Researchers reveal therapeutic strategy to kill cancer cell

Mutations in oncogenes can drive cell proliferation, pushing the gas pedal all the way to the floor, whereas mutations in tumour suppressor genes can cause tumours to grow unchecked–a situation in which there are no brakes.

However, while research has shown that these therapies are effective at inducing p53 activity, they generally can’t kill cancer cells. As observed for other biologically targeted therapies, activation of p53 has been shown to stop tumor growth for a period of time, but the cells eventually mutate and become resistant to treatment.

“When you block both the major p53 repressor, known as MDM2, and its minor repressor, known as PPM1D, p53 works much better in terms of inducing cancer cell death, and this enhanced killing activity requires the Integrated Stress Response” said Joaquin Espinosa, PhD, a professor of pharmacology in the CU School of Medicine, director of the Linda Crnic Institute for Down syndrome, and senior author of the study, adding, “This is an important step in making p53-based biologically targeted therapies more effective.”

This development is an important milestone in almost two decades of research conducted by Zdenek Andrysik, PhD, an assistant research professor of pharmacology in the CU School of Medicine, and other members of the Espinosa lab. Their and other research has worked to understand the role of MDM2 and PPM1D, two proteins that repress p53 inside tumor cells, and the mechanisms by which inhibiting them leads to cancer cell death.

“It was already established that MDM2 is a major repressor and PPM1D is a minor one,” Espinosa said, adding, “For a long time, the hope was that inhibiting just the major repressor would suffice. Much effort was invested in developing small molecules that block MDM2, millions of dollars were spent, but these drugs performed poorly in clinical trials.”

Researchers then turned to minor repressors, including PPM1D. “A lot less is known about PPM1D and other minor repressors of p53,” Andrysik said, adding, “but it soon became clear that if you inhibit both MDM2 and PPM1D, p53 can effectively induce cancer cell death. However, the underlying mechanisms driving this synergy were unknown”.

Espinosa and Andrysik have been able to demonstrate that inhibiting MDM2 and PPM1D activates the Integrated Stress Response, which is a signaling pathway that stimulates a protein called ATF4. They further demonstrated that ATF4 partners with p53, working together to cause cancer cell death.

For example, Andrysik and Espinosa repurposed the drug Nelfinavir, which originally was approved as an HIV therapy. “Now we know that Nelfinavir activates the Integrated Stress Response, thus becoming a great combination with MDM2 inhibitors,” Espinosa said.

Espinosa added that “a holy grail of cancer research has been the restoration of p53 activity to induce tumor regression. For the past 20, 30 years, a lot of research efforts have been devoted to finding more elegant solutions to broadly acting chemotherapy or radiation. As we learn more about the genes and proteins mutated in cancer, we’re more able to see when the brakes are failing and restore them, or when the gas pedal is all the way to the floor and lift it with specifically targeted inhibitors