November 20, 2023—(BRONX. NY)—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 (MECCC) 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 November 20 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 Aguirre-Ghiso, Ph.D., the study’s senior author, co-leader of MECCC’s Tumor Microenvironment & Metastasis Research Program, founding director of MECCC’s Cancer Dormancy and Tumor Microenvironment Institute, and professor cell biology, of oncology, and of medicine and the Rose C. Falkenstein Chair in Cancer Research at Albert Einstein College of Medicine.
In 2006, Dr. Aguirre-Ghiso and colleagues made the unexpected finding that survival of dormant DCCs is highly dependent on a signaling pathway called PERK (Protein Kinase R-like ER Kinase). 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 metastasis 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.
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.
Julio Aguirre-Ghiso, Ph.D.
“This work could lead to a new way of targeting metastatic disease,” said Dr. Aguirre-Ghiso. “We’re optimistic about being able to combine conventional therapies that eliminate rapidly dividing cancer cells with a therapy such as the PERK inhibitor HC4 that kills dormant cancer cells, thereby hampering a cancer’s ability to persist and then reappear in the form of deadly 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 UPR-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, Anna Adam-Artigues, Ph.D., Xin Huang, and Sho Fujisawa, Ph.D. Additional authors are Veronica Calvo, Ph.D., David Liu, Maria Fumagalli, David Surguladze, M.D., Michael E. Stokes, Ph.D., Ari Nowacek, M.D., Ph.D., Mark Mulvihill, Ph.D., and Eduardo F. Farias, all at currently or formerly HiberCell; and Kirk A. Staschke, Ph.D., Julie Cheung, B.Sc., and Ana Rita Nobre, Ph.D., all formerly at the Icahn School of Medicine at Mount Sinai.