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

626s Pediatric Oncology
9581 General Poster Session (Board #44D), Sun, 8:00 AM-12:00 PM
A phase I trial of MK 2206 in children with refractory solid tumors: A
Children’s Oncology Group study. Presenting Author: Christine L. Phillips,
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Background: AKT, a serine threonine protein kinase, is activated downstream
of phosphatidylinositol 3-kinase (PI3K) which transmits signals
from cytokines, growth factors and oncoproteins to multiple targets.
Activated AKT regulates survival, proliferation, and growth. The PI3K/AKT
pathway is downstream of most of the common growth factor tyrosine
kinase receptors in cancer, e.g., EGFR, HER2, IGFR, etc., and is a driver of
tumor progression in many cancers. AKT protein kinase is activated in many
pediatric solid tumors, including glioblastoma, malignant rhabdoid tumors,
neuroblastoma, synovial sarcoma, rhabdomyosarcoma and medulloblastoma.
MK2206, an oral allosteric AKT1, 2,3 inhibitor, has demonstrated
antitumor activity in in vitro and in vivo cancer models.A phase I trial
evaluating MK2206 was conducted in children with refractory solid
tumors. Methods: Using a rolling-6 design, MK2206 was administered
either once every 7 days (schedule 1), or once every other day (schedule 2)
in a 28-day cycle. Serial PK studies were obtained on day 1, cycle 1 and
trough samples were obtained on days 7, 14, 21 and 28. Biological studies
included analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and
post-therapy in PBMC and in tumors at diagnosis or recurrence. Results:
Forty-five patients [23 males, median age 13.6 years (range 3.1-21.9)]
with malignant glioma (14), ependymoma (4), hepatocellular carcinoma
(3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 34 were
fully evaluable for toxicity (schedule 1 n�17; schedule 2 n�17). Schedule
1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2 ; grade 4
hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2 . There were no
DLTs at 35 mg/m2 and dose level 4 (58 mg/m2 ) is currently open for patient
accrual with one enrollment. Schedule 2 DLTs included: grade 3 alkaline
phosphatase in 1/6 patients at 90 mg/m2 ; grade 3 rash in 1/6 patients at
120 mg/m2 ), and grade 3 rash in 2/6 patients at 155 mg/m2. Conclusions:
The recommended pediatric phase II dose of weekly MK2206 is 120
mg/m2 and the last cohort of patients to the every other day dosing schedule
of MMK206 is enrolling. PK and PD data are currently being analyzed and
will be presented.
9584 General Poster Session (Board #44F), Sun, 8:00 AM-12:00 PM
Integration of genomic and proteomic data to identify MYCN-regulated
genes, proteins, and interaction networks in neuroblastoma cells. Presenting
Author: Kolbrun Kristjansdottir, University of Chicago, Chicago, IL
Background: Neuroblastoma is the most common extracranial solid tumor
found in children. The most common marker prognostic of poor outcome is
amplification of the MYCN oncogene, yet the biological programs by which
MYCN affects its aggressive phenotype are largely unknown. In order to
identify biological pathways affected by MYCN amplification, we performed
global analysis of genes and proteins in the Tet 21/N neuroblastoma cell
line. Methods: MYCN expression in Tet21/N cells is regulated by tetracycline.
Gene arrays were performed on MYCN-high and MYCN-low Tet21/N
cells and SH-EP parental cells using Affymetrix GeneChip Human Exon 1.0
ST. For proteomic analysis, the cells were labeled with stable isotopes for
relative quantitation, enriched for phosphoproteins to enhance detection of
signaling proteins, and analyzed by GeLC-MS/MS analysis. Integrative
pathway analysis was performed on the genomic and proteomic datasets
using DAVE and GeneGo. Results: Integrating genomic and proteomic data
in MYCN-high and MYCN-low expressing cells identified 88 proteins and
300 genes that change in abundance. We compare these results with
previous studies and find both novel and previously identified genes and
proteins. Integrating proteomic and genomic data identified over 50 gene
products that are present in both analyses and are altered in abundance in
response to modulating MYCN expression. The majority of these have
discordant abundance changes, with protein levels more frequently altered
with no change in gene expression. We have validated changes in protein
levels using Western blots including NPM1 and MATR3. We present
interaction networks and pathways that correlate with MYCN expression.
Conclusions: We showed a significant discordance between gene and
protein expression, underscoring the need for integrative genomic and
proteomic analysis to describe complex systems. Our analysis identified
previously reported and novel genes and proteins and networks regulated by
MYCN expression that may provide new insights into the biology of
MYCN-amplified tumors.
