Exploiting Cancer's Achilles Heel to Improve Treatment Options

Scientists have developed a new strategy to target cancerous cells, while leaving normal cells alone.

Although cancer treatments can be effective, they are a double-edged sword because they attack all cells in the body, both cancerous and healthy.

In a study published in Oncotarget, investigators developed and conducted a novel synthetic lethality screen to identify molecules that target genetically modified yeast with a loss of the tumor suppressor protein NF1.

The investigators could screen thousands of drug-like compounds to identify those that kill NF1-deficient cells while sparing normal cells. Since the pathways are conserved, yeast is compliant to high throughout drug screening.

One of the lead candidates identified as being lethal was Y100, which disrupted tumor cell growth and induced the formation of superoxides that cause NF1-dficient cancer cell death.

“In this paper we describe the mechanisms by which one of our top leads, Y100, targets NF1-deficient cells,” said lead investigator Yolanda Sanchez, PhD. “Mutations that drive cells to become malignant, including loss of the tumor suppressor NF1, rewire cells’ metabolism, which makes them uniquely sensitive to a process called oxidative stress. Our data so far suggest that Y100 can exploit this vulnerability in cells that lack the NF1 tumor suppressor.”

Because of the recent findings and successes, the investigators are seeking future clinical trials.

“Our long-term objective is to work without board of scientific and clinical advisors to design phase 0/1 trials with agents that are efficacious at shrinking the tumors in ‘avatar models,’” Sanchez said. “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.”

The investigative team will work in collaboration with Jack P. Hoopes, DVM, and the Neuro-Oncology team at Norris Cotton Cancer Center. They will also seek to find the cellular target of the small molecule.