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

Ayelet Erez

Dr. Ayelet Erez says that rare genetic diseases provide a lens on cancer

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

Dr. Erez, a geneticist and medical doctor who, in addition to heading a research lab in the Weizmann Institute of Science’s Department of Biological Regulation, treats families with genetic cancer, says that 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. She and her team have been focusing on a protein they discovered in this way; promising lab tests indicate that blocking this protein might slow the progression of some cancers.

Her findings place this research in the new field of “cancer metabolism,” which seeks to understand how the aberrant, or uncontrolled, metabolic processes in cancer might be turned against it to stop its growth.

Dr. Erez 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, and avoid candy. Her research revealed that the citrin protein normally helps keep the body supplied with aspartate, an amino acid that is required for producing DNA and RNA, as well as the breakdown of glucose; thus, deficiency in this protein causes the cells to divide less.

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, Dr. Erez and her team surmised 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 it to help them divide and spread. Interestingly, the dependence on citrin for aspartate supplementation is seen in cancers both with and without ASS1 expression.

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

Dr. Ayelet Erez’s research is supported by the Moross Integrated Cancer Center; the Irving B. Harris Fund; the Adelis Foundation; the Rising Tide Foundation; the Comisaroff Family Trust; and the European Research Council. Dr. Erez is the incumbent of the Leah Omenn Career Development Chair.