(photo credit: Isral Weiss)
PHILADELPHIA – By studying tumor biology at the molecular level,
researchers are gaining a deeper understanding of drug resistance—and
how to avoid it by designing pediatric cancer treatments tailored to
specific mutations in a child’s DNA. In a fruitful collaboration,
pediatric oncologists and biochemists are targeting neuroblastoma, an
often-deadly childhood cancer of the peripheral nervous system.
scientific study allows us to move ahead in improving drug treatments
for children with a particular form of neuroblastoma,” said study
co-leader Yaël P. Mossé, M.D., a pediatric oncologist at The Children’s
Hospital of Philadelphia. Mossé teamed up in this research with the
study co-leader, Mark A. Lemmon, Ph.D., professor and chair of
Biochemistry and Biophysics at the Perelman School of Medicine of the
University of Pennsylvania.
“This has been a terrific
collaboration,” said Lemmon. “We have been working for a long time to
understand how growth factor receptors work as signaling ‘machines.’
With the Mossé group, we focused on how control of these receptors is
compromised in cancer, and can use the laboratory results to guide
directly where to go next in the clinic.”
neuroblastoma, the most common solid cancer of early childhood, roughly
10 percent of patients have mutations in ALK, the gene carrying the
code for the signaling receptor anaplastic lymphoma kinase. Mossé, who
led a team that discovered this gene’s role in 2008, was able to
expedite a pediatric clinical trial based on this finding within a year,
because an existing ALK inhibitor called crizotinib was already in
adult clinical trials for a subset of non-small cell lung cancer
Crizotinib was therefore available for use in a pediatric clinical trial
against neuroblastoma, but early results in adult cancers showed that
tumors sometimes develop resistance to the drug. The current study
combined basic biochemistry and structural biology with studies in
tumor-derived cell lines and animal models to investigate how different
ALK mutations in neuroblastoma affect how ALK activity and tumor growth
respond to crizotinib.
The researchers focused on the two most common ALK mutations found in
neuroblastoma patients. They found that crizotinib effectively halted
the proliferation of neuroblastoma cells harboring the most common
mutation, but that the second most common ALK mutation was more
resistant to the drug.
The reason for the different results, say the authors, is that the
drug-resistant mutation causes ALK to bind more tightly to a key
cellular compound called ATP that drives its signaling. Since crizotinib
must displace this compound to inhibit ALK, the increased ATP binding
caused by the resistant mutation reduces crizotinib’s effectiveness.
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The authors say these results justify increasing the dosage of
crizotinib in patients with the more drug-resistant mutation, although
human studies must first be performed to determine if a higher dose will
be safe and effective in children. Fortunately, said Mossé, unlike
conventional chemotherapy, which attacks both cancerous and normal
cells, this type of drug strikes much more specific targets, and tends
to have lower risk of overall toxicity.
“This study shows how important it is to integrate basic science into
the design of clinical trials, and how useful it can be,” Mossé added.
“If we can better individualize treatment to a child’s genetic profile
by understanding the effects of mutations on protein structure and
function, we may achieve better results for patients,” added Lemmon.
The National Institutes of Health provided funding support for the
study, as did the US Army Peer-Reviewed Medical Research Program, the
Carly Hillman Fund, the Alex’s Lemonade Stand Foundation, the St.
Baldrick’s Foundation, and the Abramson Family Cancer Research
Institute. The first authors of the study were Scott C. Bresler, M.D.,
Ph.D., of Penn Medicine and Andrew C. Wood, M.D., of Children’s
article was first published at www.newswise.com.
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