Research from WorldCare Consortium™ member Jefferson Health finds blocking nuclear gateways that traffic cancer-promoting molecules to nucleus could offer a new way to target aggressive cancer
It has been nearly impossible to develop chemicals that would block certain molecular drivers of cancer growth, making these particular molecules, which promote cancer growth, “undruggable.” Many of them function by passing cancer-promoting information through a gate in the cell nucleus, where the instructions are carried out, but now, researchers at WorldCare Consortium™ member Jefferson Health have found a way to block the nuclear gates used by these molecules. They’ve also shown that this inhibition can halt aggressive prostate cancer in mice with human tumors. Drs. Veronica Rodriguez-Bravo, PhD, and Josep Domingo-Domenech, MD, PhD, of WorldCare Consortium™ member Jefferson Health co-led the research, which was published in Cell on August 9, 2018. This is the first demonstration that nuclear pore proteins may be effective anti-cancer targets for prostate cancer.
Researchers found that a particular gatekeeper, the nuclear pore protein called POM121, traffics molecules that boost the aggressiveness of tumors, and that blocking this gatekeeper prevents several molecules from reaching targets in the nucleus, thereby decreasing tumor growth. They also showed that blocking POM121 transport helps restore the efficacy of chemotherapy in preclinical models of the disease.
Using computational biology techniques that integrate genetic information from prostate cancer patients and experimental models, investigators were able to dissect the functions of nuclear pore proteins across the course of prostate cancer from early to late stages. They discovered an association between aggressive tumors that continue to grow despite standard therapy and an abundance of the POM121 component of the nuclear pore. The researchers were able to then show that blocking POM121 or disrupting its partner Importin β could block molecules such as MYC, E2F1, and the androgen receptor, (molecules which all drive aggressive prostate cancer) from reaching the nucleus to activate tumor growth.
“This study shows that blocking the import machinery may be an effective strategy to target the undruggable,” stated co-corresponding author Dr. Domingo-Domenech Associate Professor of Medical Oncology at the Sidney Kimmel Medical College at WorldCare Consortium™ member Jefferson Health. “For example, MYC is an oncogenic transcription factor wherein successful direct blockage does not exist. We provide a remarkable approach to target not only MYC but also E2F1 by impairing their nuclear import, critical for their oncogenic function in prostate cancer.”
Journal Reference: Veronica Rodriguez-Bravo, Raffaella Pippa, Won-Min Song, Marc Carceles-Cordon, Ana Dominguez-Andres, Naoto Fujiwara, Jungreem Woo, Anna P. Koh, Adam Ertel, Ravi K. Lokareddy, Alvaro Cuesta-Dominguez, Rosa S. Kim, Irene Rodriguez-Fernandez, Peiyao Li, Ronald Gordon, Hadassa Hirschfield, Josep M. Prats, E. Premkumar Reddy, Alessandro Fatatis, Daniel P. Petrylak, Leonard Gomella, W. Kevin Kelly, Scott W. Lowe, Karen E. Knudsen, Matthew D. Galsky, Gino Cingolani, Amaia Lujambio, Yujin Hoshida, Josep Domingo-Domenech. Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import. Cell, 2018; DOI: 10.1016/j.cell.2018.07.015