overuse to proliferate.

Identifying every single part of this key enzyme paves the way for the development of new drugs. These drugs can act as obstacles in the metabolic pathway and interrupt the supply of vital resources to cancer cells. The research, published in August 2023 and August 2024, is ongoing.

Interestingly, the molecules the team hopes to develop belong to the class of metabolic cancer drugs, which were among the very first drugs used to treat cancer, such as methotrexate, which targets a different enzyme.

Over the years, cancer researchers have moved in different directions.

Today, however, it is clear that there is a need to return to metabolic drugs. A variety of intervention options, sometimes combined simultaneously in a treatment plan, can often be the best approach to fighting cancer.

“The 1C pathway is 'hijacked' by many cancers. If you think of this pathway as a highway, the enzyme we study (called SHMT) is the on-ramp the cancer takes to hijack the traffic,” said postdoctoral fellow Victoria Drago, the study's lead author.

Blocking the enzyme with inhibitors or ‘roadblocks’ prevents the cancer cells from using the highway, effectively cutting off their fuel supply and preventing their spread.”

Victoria Drago, Oak Ridge National Laboratory

To develop a drug, you need to understand the structure of the enzyme and how that structure supports its function at the atomic level. Neutrons and X-rays provide a wealth of information, for example about the positions or arrangements of light and heavy elements.

This research requires highly specialized user facilities. In this case, the research team used the High Flux Isotope Reactor and Spallation Neutron Source at Oak Ridge National Laboratory and the Advanced Photon Source at DOE's Argonne National Laboratory. These facilities are among 28 user facilities managed by the DOE Office of Science across the United States. User facilities provide researchers with cutting-edge tools and instruments to advance scientific discovery.

This work represents an important first step towards the realization of a novel drug treatment. The next steps of the research campaign are to study the enzyme at different reaction stages and to understand the details of its interactions with existing inhibitors.

“With more than 200 types, cancer remains a devastating disease,” said ORNL's Distinguished R&D Scientist Andrey Kovalevsky. “This means that if we are ever to defeat the disease, we must explore every option and study every aspect of the disease at every level – from tumors, cells and molecules to individual atoms.”