Annual Meeting Proceedings Part 1 - American Society of Clinical ...

9561 General Poster Session (Board #41H), Sun, 8:00 AM-12:00 PM
Familial risk in pediatric cancer and implications for practice. Presenting
Author: Karen Curtin, University of Utah and Huntsman Cancer Institute,
Salt Lake City, UT
Background: Using a unique genealogical resource, the Utah Population
Database, we examined risk of cancer in 1st- through 3rd-degree relatives
of 4,482 pediatric cancer cases �18 years old diagnosed between 1966
and 2009. We quantified cancer risk in relatives of children with cancer in
order to determine evidence of a familial aggregation of cancer, identify
high-risk pedigrees, and inform counseling protocols for genetic testing and
screening. Methods: We estimated cancer risk in relatives of pediatric cases
compared to random population controls matched 5:1 on sex, birth year,
and birthplace. Odds ratios were calculated using conditional logistic
regression, adjusting for number of biological relatives, their degree of
relatedness, and their person-years at risk. We included all relatives of
cases and controls with followup who linked to a pedigree of �2 generations;
this approach has been shown to lead to unbiased risk estimates. As
observations within families are non-independent, a robust variance
estimator for cluster-correlated data was incorporated. Results: Mostly
siblings, 1st-degree relatives (N�49 affected) of pediatric cases were at
2-fold increased risk of being diagnosed at age�19 with cancer themselves
(p�10-4 ); siblings of cases diagnosed at age�5 had a 4-fold risk of
pediatric cancer (p�10-7 ). Likewise, 2nd-degree relatives (N�61 affected)
and cousins (N�105 affected) of cases had a ~2-fold risk of childhood
cancer (p�10-4 ). Proband siblings were at increased risk for leukemia,
brain tumor, epithelial neoplasia, and bone cancer. While 1st-degree
relatives of pediatric cases had a slight increased risk of adult-onset cancer,
when they do develop cancer they exhibit a 50% increased risk of a
Li-Fraumeni Syndrome-related tumor diagnosis (N�142 affected relatives;
p�10-4 ). Conclusions: Our findings provide evidence of familial aggregation
of cancer and suggest a higher percent of pediatric cancers are related to
hereditary syndromes than are adult cancers. We encourage a 3-generation
family history be collected and routinely updated for all pediatric cancer
patients, and those children with family histories of early-onset cancer be
referred for genetic counseling and early surveillance when appropriate.
9563 General Poster Session (Board #42B), Sun, 8:00 AM-12:00 PM
Preclinical study of a Bcl-2 inhibitor in neuroblastoma. Presenting Author:
Assila Belounis, Research Center CHU Sainte Justine, Montréal, QC,
Canada
Background: Neurblastoma (NB) is the most common and deadly extracranial
solid tumor of childhood. This malignant tumor exhibits a broad
spectrum of clinical features, including spontaneous regression or maturation
without any treatment or progression to metastisis leading to death.
However, in spite of many therapeutic improvements, only 60% survive
long term. In fact, 40% of patients with high-risk NB still relapse and
eventually die of the disease despite aggressive combinations of multiagent
chemotherapy. In those cases, new therapeutic strategies must be
developed. Studies have shown that BCl-2, a central anti-apoptotic protein,
is over-expressed in NB. Although Bcl-2 is not a significant prognostic
factor in NB, its increased expression would contribute to chemotherapy
resistance. BCl-2 is also shown to be involved in the modulation of
autophagy by inhibiting Beclin-1. Therefore, BCl-2 protein represents an
attractive target for new therapeutic strategies in NB.The objective of this
study is to determine the efficacy in vitro of Obatoclax (OB), a BCl-2
inhibitor, used in monotherapy or in combination to cisplatine (CP), a
classical chemotherapeutic agent used in NB treatment, on NB cell
survival. Methods: Six NB cell lines (SK-N-DZ, SK-N-FI, SK-N-SH, N91,
NB8 and NB10) were treated with OB alone or in association to CP. Cell
survival was measured by MTT test. Autophagy was measured by MDC test.
Western Blots (WB) were done to evaluate the modulation of apoptotic and
autophagic pathways in treated cells. Results: OB used in monotherapy
shows promising results on NB cell lines with an average IC50 of 0.12�M.
Also, OB demonstrates synergistic effects when associated to CP. The IC50
of CP treated cells varied from 3.183�M to 6.837�M but dropped from
0.003�M to 0.008�M when combined with 0.5�M of OB. Moreover, our
WB show an increase in cleaved Caspase-3 and PARP-1 expression,
suggesting an upregulation of apoptosis in treated cells. Autophagy is also
upregulated confirmed by an increase in autophagic vacuoles and cleaved
LC3 II protein. Conclusions: OB used in monotherapy or in combination at
potentially therapeutic doses shows promising results in NB. These results
will allow for the improvement of NB treatments by introducing a new
therapeutic strategy.