9583 General Poster Session (Board #44E), Sun, 8:00 AM-12:00 PM
Development of an open-source, flexible framework for interinstitutional
data sharing and collaboration. Presenting Author: Chaim Kirby, University
of Chicago, Chicago, IL
Background: Clinical information, “-omic” datasets, and tissue samples are
becoming more difficult to harmonize and manage for advanced data
mining. We believe that clinical research data can be centralized and
provide direct access to sample availability and associated data from a
variety of information stores. Methods: We obtained a standardized set of
anonymized patient data from the International Neuroblastoma Risk
Group. The cohort consists of more than 11,000 children diagnosed
worldwide between 1974 and 2002. The data consist of 34 metrics, such
as age at diagnosis, stage of tumor, and other clinical and biological
markers. We instantiated the dataset into a Postgres database, and using
the Django web framework, created a data model for rapid development of
tools and views and built a front-end interface for generating complex
queries. To test the feasibility of accessing information on disparate and
geographically distinct data samples, we have a formal agreement with the
Children’s Oncology Group Tumor Bank at The Research Institute at
Nationwide Children’s Hospital. Based on query results, we consume the
Tumor Bank tissue inventory data through a web-facing application
programming interface. The end-user is presented only with the number of
patients who match their query search terms and for whom tissue samples
are available. Results: We have completed our initial implementation and
have agreements for collaboration with other international consortium
groups. We have created a paradigm for statisticians to securely update and
add data, and a verification system checks for internal validity and provides
a report of the transaction. Our system can initiate queries and accept
results in a variety of standards-compliant formats, and will be available in
demonstration form by May 2012. Conclusions: Querying patient data while
interrogating external sources allows researchers to observe which ancillary
data and samples are available and to quickly download data or request any
samples. While designed around a neuroblastoma dataset, our system can
be applied to a variety of clinical scenarios and will be made available
through an open-source license.
9585 General Poster Session (Board #44G), Sun, 8:00 AM-12:00 PM
Proton radiotherapy for rhabomyosarcoma: Preliminary results from a
multicenter prospective study. Presenting Author: Torunn I. Yock, Massachusetts
General Hospital, Boston, MA
Background: Pediatric rhabdomyosarcoma (RMS) is commonly cured with
chemotherapy and radiation. However, late effects of radiotherapy (RT) can
be disabling. Proton RT irradiates less normal tissue, which should result in
fewer late side effects of treatment. The purpose of this study was to
describe the disease control and side effect profile of proton RT in RMS
patients (pts). Methods: Eligible pts included those with localized disease
and metastatic embryonal RMS if age 2-10. All pts were treated with VAC
(vincristine, actinomycin, cyclophosphamide) based chemotherapy and
proton RT, median dose 50.4 Gy (36-50.4 GyRBE). Concurrent enrollment
in COG protocols was allowed. All pathology/imaging was reviewed at the
treating institution. Results: 47 pts with RMS were prospectively enrolled
from January 2005 to June 2011 and evaluable for analysis. Median age
was 3.1 yrs, (range 0.6-15.6 years; M/F ratio 23:24). There were 1, 7, 37,
and 2 Group I, II, III and IV and 14, 12, 19 and 2, Stage I-IV pts
respectively, and 33 with embryonal 14 with alveolar/other. Most common
sites included PM (48.9%), orbital (23.4%) bladder/prostate (6.4%), H&N
non-PM (6.4%), extremities (4.3%), trunk/abdomen 2.1%), perineal/anal
region (2.1%) and other (6.4%). Median follow-up is 15.2 months.
One/two-year overall survival (OS) and progression-free survival (PFS) for
the entire group is 94/81% (OS) and 79/73% (PFS). 2-year OS for stage
I,II/III,IV pts is 91/66% (OS, p�0.114) and two-year PFS for these pts is
86/57%, respectively, (p�0.083. 16 (34%) had grade 3/4 acute toxicities
attributable to the radiation during treatment, the most common of which
was mucositis/oral pain (12.8%), anorexia (4.3%), and erythema (4.3%).
Among the 24 pts analyzable for late toxicities with at least 2 yrs of follow
up, there were no grade 3 or 4 late toxicities attributable to radiation.
Conclusions: Early results of this prospective trial demonstrate comparable
disease outcomes and thus far limited late effects in a young pediatric RMS
population. However, additional follow up is needed to determine if protons
truly reduce rates and severity of late effects compared with photon cohorts
published in the literature.
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