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CHOP Researchers Exploring New Approach for High-Risk Neuroblastoma
shafere1 [at] chop.edu (By Emily Shafer)
High-risk neuroblastoma is notoriously difficult to treat because it is often highly resistant to chemotherapy. Researchers at Children’s Hospital of Philadelphia are working to develop ways to overcome this treatment resistance and toxicity, supported by a new grant from the National Cancer Institute.
The new study, which recently launched, is evaluating a treatment that is designed to skip over the healthy cells and deliver a higher dose of the drug to the tumor. This would improve the therapeutic window, which is the drug dosage range required to effectively manage the disease, without having major toxic effects.
“Ideally, drugs would be effective at much lower levels than what causes toxicity,” said Michael Chorny, PhD, a CHOP investigator and research associate professor at Perelman School of Medicine at the University of Pennsylvania. “Many of the chemotherapeutics used for neuroblastoma have a very low selectivity for tumor cells, and as a result, the therapeutic window is very narrow or may not even exist. In the meantime, the treatment is also killing normal cells and causing strong adverse effects. Thus, we cannot increase the dose, which poses the risk that the disease will be undertreated and might come back in a more aggressive form.”
Dr. Chorny and Garrett M. Brodeur, MD, Audrey E. Evans Endowed Chair in Pediatric Oncology at CHOP, and professor of Pediatrics at Perelman School of Medicine at the University of Pennsylvania, are co-primary investigators for the study. They will be evaluating a dual-selective experimental drug delivery strategy that targets neuroblastoma in two different ways: modulating tumor accumulation of the drug driven by norepinephrine transporter (NET) and confining the cell killing effect to rapidly dividing tumor cells. They collaborated with Ivan Alferiev, PhD, research associate professor of Pediatrics at CHOP, to engineer the prodrug designed to achieve these two goals. Prodrugs are medications that are inert until they are activated by the body.
One of the ways the investigational prodrug works is by increasing its selectivity to the NET that is expressed only by neuroendocrine cells. The drugs then bypass healthy cells that do not express NET. The other way the drug works is by directing its effect exclusively to dividing cells, thus making sure that it acts only on the neuroblastoma cells but not on other cells expressing NET found in healthy organs that normally would not be dividing. This will allow much more drug to be delivered the tumor, but also to make it act with much greater selectively on the cancer cells.
“On their own, each of these selectivities may be less than perfect,” Dr. Brodeur said. “But we hypothesize that pursuing these selectivities in parallel will optimize treatment and allow us to get much more drug to the tumor so that we can overcome many mechanisms of drug resistance. In the end, we need more effective and less toxic therapy, and this formulation achieves both of those goals.”
Although this preclinical study in animal models focuses on neuroblastoma, there are other cancers that express NET, and this novel drug delivery conceptapplies to other tumor types, Dr. Brodeur said.