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Classification of gene mutations in a children's cancer may point to

improved treatments
Date: November 10, 2014

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Source: Perelman School of Medicine at the University of Pennsylvania

Summary: Oncology researchers studying gene mutations in the childhood cancer
neuroblastoma are refining their diagnostic tools to predict which
patients are more likely to respond to drugs called ALK inhibitors that
target such mutations. Removing some of the guesswork in diagnosis
and treatment may lead to more successful outcomes.

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ncology researchers studying gene mutations in the childhood cancer

neuroblastoma are refining their diagnostic tools to predict which
patients are more likely to respond to drugs called ALK inhibitors that
target such mutations. Removing some of the guesswork in diagnosis and
treatment, the researchers say, may lead to more successful outcomes for
children with this often-deadly cancer.
"Some mutations are more important than others," said
Yal P. Moss, MD, a pediatric oncologist at The
Children's Hospital of Philadelphia, and a co-leader of
the new study published online today in the journal
Cancer Cell. "By integrating biochemistry into our
clinical strategies, we can better match a patient's
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specific ALK-mutation profile with an optimum

treatment." Moss is also an assistant professor of
Pediatrics in the Perelman School of Medicine,
University of Pennsylvania.

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"Understanding the specific mutations that trigger

signals in cell receptors to stimulate cell growth will
help us identify biomarkers for specific subtypes of neuroblastoma," said study coleader Mark A. Lemmon, PhD, professor and chair of Biochemistry and Biophysics at
Penn. Lemmon's research focuses on cell receptors in cancer.
Moss, Lemmon and their computational collaborator Ravi Radhakrishnan, PhD, an
associate professor in the department of Bioengineering at Penn, say their new
findings will provide crucial data for a pivotal phase 3 study for patients with ALK-driven
high-risk neuroblastoma. This trial will be conducted through the Children's Oncology
Group (COG), a cooperative research organization encompassing over 250 pediatric
cancer programs in North America. The COG is supported by the National Cancer
Institute.

this disease. Unexpectedly, the scientists found

relatively few ... full story

Scientists Develop New Strategy to

Overcome Drug-Resistant Childhood
Cancer
July 11, 2012 A new drug combination could offer
hope to children with neuroblastoma one of the
deadliest forms of childhood cancer by boosting
the effectiveness of a promising new gene-targeted
treatment. ... full story

Children With Cancer Have

Complete Responses in a COG
Phase 1 Trial: Pills Zero in on
Abnormal Genes That Drive
Specific Cancers

A solid tumor of the peripheral nervous system, often appearing in the chest or
abdomen, neuroblastoma is the most common cancer in infants. It accounts for a
disproportionate share of cancer deaths in children, with cure rates lagging behind
those for other pediatric cancers.

May 16, 2012 A pill designed to zero in on

abnormal genes that drive specific cancers has
produced encouraging early results in children with
an uncommon but aggressive type of lymphoma, as
well as in children ... full story

The current study concentrates on various mutations in ALK, the anaplastic lymphoma
kinase gene. Moss led a team that first discovered in 2008 that an ALK mutation
caused a hereditary form of neuroblastoma, and also identified ALK mutations
implicated in some non-hereditary neuroblastoma.

Predicting Drug Responsiveness in

Cancer Patients

Moss was subsequently able to expedite a phase 1 pediatric trial for neuroblastoma
and other ALK-dependent childhood cancers using an existing drug called crizotinib, a
molecule that inhibits the ALK protein when it is switched on by some ALK gene
mutations. Crizotinib had a stronger anticancer effect against some ALK mutations
than in others. In later collaboration with Lemmon, the investigators analyzed the
biochemistry of how the two most common ALK mutations responded to crizotinib.
The results strongly suggested that higher doses of the drug would be necessary for
children with one mutation compared to the other -- and that this knowledge could help
oncologists define the correct dosage before an initial treatment.
Neuroblastoma is complex, with many subtypes of the disease. The current study
explored the full spectrum of neuroblastoma, analyzing DNA from a COG tumor bank
drawn from nearly 1,600 patients. The team discovered ALK mutations in 8 percent of
the tumors, with a higher rate among tumors from older patients and those with highrisk neuroblastoma. The researchers also investigated which ALK mutations were
more sensitive to crizotinib in cell cultures.

July 26, 2010 Drugs that target the protein

mTOR are used to treat several forms of cancer, but
not all patients respond to the treatment. Now, a
team of researchers has identified a way to help
predict which ... full story

Neuroblastoma Expert Reviews Progress

Versus Challenging Childhood Cancer
June 14, 2010 A pediatric oncologist describes
the current state of the science in combating
neuroblastoma, the most common solid cancer of
early ... full story
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"Our computational approach can predict which ALK mutations are activating -- that is,
which ones drive cancer -- and just as importantly, which mutations are not," said
Radhakrishnan. "This will give oncologists a way to avoid overtreating or undertreating

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each patient, by knowing whether crizotinib or similar ALK inhibitors will be necessary
and effective," added Lemmon. They commented that their analytical method also
holds great promise in predicting the behavior of new ALK mutations not yet
discovered.
Using crizotinib to inhibit ALK activity is not always effective, because children are
often treated previously with other drugs that cause neuroblastoma tumors to develop
drug resistance. "Our goal is to leverage our ongoing preclinical work to design a
phase 3 clinical trial that will integrate crizotinib into the treatment regimen for newly
diagnosed patients, who will be carefully selected according to which ALK mutation
their tumor carries," added Moss. "Characterizing which patients are likely to benefit
from ALK inhibition and treating them upfront before they develop drug resistance may
save more children's lives."

Strange & Offbeat Stories

Story Source:
The above story is based on materials provided by Perelman School of Medicine at
the University of Pennsylvania. Note: Materials may be edited for content and
length.
Journal Reference:
1. Scott C. Bresler, Daniel A. Weiser, Peter J. Huwe, Jin H. Park, Kateryna Krytska,
Hannah Ryles, Marci Laudenslager, Eric F. Rappaport, Andrew C. Wood,
Patrick W. McGrady, Michael D. Hogarty, Wendy B. London, Ravi Radhakrishnan,
Mark A. Lemmon, Yal P. Moss. ALK Mutations Confer Differential
Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in
Neuroblastoma. Cancer Cell, 2014; 26 (5): 682 DOI: 10.1016/j.ccell.2014.09.019

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Perelman School of Medicine at the University of Pennsylvania. "Classification of

gene mutations in a children's cancer may point to improved treatments."
ScienceDaily. ScienceDaily, 10 November 2014.
<www.sciencedaily.com/releases/2014/11/141110123457.htm>.

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