Renslo Lab develops new type of targeted chemotherapy that proves effective in mice
Research in the lab of UCSF School of Pharmacy faculty member Adam Renslo, PhD, has developed a new way of selectively targeting cancer cells with drugs. In experiments with mice, the new approach allowed for the delivery of fifty times higher doses of chemotherapy to tumors while avoiding toxic effects on healthy cells.
This novel method is based on the fact that cancer cells contain unusually high levels of free iron—as distinct from the iron that is bound to protein molecules throughout the body. This is a result of the increased requirements for such iron to support the revved-up metabolism of the rapidly proliferating malignant cells.
Research in the Renslo Lab developed a new class of targeted prodrugs (drugs activated by processes within the body) by designing a molecular scaffold, dubbed TRX, which only breaks apart and releases its drug payload when it encounters free ferrous iron.
The new strategy and its results are described in a study published in its final version online on December 12, 2016 in the Journal of Medicinal Chemistry, senior-authored by Renslo and lead-authored by Benjamin Spangler, PhD, a former graduate student in the lab who is now a postdoctoral fellow at Novartis Institutes for BioMedical Research.
“We chose two very potent and toxic chemicals on purpose. …we wanted to show that even these drugs could be safe and effective—if they could be targeted.” — Adam Renslo, PhD
The scientists showed that the TRX scaffold blocked the toxic effects of its enclosed chemotherapy compounds in healthy cell cultures, but released the cell-killing cargo when delivered to cancerous cell lines. They further demonstrated their approach’s efficacy in mouse xenograft models, in which human cancers are grafted onto laboratory mice. In those animal models, they established that very little toxic chemotherapy was released outside of the tumors; as a result, the mice could tolerate as much as a 50-fold higher dose of the prodrug than the chemotherapy agent on its own.
For the tumor-activated chemotherapies, Renslo said, “We chose two very potent and toxic chemicals on purpose. These compounds are too toxic and non-selective to be used in patients on their own, but we wanted to show that even these drugs could be safe and effective—if they could be targeted.”
“Most chemotherapy drugs are already being used at their maximum tolerable dose. Clinicians would like to give higher doses if they could without harming the patient,” he said.
Indeed, the JMC study found that the combination of the higher doses and the prodrug’s improved targeting of cancer cells resulted in robust and lasting reduction of the tumors in the mice. This suggests a particularly exciting but as yet untested possibility—that cancers would be less likely to evolve resistance to iron-targeted chemotherapy.
“As far as we know, malignant cancers must acquire and maintain elevated free ferrous iron in order to replicate and spread,” Renslo said. “They cannot switch to another metal for these purposes; and so, any mutations in cancer cells that reduced their free iron enough to avoid triggering the prodrug would likely also make the cells less aggressive. We think there’s nowhere they can hide.”
The Renslo Lab is based in the School’s Department of Pharmaceutical Chemistry. The new study’s School co-authors include Renslo’s department colleague James Wells, PhD, and Shaun Fontaine, PhD, a former postdoctoral scholar in the Renslo lab, who is now a scientist at ProLynx LLC.
About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American west. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.