Espinosa’s first proposals to fund his functional genomics experiments were rejected by the National Institutes of Health and private foundations. But he persisted, eventually securing support from HHMI, the BioFrontiers Institute, and the University of Colorado Cancer Center. The Functional Genomics Facility at the University of Colorado at Boulder began operations in May 2010 with Espinosa at its helm. “We could finally do our dream experiment,” Espinosa says.

In a series of investigations published online June 3, 2012, in Nature Chemical Biology, Espinosa’s group identified genes that, when inhibited, allow p53 to kill cancer cell types that wouldn’t otherwise respond. They accomplished this using an experimental drug called Nutlin-3, which activates the p53 protein, yet fails to induce cell death in most tumors. Using functional genomics, Espinosa’s team screened thousands of genes and identified a few hundred whose inhibition made Nutlin-3 effective at killing cancer cells. To their delight, they discovered that compounds to inhibit the protein products of two of these genes, ATM and MET, were already available.

When they combined the ATM or MET inhibitors with Nutlin-3, the treatment destroyed cancer cells that didn’t respond to any of the drugs individually. “If you treat cancer cells with one of the drugs, nothing happens, but if you treat them with both drugs, the drugs kill them,” Espinosa says. The drug combination delivered a one-two punch—Nutlin-3 turned on p53, then the ATM or MET inhibitor blocked the proteins that would allow the cancer cell to thrive despite p53 activation. “With one genetic screen, we identified a combination of drugs that will kill tumors that otherwise resist them,” Espinosa says. His team is collaborating with clinical investigators to test these drug combinations in animal models and human tumors grown in mice.

By hitting multiple genetic targets, Espinosa hopes to drive cancer cells into a dead end. “You can block resistance genes before they ever have a chance,” he says. With this strategy, new treatments can be designed to overcome a tumor’s natural work‑rounds. “The future is not in isolated drugs, but rather in combinations of drugs,” Espinosa says.

Clinical trials are costly and time-consuming, and Espinosa hopes his studies can help drug researchers predict and anticipate how their p53-related treatments will work in the clinic, long before they’ve spent millions on trials. “These are very basic experiments we can do in the lab to get ahead of problems we'll see in clinic.”

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