Pediatric Oncology
621s
9562 General Poster Session (Board #42A), Sun, 8:00 AM-12:00 PM
Mitigating smoothened inhibitor-induced growth plate closure with parathyroid
hormone. Presenting Author: Yoav E. Timsit, Novartis Institutes for
BioMedical Research Inc., Cambridge, MA
Background: The Hedgehog pathway plays an important role in regulating
growth plate patency by activating PTH/PTHrP signaling, and loss of
PTH/PTHrP signaling is an expected pharmacological effect of smoothened
(Smo) inhibition. LDE225, a Smo inhibitor currently in phase I/II trials for
the treatment of basal cell carcinoma (BCC) and medulloblastoma (MB),
causes closure of the epiphyseal (growth) plate in rodents and dogs. As a
therapeutic strategy to mitigate these effects, we investigated whether
administration of human parathyroid hormone (PTH amino acids 1-34 or
PTH1-34) could prevent premature growth plate closure caused by LDE225.
Methods: Oral LDE225 was given once daily to rapidly growing male rats
(starting at 4 or 6 weeks of age) in combination with hPTH1-34 administered
subcutaneously as a continuous infusion (to mimic signaling by locallyproduced
PTHrP) or as once-daily injections. Femur and tibial growth
plates were scanned by microCT and growth plate volumes were calculated.
Growth plates were also assessed histologically. Results: Continuous
delivery of hPTH1-34 provided the greatest effect for maintaining patent
growth plates compared to once-daily subcutaneous injections. However,
the dose of continuous hPTH1-34 giving the greatest protection was not
well-tolerated beyond 1 week due to PTH-induced hyperparathyroidism,
confirmed by clinical chemistry and histological assessment. Reduction in
the dose of continuous hPTH1-34 improved tolerability, but provided less
protection to the growth plate. Once-daily hPTH1-34 injection for two weeks
was well-tolerated, with anabolic effects clearly observed by histology and
microCT. The extent of closure in animals co-treated with LDE225 and
once-daily hPTH1-34 injections was less compared to that caused by
LDE225 treatment alone. Conclusions: As shown in this preclinical model,
hPTH1-34 administration mitigates LDE225-induced growth plate closure.
Although hPTH1-34 shows promise experimentally, current use is restricted
in pediatric patients and further study will be needed before considering
hPTH1-34 treatment concurrent with LDE225 therapy in children or
adolescents.
9564 General Poster Session (Board #42C), Sun, 8:00 AM-12:00 PM
Effect of insulin-like growth factor 2 gene expression on pleuropulmonary
blastoma and embryonal rhabdomyosarcoma. Presenting Author: Rajkumar
Venkatramani, Children’s Hospital Los Angeles, Los Angeles, CA
Background: The sarcomatous element in pleuropulmonary blastoma (PPB)
often cannot be differentiated from embryonal rhabdomyosarcoma (ERMS)
by histology, particularly when characteristic elements like cartilage and
respiratory mucosa are inapparent. The initial diagnosis is often ERMS. A
diagnosis of PPB is based on a combination of clinical (age, location) and
pathologic features. We hypothesized that the sarcomatous portions of PPB
are a form of ERMS indistinguishable from typical ERMS. We reasoned that
a detailed comparison of RNA expression could clarify this hypothesis.
Methods: Samples from 7 PPB patients were obtained from the rhabdomyosarcomatous
portion of the tumor by macro-dissection after pathologic
review of all material. Representative ERMS tumor tissue was selected from
21 ERMS cases. FFPE tissue scrolls from each case were analyzed using
Affymetrix Human Exon arrays after RNA extraction with Agincourt Formapure
extraction kit and amplification using the NuGEN Ovation FFPE WTA
kit and labeling with the Encore Biotin Module. Data analysis utilized
Partek and Genetrix software. Results: All PPB cases and 7 of 21 ERMS
cases were � 4 years old. 20 transcripts (10 annotated, 10 non-coding
RNAs) were significantly differentially expressed in ERMS when compared
to PPB patients. Insulin-like growth factor 2 (IGF2) was uniformly overexpressed
in ERMS (19/21 � 200) but was expressed at low levels in PPB
(p�0.001). 2 ERMS cases which had low level IGF2 expression were � 4
years of age. Expression in the other 5 ERMS aged �4 years was similar to
ERMS overall (range, 500-2,000). No other differences between the two
approached this degree of significance, despite a common rhabdomyogenic
phenotype in the sarcomatous areas of PPB. Conclusions: We conclude that
PPB is a distinct entity from most ERMS, and is not driven by IGF2
signaling. Rare cases of ERMS in the very young are more similar to PPB
than common ERMS. This observation is highly significant, as IGF2 is
known to drive growth in ERMS, generally related to demethylation
secondary to LOH of 11p.
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