Cutting the Liver Cancer Nutrient Supply Chain

The World Health Organization projects that from 2030more than one million people will die each year from liver cancer. Cold Spring Harbor Laboratory (CSHL) Professor Adrian Krainer, former post-doc Wai Kit Ma, and Dillon Voss, MD-Ph.D. from Stony Brook University. residency student in Krainer’s lab, have found a way to interfere with the energetic pathway that allows this cancer to grow and spread. They recently published their work, which was a collaboration with Ionis Pharmaceuticalsin the review Research against cancer.

CSHL scientists used antisense oligonucleotides (ASOs), which are synthetic combinations of genetic code that bind to RNA and change the way cells make proteins. These molecules switch the enzyme used by liver cancer cells from one type of protein pyruvate kinase (PKM2), which is normally expressed in embryonic and cancer cells, to another form of protein pyruvate kinase (PKM1), which improves tumor suppression behavior. Changing the function of this protein affects how cancer cells use nutrients, which can limit their growth. As Krainer explains, “What’s unique about our approach is that we’re doing two things at the same time: we’re denying PKM2 and augmenting PKM1. And we think both are important.

ASOs show promise for this type of cancer because after injecting them under the skin, the body would send them directly to the liver. Liver cancer would be prevented from growing and spreading to other organs. The researchers found a significant reduction in tumor development in both mouse models they studied. This study builds on previous research in Krainer’s lab in which they replaced PKM2 with PKM1 in cultured cells of an aggressive type of brain cancer called glioblastoma.

This strategy also has another advantage, because healthy liver cells do not make the same RNA that ASOs would target in liver cancer cells. This reduces the likelihood of off-target effects. Voss says, “Being able to deliver this therapy directly to the liver, without affecting normal liver cells, may provide a more effective and safer option for treating liver cancer in the future.”

Krainer, who works with antisense oligonucleotides in other diseases, including cystic fibrosis and spinal muscular atrophy, plans to continue using these therapeutic tools to research ways to treat liver cancer. Among other questions, researchers hope to explore whether RNA molecules can help contain cancer metastasis to the liver from other organs.

Written by: Daniel Dunaief, science writer | [email protected] | 516-367-8455


Funding

National Cancer Institute

Quote

Ma, WK, et al., “ASO-Based PKM Splicing Switch Therapy Inhibits Hepatocellular Carcinoma Cell Growth”, Research against cancer17 December 2021. DOI: 10.1158/0008-5472.CAN-20-0948

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