New possible cancer treatment by targeting one-carbon metabolism

• Department of Cancer Research
• Cancer Metabolism Group

LIH scientists, in collaboration with researchers from the University of Sheffield and the Karolinska Institute in Sweden, have described a new approach for attacking cancer cells by targeting one-carbon (1C) metabolism, a crucial pathway for DNA synthesis and repair. Cancer cells upregulate enzymes involved in 1C metabolism in order to meet their increased need for nucleotides, the building blocks of DNA. However, this upregulation also creates a potential vulnerability that can be exploited for therapeutic intervention.

In a previous study, researchers at the Karolinska Institute developed the novel small molecule TH9619, which targets enzymes involved in 1C metabolism to selectively kill cancer cells. While they were able to show the efficacy of this compound, the mechanism behind its actions remained unknown until recently. In the present study, researchers of the Cancer Metabolism Group of the Dept. of Cancer Research at the LIH and their colleagues at University of Sheffield and Karolinska Institute detail the mode of action of TH9619. In their joint publication, the researchers describe how TH9619 selectively kills cancer cells by inducing the accumulation of the 1C metabolism intermediate 10-formyl-tetrahydrofolate. They denominate this toxic mechanism a “folate trap” as it starves cancer cells of the tetrahydrofolate necessary for DNA synthesis and repair, resulting in their death.

This folate trapping mechanism differs from other 1C metabolism inhibitors and anti-folates, making TH9619 a promising new candidate for cancer treatment. The researchers believe that this new approach to attack cancer cells could potentially also be used in combination with existing treatments to enhance their effectiveness.

This folate trapping mechanism differs from other 1C metabolism inhibitors and anti-folates, making TH9619 a promising new candidate for cancer treatment. The researchers believe that this new approach to attack cancer cells could potentially also be used in combination with existing treatments to enhance their effectiveness.

explained LIH lead authors Dr Johannes Meiser and Dr Nicole Kiweler.

The paper was published in the journal Nature Metabolism on April 3 and can be read online.