Researchers are closing in on cancer from every angle. Recently a team at the Colorado University (CU) Cancer Center has been focusing on p53, a common gene mutation found in cancers.
A recent article in EurekAlert features CU’s efforts to identify the mechanisms that prevent the activation of p53 from causing the death of cancer cells.
For over two decades, researchers have focused on designing targeted therapies to activate p53. Although they were successful in activating p53, they were unsuccessful in killing cancer. Millions of dollars were spent, yet the drugs did not perform well in clinical trials.
Integrated Stress Response
The new approach inhibits two p53 repressors and activates a gene network called Integrated Stress Response. Now the team was able to achieve cancer cell death.
It has been established that changes to certain genes alter the manner in which our cells function. These altered (mutated) genes fall under two categories that can potentially cause normal cells to be cancerous: tumor suppressors and oncogenes.
Mutations in oncogenes and tumor suppressors will activate abnormal cell growth. Both mutated gene types have high rates of cell division and growth.
Two proteins that repress p53 within tumor cells are MDM2, a major repressor, and PPM1D, a minor repressor. Studies are underway to learn how the mechanisms that inhibit these repressors will lead to cancer cell death.
Researchers do know, however, that blocking MDM2 and PPM1D will result in better performance by p53 to cause cell death. As discussed, the killing activity is accomplished through a complementary gene network called the Integrated Stress Response.
This new development is hailed as a significant milestone after almost two decades of research conducted by Professor Zdenek Andrysik of CU.
A Recap
Professors Andrysik and Espinosa have shown that by inhibiting PPM1D and MDM2, the Integrated Stress Response is activated. This in turn stimulates the ATF4 protein which partners with p53 and causes the death of cancer cells. Professor Andrysik said that the process shows promise in the treatment of many other types of cancer.
In addition, the professors knew that the drug Nelfinavir, which was initially approved for HIV therapy, activates the Integrated Stress Response. They repurposed it to be used in combination with MDM2 inhibitors.
Professor Espinosa reiterates that for the past twenty to thirty years the emphasis has been on finding solutions to the broad-brush approach of radiation and chemotherapy. He believes that they are now on track to find targeted solutions to attack cancer.
