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Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment.

Now, a research team led by researchers at Dartmouth’s Norris Cotton Cancer Center have devised a strategy to target cancer cells while sparing normal cells.

The approach detailed in a paper appearing in Oncotarget capitalizes on the fact that processes that allow a cell to form a tumor, such as loss or mutation of the tumor suppressor neurofibromin 1 (NF1), also expose vulnerabilities in the tumor cell that are absent in normal cells.

“…we developed and conducted a synthetic lethality screen to discover molecules that target yeast lacking the homolog of NF1, IRA2. One of the lead candidates that was observed to be synthetic lethal with ira2Δyeast is Y100,” write the investigators. “Here, we describe the mechanisms by which Y100 targets ira2Δ yeast and NF1-deficient tumor cells. Y100 treatment disrupted proteostasis, metabolic homeostasis, and induced the formation of mitochondrial superoxide in NF1-deficient cancer cells.”

Loss or mutation of the tumor suppressor, NF1 protein is believed to be a possible cause of aggressive neurological cancers, and has also been observed among sporadic cancers. Led by Norris Cotton Cancer Center’s Yolanda Sanchez, a multi-institutional research team has developed and conducted

a novel synthetic lethality screen to discover molecules that target genetically modified yeast lacking NF1.

Yeast is uniquely amenable to high throughput drug screening because the pathways are conserved. The team was therefore able to screen thousands of drug-like compounds for ones that would kill the NF1-deficient cells while sparing the wild-type (normal) cells, and sorted out the lead compounds that were successful in doing so.

One of the lead candidates that was observed to be lethal with this particular mutation is called Y100. Y100 treatment disrupted growth of tumor cells and induced the formation of superoxides that caused the death of NF1-deficient cancer cells.

The team therefore hypothesizes that the use of Y100 and molecules with related mechanisms of action could represent a feasible therapeutic strategy for targeting NF1 deficient cells.

“Our long-term objective is to work with our board of scientific and clinical advisors to design Phase 0/I trials with agents that are efficacious at shrinking the tumors in ‘avatar’ models,” says Dr. Sanchez. “In order to test the efficacy of Y100 against GBM tumors in whole organisms, we first need to examine the toxicity of Y100. To test the efficacy of Y100 we will use ‘avatars,’ which are mice carrying identical copies of patients’ GBM tumors. When we identify the cellular target of Y100, then we can find additional inhibitors or drugs to test in the avatar models.”

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