Aggressive forms of breast and prostate cancer may face a more effective approach from oncologists in the future as new findings have identified new drug targets for which new pharmaceuticals can home in on and prove efficacious.
The new targets center around the Myc oncogene, a genetic catalyst that accelerates cancer cell growth exponentially. While Myc is a notoriously difficult target, due to its lack of efficient binding sites for drug compounds, researchers from Harvard Medical School took a more innovative approach that is more fully described in the December 8 online edition of Science.
Stephen Elledge PhD, a Professor in the Department of Genetics at Harvard Medical School, and a senior author on the paper, and his collaborator and co-senior author Thomas Westbrook PhD, an Assistant Professor at the Baylor College of Medicine, decided to disable myc’s helper genes rather than the oncogene itself.
They achieved this by taking into account “synthetic lethality,” or the cell-killing upshot of observing two incompatible mutations in a shared genetic pathway. Elledge and Westbrook hoped to repeat the positive results observed in research that focused on genes linked to inherited breast cancer.
“This study show us that Myc-driven cancers become addicted to unique sets of proteins that are not required in normal, non-cancerous tissues,” said Westbrook. “And many of these cancer vulnerabilities are enzymes, giving us new, rapid directions for treatments for these notoriously bad cancers.”
In its non-cancerous, normal state, Myc monitors how genetic data is translated into proteins, normally those involved in new cell proliferation. Howver, mutations can result in Myc becoming hyper-activated, or oncogenic. When this occurs, cells multiply wildly and tumors are formed. Myc-dependent cancer cells rely enormously on this oncogene, so much so that they’ll die if it’s disabled.
To locate the genes, Elledge and Westbrook incorporated an approach that uses small RNA molecules (short-hairpin RNA or shRNAs) that obstruct the actions of certain genes. The team utilised these shRNAs in studies that used human breast epithelial cells in which Myc could be selectively hyper-activated. Every cell in the experiment contained just one silenced gene. If the cell died when Myc’s cancer activity was triggered, then that silenced gene was clearly one Myc needed to form tumors.
In total the team tested close to 75,000 shRNAs, and found 403 potential candidates; some known in the field of Myc biology. “These genes aren’t oncogenes in and of themselves, but they do code for proteins that Myc relies on to cause cancer,” said Elledge, who is also a professor of medicine at Brigham and Women’s Hospital. “We see them as potential targets for drug therapy—even if you can’t target Myc, you can target these other genes and inactivate its effects.”
One highlight among the new candidates was the gene SAE2. Myc-activated cells in which SAE2 is depleted are unable to build normal spindles—the internal structures that guide mitosis. This suggests the cells die because they’re not able to divide correctly. The researchers determined that SAE2 depletion blocks Myc’s ability to activate genes involved in spindle formation.
To reinforce the strength of their findings, the two research teams confirmed that SAE2 depletion slows growth rates of human, Myc-driven breast cancer cells both in a dish and after transplantation into immune-compromised mice. Finally, the researchers stratified gene expression data for nearly 1,300 breast cancer patients according to whether Myc activity was high or low. Consistent with their prior findings, they found that Myc-high patients fared better in terms of metastasis-free survival if they had naturally low SAE2 levels, while among Myc-low patients, SAE2 levels made no difference.
These findings provide a string case for disabling SAE2 and similar enzymes as a new therapeutic strategy for patients with Myc-driven cancer, the researchers concluded in the paper. According to Elledge, future research will look at the consequences of inactivating these genes in animals. “We’d also like to delve more into the mechanism,” Elledge said. “We’d like to know more specifically which proteins Myc depends on—if we can hit those targets with drugs, we might be able to turn Myc off and kill cancer cells selectively.”