Nuclear pore proteins may be effective anticancer targets for prostate cancer, according to researchers at Sidney Kimmel Cancer Center – Jefferson Health in Philadelphia. Their findings, published in the journal Cell, report that a particular gatekeeper—the nuclear pore protein called POM121—traffics molecules that increase tumor aggressiveness in prostate cancer.
First author Veronica Rodriguez-Bravo, PhD, assistant professor of cancer biology at Thomas Jefferson University in Philadelphia, said that blocking this gatekeeper prevents several molecules from reaching their targets in the nucleus, thus decreasing tumor growth. She and her colleagues showed that blocking POM121 transport helps restore chemotherapy efficacy in preclinical models of the disease.
“It was surprising to us to find such a striking nuclear pore composition change in advanced metastatic prostate cancer--specifically considering it was not known before and that these changes are related to mechanisms driving the disease,” Rodriguez-Bravo told Cancer Network.
Using computational biology techniques that integrate genetic information from prostate cancer patients and experimental models, the investigators dissected the functions of nuclear pore proteins across the course of the disease from early to late stages. They discovered that an abundance of the POM121 component of the nuclear pore was associated with aggressive tumors that continue to grow despite standard therapy. The researchers also showed that blocking POM121 could block molecules such as MYC, E2F1, and the androgen receptor from reaching the nucleus to activate tumor growth. These three molecules are known to drive aggressive prostate cancer.
Study coauthor Josep Domingo-Domenech, MD, PhD, associate professor of medical oncology at Sidney Kimmel Medical College at Jefferson, said this study demonstrates that blocking the import machinery may be an effective strategy to target the undruggable. MYC is an oncogenic transcription factor in which successful direct blockage does not exist, he said.
“The clinical implication of our study is the description of a paradigm-shifting treatment option for advanced prostate cancer patients. We believe analyzing the status of the nuclear pore will allow identification and stratification of patients in levels of aggressiveness of the tumors. Furthermore, this information will hopefully allow nuclear import inhibitors to be considered as a therapeutic option for such patients,” Domingo-Domenech told Cancer Network.
The researchers are now hoping to identify specific chemical compounds against POM121 and determine their efficacy and toxicity for use in human clinical trials. Soroush Rais-Bahrami, MD, assistant professor of urology and radiology and codirector of the University of Alabama at Birmingham Program for Personalized Prostate Cancer Care in Birmingham, Alabama, said this study shows a promising finding which may change the paradigm of how patients are treated in the future.
“We may be able to sensitize patients with advanced metastatic prostate cancer to various treatments they may otherwise be resistant to. It does need further validation in preclinical studies and clinical trials prior to altering the treatment workflow for these patients with incurable forms of prostate cancer. However, it may provide a path for more successful treatments,” Rais-Bahrami told Cancer Network.