A Promising New Approach Targets Dormant Yet Deadly Cancer Cells

One of the main hallmarks of cancer is out-of-control cell division—the reason chemotherapy drugs target rapidly dividing cells in primary tumors or in tumors that have spread to other parts of the body. However, even before a primary tumor is detectable, some of its cells may travel to distant organs where they thwart chemotherapy by entering a dormant state. Years later, those cells may “awaken” to form metastatic tumors, which account for more than two-thirds of cancer deaths.

A study by researchers at the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center has shown that an experimental drug is able to target dormant disseminated cancer cells (DCCs) (i.e., dormant cancer cells that have spread from the primary tumor) and prevent those cells from causing metastases. The research is described in a new study published online on December 15 in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“This is the first study to show that it’s possible to target the signaling pathway that dormant DCCs require for staying alive during their long hibernation,” said Julio A. Aguirre-Ghiso, PhD, Co-Leader, Tumor Microenvironment & Metastasis Research Program, Founding Director,  Cancer Dormancy and Tumor Microenvironment Institute, Montefiore Einstein Comprehensive Cancer Center, and the Rose C. Falkenstein Chair in Cancer Research, Professor, Cell Biology, Oncology, Medicine, Albert Einstein College of Medicine, and the study’s senior author.

In 2006, Dr. Aguirre-Ghiso and colleagues made the unexpected finding that survival of dormant DCCs is highly dependent on a signaling pathway called Protein Kinase R-like ER Kinase (PERK). Since then, Dr. Aguirre-Ghiso and his team have investigated how PERK becomes activated in dormant DCCs and have looked for compounds that can selectively eliminate dormant cancer cells by inactivating the PERK pathway.

The Clinical Cancer Research paper featured several experiments in which the PERK inhibitor HC4 (HC-5404) successfully blocked metastasis in mouse models of cancer by killing dormant DCCs. Key experiments involved a mouse model in which a subtype of breast cancer (HER2+) develops and spreads spontaneously, forming lung metastases similar to those found in humans. Mice known to carry dormant DCCs in their lungs and bone marrow were treated for two to four weeks with HC4. Compared with untreated animals, the HC4-treated mice were found to have significantly fewer metastatic lung lesions and fewer dormant DCCs in their bone marrow. HC4 was exerting its metastasis-inhibitory effect by eliminating the dormant DCCs that seed metastases.

The HC4 (HC-5404) is under development at HiberCell and recently completed a phase 1 clinical trial for solid tumors (NCT04834778). Dr. Aguirre-Ghiso’s research on HC4 was instrumental in the founding of HiberCell. He is a scientific co-founder, scientific advisory board member and equity owner of HiberCell and receives financial compensation as a consultant to the company.

The Clinical Cancer Research paper is titled “A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response-Dependent Survival of Quiescent Cancer Cells.” In addition to Dr. Aguirre-Ghiso, other authors on the paper who are currently or formerly at Einstein are Wei Zheng, PhD, Anna Adam-Artigues, PhD, Xin Huang and Sho Fujisawa, PhD. Additional authors are Veronica Calvo, PhD, David Liu, Maria Fumagalli, David Surguladze, MD, Michael E. Stokes, PhD, Ari Nowacek, MD, PhD, Mark Mulvihill, PhD, and Eduardo F. Farias, PhD, all at currently or formerly HiberCell; and Kirk A. Staschke, PhD, Julie Cheung, BSc, and Ana Rita Nobre, PhD, all formerly at the Icahn School of Medicine at Mount Sinai.