It’s long been known that cancer cells have a preferred source of fuel: glucose. They gobble it up to produce energy rapidly in a metabolic process known as the Warburg effect. It’s for that reason that many cancer researchers have tried to slow down cancer by starving it of its glucose supply.
Now, a team led by Xiaolu (Lulu) Lim Ang Cambronne and Ku-Lung (Ken) Hsu at the University of Texas at Austin, has tried the opposite approach: making cancer cells eat so much glucose that it puts them under extreme metabolic stress, while at the same time making sure they can’t process fat as backup fuel source. The new work was recently published in Nature Chemical Biology.
“I like to think of this technology like a two-headed dragon,” said Cambronne in the press release. “We are putting one part of the cell into overdrive while simultaneously weakening another part.”
The authors claim that the experimental drug — a covalent PFKL (phosphofructokinase-1 liver type) activator — could be a better alternative to antibody-drug conjugates (ADCs). The team refers to their therapy as an “electrophile-drug conjugate” or EDC due to its electrophile component that covalently targets PFLK.
Taming tumor growth
Just as ADCs deliver both an antibody to target cancer cells and a payload to kill the cells, the researchers’ new EDC attacks cancer with a two-pronged approach. First, the targeting agent, XJ-4-85, binds to the PFKL enzyme and pushes it into overdrive in breaking down excessive amounts of glucose, leading to a metabolic crisis. Then, after XJ-4-85 binds to PFKL, it releases a payload that targets the CPT2 (carnitine palmitoyltransferase 2) enzyme to ensure that the cancer cell can’t break down fatty acids for energy either.
The result is a tumor that, with both metabolic processes stifled, can no longer grow.
Cambronne and Hsu’s team tested this in several types of human cancer cell lines, including leukemia, liver cancer, neuroblastoma, breast cancer, and melanoma. In a melanoma mouse model, the team tested out the new EDC drug and showed that it selectively targeted cancer cells and led to reduced tumor growth.
“It appears to be extremely potent,” said Cambronne.
Small but mighty
The research team claims that not only is their EDC approach similar to ADCs, but it offers several advantages.
“Antibodies are difficult to make, and because they’re so large they’re only able to target proteins in the surface of cancer cells,” said Hsu in the press release. “We think of this new compound as a fully chemical counterpart to ADCs. They are much easier to manufacture. And because they are smaller, they are able to target even proteins that are inside cells.”
Their results provide a proof of concept for the EDC mechanism in cancer cells, though the scientists are also optimistic that the approach could also be helpful beyond cancer.
“Although we focused on cancer in this study, PFKL activators have broader applications, including reversing the glycolytically deficient state of neurons in neurodegeneration and resensitizing bacteria to antibiotic treatments,” wrote the authors in the study.
