Norfolk, VA, Dec. 16, 2021 (GLOBE NEWSWIRE) -- Old Dominion University researchers have discovered a potential major treatment approach to overcome cancer therapy resistance through successful exploitation of a common vulnerability in the survival of cancer cells. Cancer therapy resistance is responsible for approximately 90% of cancer-related deaths.
As published today in the “Proceedings of the National Academy of Sciences (PNAS) of the United States of America,” researchers report in a laboratory study that a specially engineered gas discharge, composed of charged and highly reactive molecules known as cold atmospheric plasma (CAP), was highly effective in killing drug-resistant cancer cells without harming the surrounding healthy cells. Counterintuitively, this was achieved not by maximizing CAP intensity for blunt killing but by reducing its intensity for simultaneous blockade of multiple cancer cell survival pathways.
Cancer cells are exceptionally flexible in evading therapy by adapting to alternative ways to proliferate, survive and acquire drug resistance. As a consequence of aerobic life, many cancer cell survival pathways are intimately influenced by oxygen and its products of reactive oxygen species (ROS). This vulnerability has been recognized as an important therapy target; however its effective exploitation remains elusive. At present, scientists are developing a number of ROS-generating approaches to explore when cancer cells become particularly vulnerable.
The study was led jointly by co-corresponding authors Michael Kong, Ph.D., and Hai-Lan Chen, Ph.D., at Frank Reidy Research Center for Bioelectrics (FRRCBE) at ODU. They noted a common irony with many types of ROS, which at a high dose may kill cancer cells but almost always promote cancer cell survival, or conversely an ROS at low dose may suppress the survival of cancer cells but is ineffective in killing cancer cells. Indeed, this may be a limiting factor in many ROS-generating therapies. Kong and Chen pondered whether a unique collection of different ROS may suppress the survival pathways of cancer cells at their low dose and kill them with their synergy. They had found that their idea worked with drug-resistant cancer cell lines from different types of tumors. However, they were keen to test the idea in clinically relevant settings using drug-resistant cancer cells from patients.
In need of appropriate clinical samples, they approached Huntsman Cancer Institute (HCI) at the University of Utah, where the HCI Hematology Biobank provided patient-donated leukemia samples with the precise characteristics needed to conduct the study to determine whether CAP blocks the survival strategies used by leukemia cells. “Our entire team of study coordinators, specimen processors, database specialists and healthcare providers spent many years collecting thousands of samples donated by thousands of patients at Huntsman Cancer Institute so we could have just the right diagnosis, cell type, cell count, treatment histories and mutations for this study,” said study co-first author Tony Pomicter, MS, who leads the team that runs HCI’s Hematology Biobank.
Kong, Batten Endowed Chair in Bioelectrics at ODU, reflected on how the journey to the discovery started in a different field.
“In our work in developing CAP to overcoming drug-resistant microbial pathogens, we noted that an excellent antimicrobial activity of CAP is centered on the cooperation of its many components,” he said. “We reasoned that potent anticancer activity may be achieved by engineering such cooperation of CAP’s many components at very low doses to kill cancer cells. To our surprise, the strategy of leveraging the cooperation of diverse, low-dose reactive oxygen species, ions and other effectors actually enables simultaneous blockade of three fundamental cancer cell resistance pathways, leading to a very high-rate of death in drug-resistant leukemia cells.”
Kong cited the central importance of the interdisciplinary cross-fertilization between gas plasma physicists, biomedical engineers and molecular biologists as well as the catalyst of working with Huntsman Cancer Institute.
Chen, research associate professor in molecular biology, and Bo Guo, Ph.D., study co-first author, both agree.
“Chronic myeloid leukemia is an exceptional model to test CAP since it is caused by a single molecular event and the mutations are well understood,” Chen said. “Efficacy data with chronic myeloid leukemia cells allowed us to establish a clear picture of the underlying mechanisms with little risk of ambiguity. We look forward to future collaborations with Huntsman Cancer Institute to take this work forward on leukemia and other cancers.”
Kong and Chen worked with the HCI team to identify the specific samples from its biobank for study. Using the detailed records the HCI team developed for its biobank, they identified blood samples with the most-difficult-to-treat mutation, as well as samples from healthy donors. These leukemia and healthy cells were cultured in the lab so the team could conduct experiments using different formulations of CAP. “It was critical to evaluate healthy cells alongside leukemia samples,” Pomicter said. “We always need to understand whether a novel agent is killing all cells, which means it is a toxin, or selectively killing cancer cells, which means it is potentially a drug.”
The ODU-HCI team found that the cold atmospheric plasma appears to be effective at killing the leukemia cells, but not the healthy cells, making it a promising approach for possible future use in the clinic on other difficult-to-treat hematologic malignancies like acute myeloid leukemia and acute lymphoblastic leukemia, as well as drug-resistant solid tumors.
“This is a highly promising and novel approach to drug resistance and I look forward to clinical studies by this team and others,” said Brian Druker, MD, director of the Oregon Health & Science University Knight Cancer Institute. Druker, who was not involved in the study, is widely recognized in the field for his work in the development of a new drug for treatment of chronic myeloid leukemia.
The researchers acknowledge the critical role of all study authors, including Guo, who helped to formulate Trident CAP and performed experiments. Michael Deininger, M.D., Ph.D., at HCI at the time of the study and now executive vice president and chief scientific officer at Versiti Blood Research Institute, provided critical leadership in the expansion of HCI’s Hematology Biobank. Other study authors include Francis Li, Sudhir Bhatt and Chen Chen of Old Dominion University; and Wen Li, Miao Qi, Dei-Hui Xu and Chen Huang of Xi’an Jiotong University in China. HCI’s Research Informatics and Biorepository and Molecular Pathology Shared Resources were instrumental in the work. The study was funded by Batten Endowed Chair Fund at Old Dominion University and Huntsman Cancer Foundation.
###
About Old Dominion University:
Old Dominion University, located in Norfolk, is Virginia’s forward-focused public doctoral research institution with approximately 23,500 students, rigorous academics, an energetic residential community and initiatives that contribute $2.6 billion annually to Virginia’s economy.
About the Frank Reidy Research Center of Bioelectrics at Old Dominion University:
Frank Reidy Research Center of Bioelectrics (FRRCBE) at Old Dominion University represents the largest research concentration in the field of biological effects of pulsed electric field and gas plasma in the US. With diverse expertise in physical and life sciences and close collaborative links medical schools, FRRCBE faculty members focus on basic and translational research as well as education of next-generation scientists and technologists
About Huntsman Cancer Institute at the University of Utah:
Huntsman Cancer Institute (HCI) at the University of Utah is the official cancer center of Utah and the only National Cancer Institute (NCI)-Designated Comprehensive Cancer Center in the Mountain West. The campus includes a state-of-the-art cancer specialty hospital, and two buildings dedicated to cancer research. HCI provides patient care, cancer screening, and education at community clinics and affiliate hospitals throughout the Mountain West. HCI is consistently recognized among the best cancer hospitals in the country by U.S. News and World Report. The region’s first proton therapy center opened in 2021 and a major hospital expansion is underway. HCI is committed to creating a diverse and inclusive environment for staff, students, patients, and communities. Advancing cancer research discoveries and treatments to meet the needs of patients who live far away from a major medical center is a unique focus. More genes for inherited cancers have been discovered at HCI than at any other cancer center, including genes responsible for breast, ovarian, colon, head and neck cancers, and melanoma. HCI was founded by Jon M. and Karen Huntsman.
Attachment
