A UNC Eshelman School of Pharmacy scientist is a leader in a large research collaboration that has discovered a new compound that suppressed the spread of cancer — a process known as metastasis — in three different animal models of human cancer.
When cancer metastasizes, it spreads from its starting point to a different part of the body. The new compound created by the research team and named metarrestin significantly inhibited metastasis in human breast cancer, human prostate cancer and human pancreatic cancer that had been grafted into mice. Mice treated with the compound had fewer metastatic tumors in the lungs and liver and lived significantly longer than mice that did not receive treatment.
Kevin Frankowski, Ph.D., a research assistant professor in the School’s Division of Chemical Biology and Medicinal Chemistry, is the co-lead author of the study and the chemistry lead on the project. He is a member of the School’s Center for Integrative Chemical Biology and Drug Discovery. The research team’s finding were published in Science Translational Medicine.
Along with Frankowski, scientists from Northwestern University in Chicago, the National Cancer Institute, the University of Kansas and the National Center for Advancing Translational Science all worked together to make the discovery possible.
“We’ve come a long way in being able to do surgery on the primary tumor. Radiation and chemotherapy work fairly effectively,” Frankowski said. “But once a cancer has metastasized to other organs, there is a largely unmet medical need for treating those metastatic lesions before they lead to death.”
For example, pancreatic cancer has a tendency to metastasize early, and most people don’t know they have it until it does. Once metastasis has occurred, the five-year survival rate for pancreatic cancer patients is 5 to 7 percent, which has not changed over the last 30 years. Metarrestin treatment more than doubled the time the mice with pancreatic cancer survived when treatment was begun after the cancer had already spread to the liver.
Metastasis remains a leading cause of cancer mortality in part because scientists have not succeeded in identifying all the key genetic or protein markers associated with cancer metastasis, which has made developing specific inhibitors for metastasis difficult.
In this study, the research team targeted a structure that forms in cancer cells called the perinucleolar compartment. The PNC is a complex structure in the cell’s nucleus that is associated with metastatic behavior. It was discovered in the 1990s by Sui Huang, M.D., Ph.D., an associate professor at Northwestern University and senior author of the study.
“What’s unusual about the perinucleolar compartment is that it is usually only seen in metastatic cells,” Frankowski said. “While the PNC’s function is unclear, it has been associated with the progression of various types of cancer, such as breast, ovarian and colon cancers. The higher the PNC level, the worse the prognosis.”
For this new study, NCATS scientists tested 140,000 compounds to find any that would disrupt the perinucleolar compartment with no obvious toxicity. They finally found such a compound and made a large number of structural modifications to make it more effective. The compound with the best activity, selectivity and other properties was chosen for further investigation in animal proof-of-concept studies.
The researchers then introduced cancer cells originally derived from human pancreatic cancer and prostate cancer into mouse organs to generate tissue grafts that were then implanted in mice. These mice were treated with metarrestin and a control treatment.
In the breast cancer experiment, cancer cells were collected from a patient whose breast cancer had metastasized. The cells were directly inoculated into mice without going through the culture system. This type of tissue graft, called a patient-derived xenograft, is considered more representative of a human cancer condition.
“This is pretty exciting research,” Frankowski said. “We’re still a long way from a drug candidate, but we’re pretty optimistic about the preclinical potential of this compound.”
Authors and Funding
The research was funded by the National Center for Advancing Translational Sciences and NCI through their intramural programs, the National Human Genome Research Institute grant U54HG005031, the National Institute of General Medical Sciences grants R01GM078555 and R01GM0115710, NCI grant 2 P30 CA060553-19, the V Foundation, a donation from the Baskes family to the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, the Robert H. Lurie Comprehensive Cancer Center – Translational Bridge Program Fellowship in Lymphoma Research and the Molecular Libraries Initiative funding (U54HG005031) to the University of Kansas Specialized Chemistry Center.
