Study is the first to identify malignant cells
responsible for relapse in high-risk neuroblastoma
PHILADELPHIA, Aug. 15,
2024 /PRNewswire/ -- Researchers at Children's
Hospital of Philadelphia (CHOP)
announced a significant breakthrough in understanding chemotherapy
resistance in high-risk neuroblastoma, a common and potentially
deadly childhood cancer arising within the peripheral nervous
system. The study marks the first time that researchers identified
malignant cells responsible for relapse in neuroblastoma and offers
insights for potential new therapeutic targets. The findings were
published recently in the journal Cancer Discovery.
In the United States, about 800
new cases of neuroblastoma are diagnosed each year, more
often in boys. The average age of diagnosis is about 18 months but
occasionally the disease is seen in teens and young
adults. Neuroblastoma has a high mortality rate and despite
extensive studies, the malignant cells responsible for relapse were
not well understood until this research.
This study is part of research conducted by the Human Tumor
Atlas Network (HTAN), a National Cancer Institute (NCI) Moonshot
initiative led by Kai Tan, PhD, an
investigator in the Center for Childhood Cancer Research at CHOP,
and a multi-institutional NCI Program Project Grant (PPG) focused
on neuroblastoma and led by John M.
Maris, MD, a study co-author and pediatric oncologist at
CHOP.
"This study is a major step forward in identifying why
neuroblastoma is so difficult to cure," said Maris, who also holds
the Giulio D'Angio Chair in Neuroblastoma Research. "Targeting
specific cells and pathways responsible for relapse empowers us to
chart a new path forward, allowing us to develop potentially safe
and effective treatments for children and families battling this
aggressive cancer."
The CHOP research team employed advanced single nucleus RNA
sequencing (snRNA-seq) and bulk whole genome sequencing techniques
to analyze the genetic and transcriptional profiles of tumor
samples from 20 pediatric patients with high-risk neuroblastoma who
were treated between 2007 and 2022. The samples included matched
diagnostic biopsies and definitive surgery specimens obtained after
several cycles of induction chemotherapy.
"HTAN played a crucial role in generating the powerful
multi-omics dataset that led to the hypothesis we tested in this
paper," said Tan, who is also a professor in the Department of
Pediatrics at CHOP and spearheads CHOP's participation in the HTAN.
"It supports the broader application of the identified therapeutic
targets and resistance mechanisms in high-risk neuroblastoma."
The investigators discovered and validated the fact that
neuroblastoma can evade chemotherapy by becoming dormant and not
constantly multiplying—a major hallmark of cancer. Thus, these
"non-cycling" cells are resistant to chemotherapy, which is
designed to kill cells that are actively multiplying. These
"persister cells" can hide in the body for months or even years and
see a relapse when they later awaken.
To validate their findings and enhance the analysis, the
researchers leveraged independent post-induction chemotherapy data
generated by other groups in the HTAN. By assessing the primary
study's findings within the context of other datasets, the
researchers ensured consistency and reliability in the
transcriptional subtypes they identified.
For example, researchers were able to study the expression level
of the MYCN gene and its relationship to the transcriptional
subtypes. This provided several insights into the biology of
neuroblastoma and offered promising new therapies. As a result,
Maris noted that the NCI-funded neuroblastoma PPG is actively
pursuing research and that several immunotherapeutic strategies to
eliminate persister cells are already being tested.
"This research could have far-reaching implications beyond
neuroblastoma, as it enhances our understanding of chemotherapy
resistance mechanisms," said Liron
Grossmann, MD, MSc, the study's lead author, who managed the
research during his Hematology-Oncology fellowship at CHOP, and is
currently a Senior Attending Physician at Sheba Medical Center in
Israel. "We've gained invaluable
insights that can inform new approaches for various cancers,
potentially improving treatment outcomes and reducing relapse rates
across a broad spectrum of malignancies."
The study was supported by Human Tumor Atlas Network U2C
CA233285 and the National Cancer Institute (NCI) grants R35
CA220500, P01 CA217959, and K08 CA266914. This work was also
supported by the Sheba Medical Center Physician-Scientist
Program, the Giulio D'Angio Endowed Chair, the Richard & Sheila
Sanford Endowed Chair and the Patricia Brophy Endowed Chair.
Grossmann et al. "Identification and characterization of
chemotherapy resistant high-risk neuroblastoma persister cells."
Cancer Discovery. Online July 31,
2024. DOI: 10.1158/2159-8290.CD-24-0046.
About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of
Philadelphia was founded in 1855
as the nation's first pediatric hospital. Through its long-standing
commitment to providing exceptional patient care, training new
generations of pediatric healthcare professionals, and pioneering
major research initiatives, the hospital has fostered many
discoveries that have benefited children worldwide. Its pediatric
research program is among the largest in the country. The
institution has a well-established history of providing advanced
pediatric care close to home through its CHOP Care Network, which
includes more than 50 primary care practices, specialty care and
surgical centers, urgent care centers, and community hospital
alliances throughout Pennsylvania
and New Jersey, as well as the
Middleman Family Pavilion and its dedicated pediatric
emergency department in King of
Prussia. In addition, its unique family-centered care and
public service programs have brought Children's Hospital of
Philadelphia recognition as a
leading advocate for children and adolescents. For more
information, visit https://www.chop.edu.
Contact: Jennifer Lee
Children's Hospital of Philadelphia
(267) 426-6084
leej41@chop.edu
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SOURCE Children's Hospital of Philadelphia