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How a Rare Genetic Defect May Solve Cancer Cure Problem



Rare Genetic Defect May Lead To Cancer Drug, Israeli Researchers Say

By Einat Paz-Frankel,

The path to understanding what goes wrong in cancer could benefit from a detour through studies of rare childhood diseases.

Cancer generally involves dozens – if not hundreds – of mutations, and sorting out the various functions and malfunctions of each may be nearly impossible. Rare childhood diseases, in contrast, generally involve mutations to a single gene. According to Israel’s Weizmann Institute, children with rare genetic syndromes may serve as a “lens” when trying to understand the role of a specific gene in a complex disease such as cancer.

Dr. Ayelet Erez and her colleagues recently tested the protein citrin and found that blocking this protein might slow the progression of some cancers.

Lung cancer cell dividing

A cancer cell dividing

Erez, a geneticist and medical doctor who treats families with genetic cancer in addition to heading a research lab at the Weizmann Institute, is a researcher in the new field of “cancer metabolism,” which seeks to understand how the uncontrolled metabolic processes in cancers might be turned against them to stop their growth.

She and her team studied cells from children suffering from an extremely rare disease, citrullinemia type II, who are missing the gene for a protein called citrin. Clinically, children with this disease tend to be smaller than average. Erez’s research revealed that this protein normally helps keep the body supplied with an amino acid called aspartate which is required to produce DNA and RNA in addition to the breakdown of glucose; so deficiency in this protein causes the cells to divide less.

Cancer cells rely on aspartate to divide and migrate

Research into another genetic childhood disease, citrullinemia type I, had already given the team the lens they needed to understand how cancer cells rely on aspartate to divide and migrate. Children born with this disease are missing a gene called ASS1; the lack of ASS1 connects the disease to particularly aggressive, hard-to-treat cancers in which this gene tends to be silenced or mutated.

Since this gene also requires aspartate to function, Erez and her team concluded that the silencing had less to do with the gene’s function and more with competition for aspartate and the cancer cells’ craving for ever more of this amino acid to help them divide and spread. Interestingly, the dependence on citrin for aspartate supplementation is seen in cancers both with and without ASS1 expression.

A lack of the protein citrin slows children’s growth; blocking it in cancer slows tumor growth

The team then realized that citrin – the protein that helps regulate childhood growth – could present a possible target for anticancer therapies. Blocking this protein would hopefully disrupt the  cancer’s overactive metabolic cycle, diminish the cancer cells’ aspartate supply and slow their growth, thus making them less aggressive, less likely to spread and possibly more treatable with other, conventional means.

To that end, Erez and her group have been developing a molecule to block citrin, and testing it in the lab. Yeda Research and Development, the technology transfer arm of the Weizmann Institute of Science, is working with Erez to advance her research to the point that it can be developed for biomedical application.


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