- Kevin J. Frankowski, Ph.D., Research Assistant Professor, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
- Chen Wang, Ph.D., M.S., Postdoctoral Fellow, Northwestern University
- Samarjit Patnaik, Ph.D., Research Scientist, NIH National Center for Advancing Translational Sciences
- Frank J. Schoenen, Ph.D., Associate Director, The University of Kansas Specialized Chemistry Center
- Noel Southall, Ph.D., Leader of Informatics, NIH National Center for Advancing Translational Sciences
- Dandan Li, Ph.D., Postdoctoral Research Fellow, NIH National Cancer Institute
- Yaroslav Teper, Ph.D., M.S., Biological Scientist, NIH National Cancer Institute
- Wei Sun, Ph.D., Staff Scientist, NIH National Center for Advancing Translational Sciences
- Irawati Kandela, Ph.D., Research Assistant Professor, Northwestern University
- Deqing Hu, Ph.D., Postdoctoral Fellow, Northwestern University
- Christopher Dextras, Research Scientist, NIH National Center for Advancing Translational Sciences
- Zachary Knotts, Cancer Research Fellow, NIH National Cancer Institute
- Yansong Bian, M.D., Ph.D., NIH National Cancer Institute
- John Norton, Ph.D., M.B.A., Northwestern University
- Steve Titus, Staff Scientist, NIH National Center for Advancing Translational Sciences
- Marzena A. Lewandowska, Ph.D., Postdoctoral Associate, Northwestern University
- Yiping Wen, Northwestern University
- Katherine I. Farley, Ph.D. Candidate, Yale University
- Lesley Mathews Griner, Ph.D., Research Scientist, NIH National Center for Advancing Translational Sciences
- Jamey Sultan, NIH National Center for Advancing Translational Sciences
- Zhaojing Meng, Ph.D., Staff Scientist, Frederick National Laboratory for Cancer Research
- Ming Zhou, Ph.D., M.S., Senior Research Scientist, Frederick National Laboratory for Cancer Research
- Tomas Vilimas, Ph.D., Staff Scientist, Frederick National Laboratory for Cancer Research
- Astin S. Powers, Ph.D., Clinical Fellow, National Institutes of Health Center for Cancer Research
- Serguei Kozlov, Ph.D., M.B.A., Principal Scientist, Frederick National Laboratory for Cancer Research
- Kunio Nagashima, Center for Molecular Microscopy, Frederick National Laboratory for Cancer Research
- Humair S. Quadri, M.D., Surgical oncology Fellow, NIH National Cancer Institute
- Min Fang, Ph.D., M.S., Research Assistant Professor, Tufts University School of Medicine
- Charles Long, Research Technician, Northwestern University
- Ojus Khanolkar, Student Researcher, Northwestern University
- Warren Chen, Northwestern University
- Jinsol Kang, Student Researcher, Northwestern University
- Helen Huang, Biostatistics Research Associate, Northwestern University
- Eric Chow, Northwestern University
- Esthermanya Goldberg, Northwestern University
- Coral Feldman, Student Researcher, Northwestern University
- Romi Xi, Northwestern University
- Hye Rim Kim, M.S., Cancer Biology Graduate Student, Emory University School of Medicine
- Gary Sahagian, Ph.D., Professor, Tufts University School of Medicine
- Susan J. Baserga, M.D., Ph.D., Professor, Yale University
- Andrew Mazar, Ph.D., Adjunct Professor, Northwestern University
- Marc Ferrer, Ph.D., Team Leader of Chemical Genomics Center, NIH National Center for Advancing Translational Sciences
- Wei Zheng, Ph.D., Team Leader of Biology, NIH National Center for Advancing Translational Sciences
- Ali Shilatifard, Ph.D., Chair of Dept. of Biochemistry and Molecular Genetics, Northwestern University
- Jeffrey Aubé, Ph.D., Fred Eshelman Distinguished Professor, UNC Eshelman School of Pharmacy
- Udo Rudloff, M.D., Ph.D., Investigator, NIH National Cancer Institute
- Juan Jose Marugan, Ph.D., Team Leader of Chemistry, NIH National Center for Advancing Translational Sciences
- Sui Huang, M.D., Ph.D., Associate Professor, Northwestern University