Researchers from the University of California at San Francisco have discovered a promising method of dealing with a deadly resistant prostate cancer treatment. Analysis hundred human prostate tumors showed that the most aggressive cancers dependent cellular stress response. Experiments on mice and human cells have shown that blocking the stress response of the experimental drug leads to self-destruction of cancer cells that are resistant to resistance, while normal cells immutability. A new study published in Science Translational Medicine.
"We have learned that cancer cells become" dependent "on the protein synthesis to stimulate demand growth, but excessive protein synthesis can be toxic, - says senior author David Ruggiero -. We have found the molecular restrictions that allow cancer cells to control their addiction and show that if we remove these restrictions, the cells quickly "burn out."
Prostate cancer is one of the causes of death in men. Tumors that do not respond to surgery or radiation therapy, is usually treated with hormone therapy, which targets the cancer dependent on testosterone. Unfortunately, most cancers eventually develop resistance to hormonal therapy and are becoming even more aggressive.
Many cancers contain mutations in the genes that lead to the production of proteins with such a high speed that they initiate built-in mechanisms of self-destruction of cells. But aggressive, treatment-resistant prostate cancer usually contains several such mutations.
To investigate this issue, researchers have developed a prostate tumor model, comprising a pair of mutations observed in up to 50 percent of patients with refractory prostate cancer. They were surprised to find that aggressive types of cancer associated with these mutations actually have a lower protein synthesis performance compared with weaker cancers with a single mutation.
Experiments have shown that a combination of MYC mutations and PTEN cell initiates of the control system, called resolvable protein response (UPR), which responds to cellular stress, reducing protein synthesis levels throughout the cell. These mutations alter the activity of a protein called eIF2a, the main regulator of protein synthesis, transforming it into an alternative form P-eIF2a.
To evaluate whether P-eIF2a levels in tumors of patients used to predict the development of aggressive disease, the researchers examined 422 tumor surgically extracted from patients with prostate cancer. They measured the protein levels of PTEN, Myc and P-eIF2a in these tumors, and then examined how these biomarkers predicting outcome of patients using clinical observation of the subsequent data.
They found that levels of P-eIF2a are an indication of worse outcomes in patients with PTEN-tumor mutations. Scientists have identified ISRIB molecule that changes the effect of the activity of P-eIF2a. They tested ISRIB in mice with prostate tumors and human cancer cell lines and found that the drug forced aggressive cancer cells operate at full capacity for protein synthesis, which leads to their destruction. In the mouse prostate tumor PTEN / MYC started to decline within 3 weeks of initiation of treatment ISRIB not recovered after 6 weeks of treatment.
The researchers hope that this discovery will quickly lead to clinical trials ISRIB molecules and related drugs for patients with advanced, aggressive prostate cancer.