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Researchers hope that creating a model system that more closely simulates the environment faced by cells in the human blood stream will help advance blood cancer research efforts.
Dr. Jason Cantor, Assistant Professor in UW’s Department of Biochemistry and an investigator in the Morgridge Institute for Research, is leading a research effort to uncover new therapeutic targets for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) – specifically, using CRISPR-based DNA-editing technology to discover novel T-ALL vulnerabilities in an environment that better mimics the growth conditions that these cells would encounter in the human body.
If successful, this work could reveal promising new T-ALL therapeutic targets with unprecedented relevance to human physiology, and therefore a potentially higher likelihood for successful translation in the clinic.
“If we start out by studying these cells in a system that models an environment they’ll arguably never see, it becomes more difficult, I think, to expect those outcomes to translate as well as we would like,” Cantor said. “In terms of understanding basic cancer physiology, and even drug sensitivity, these types of modeling questions become particularly relevant.”
He is partnering with physician-scientist Dr. Christian Capitini, the Jean R. Finley Professor in Pediatric Hematology and Oncology in UW’s Department of Pediatrics and Co-leader of Developmental Therapeutics at Carbone Cancer Center, to eventually test his team’s findings in mouse models as well.
“What’s exciting about this approach is that it’s such a departure from the traditional way that we grow cells that there is a real possibility that we can unlock a whole bunch of new therapy targets because we are using something that better represents what’s actually in the body,” Capitini said.
Cantor received a 2021 Hartwell Individual Biomedical Research Award to pursue this project, which provides $100,000 in annual funding over the next three years. He is among 10 recipients nationwide.
Cantor said historically, growth media used in the lab prioritize cell survival and their ability to rapidly proliferate. However, if these historical reagents provide nutrient conditions that don’t reflect those in a living human, such as unnaturally high glucose levels, they can influence the results that researchers observe in the lab and how well these may translate in a more advanced stage of study.
He also noted that a very high percentage of promising pre-clinical cancer therapies fail to translate in the clinic—a major problem attributed in part to the limited predictive value of existing model systems.
“Several years ago, we posed what I think now was a deceptively basic question: Do the growth media that we use for nearly all of cell culture work, do they provide nutrient conditions that look at all like those seen by cells in the body? And, thinking about the objectives behind the development of those classic media formulations, the answer of course proved to be a pretty resounding ‘no’,” Cantor said.
Cantor previously developed Human Plasma-Like Medium (HPLM), the first synthetic cell culture medium designed to recapitulate the metabolic composition of human blood more closely – or, more broadly, of any biofluid. HPLM became commercially available from Thermo Fisher Scientific in 2021.
For this research effort, his team will combine HPLM with a “continuous flow” bioreactor system that allows them to tightly control and monitor components of the cell environment, such as temperature, pH, oxygen tension, and nutrient availability.
By taking advantage of this platform, Cantor said that his team can also more precisely address other questions as well – for example, how manipulating the levels of specific blood metabolites can either affect cell growth or perhaps impact drug efficacy.
“One of our bigger picture ideas, instead of just giving a patient a drug, can we use what we discover at the bench to ultimately tune how effective that drug works by manipulating specific metabolite levels in the blood?” Cantor asked.
Capitini is excited by the team’s focus on tumor microenvironment specific to the bloodstream.
“A lot of that study is happening in the solid tumor space, for adults and pediatrics, but less commonly in blood cancers,” he said.
Capitini’s clinical background complements the group’s work by helping determine the studies with the most feasible potential to be successful in live testing. The use of Cantor’s media, in addition to the close attention to an authentic leukemia microenvironment, gives Capitini more hope for effective translation for new treatments, especially for pediatric patients.
“Childhood cancers are relatively understudied and underfunded, so having someone with Jason’s expertise really dedicated to a project that could impact the lives of a lot of children is a real honor, and I hope that something really great comes out of this collaboration,” he said.