Chromosomal damage that can transform healthy cells into cancer cells may also create weaknesses that can be exploited to kill the cancer cells, a new study suggests. The idea, called “collateral vulnerability,” could be used to identify new targets for drug therapy in multiple cancers, according to researchers from the Dana-Farber Cancer Institute and the University of Texas MD Anderson Cancer Center. The study was published August 16 in Nature.

Directly targeting genetic mutations that drive cancer with drugs is difficult, particularly in the case of mutations that delete tumor suppressor genes. Using data on the brain cancer glioblastoma multiforme (GBM) from The Cancer Genome Atlas (TCGA) initiative, the research team identified a number of “collateral” or “passenger” gene deletions that occurred during chromosomal damage that resulted in the loss of tumor suppressor genes.

The researchers next looked for passenger gene deletions that met two criteria: the deleted genes were involved in functions vital to cell survival, and the deleted genes were closely related to existing genes that perform similar functions. This loss of redundancy caused by passenger gene deletions can potentially be exploited to selectively kill tumor cells, the authors explained.

One gene that met these criteria is ENO1. ENO1 produces enolase 1, an enzyme that plays a central role in a process cells use to make energy. Human cells have a closely related gene (ENO2) that produces the enzyme enolase 2, which acts as a back-up for enolase 1 in brain tissue. Brain cells normally have a high level of enolase 1 activity and a small amount of enolase 2 activity. In some patients with GBM, however, the tumor cells lack enolase 1 activity because ENO1 was deleted when a tumor suppressor gene was deleted. This lack of enolase 1 activity could make these tumor cells more vulnerable to enolase inhibition.

This idea was tested using two targeting strategies. First, in GBM cell lines that lacked ENO1, the investigators showed that silencing ENO2 gene expression with a short hairpin RNA (a short RNA sequence that blocks the production of enolase 2 protein from ENO2 messenger RNA) sharply reduced cell growth, and tumors failed to form in mice injected with the treated cells.

The second approach involved a drug that targets the enolase 1 and enolase 2 proteins. Treatment of GBM cell lines lacking ENO1 with the drug caused the cancer cells to die because of the low overall enolase levels in these cells. But drug treatment had little effect on normal brain cells or GBM cells that had ENO1, since these cells have high levels of ENO1 gene expression and are, therefore, less sensitive to the drug.

The collateral vulnerability concept is similar in some respects to the idea of synthetic lethality, which uses genetic mutations in cancer-associated genes to identify other potential cellular vulnerabilities, explained the study’s co-lead author, Dr. Florian Muller of MD Anderson.

There are many more passenger gene deletions than tumor suppressor gene deletions, “and some of these passenger-deleted genes perform functions critical for cell survival,” Dr. Muller continued. “So, by expanding the concept to passenger genes, we vastly expand the possibility of finding these relationships, and, in the case of essential-redundant gene pairs like ENO1 and ENO2, we also provide a rational, knowledge-based method of drug-target discovery.”

The researchers are extending their work to other passenger gene deletions in GBM, Dr. Muller said.

This research was supported in part by the National Institutes of Health (CA95616-10 and CA009361).

Also in the Journals: Youth Tobacco Use Dropped between 2000 and 2011

Tobacco use and cigarette smoking fell among middle and high school students between 2000 and 2011, according to data from the National Youth Tobacco Survey, a school-based, self-administered questionnaire given to students in grades 6 through 12. Researchers from the Centers for Disease Control and Prevention published the findings last month in Morbidity and Mortality Weekly Report.

Percentage of U.S. Middle and High School Students Using Tobacco

Source: NCI