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outcome with molecular targeted inhibitors
(e.g., Figitumumab/Neratinib/ABT-888).
I-SPY 1 and I-SPY 2 Breast Cancer Trials
I-SPY 1 and I-SPY 2 (Investigation of Serial
Studies to Predict Your Therapeutic Response
with Imaging and Molecular Analysis) are
a series of national clinical trials sponsored by
the Foundation for the National Institutes of
Health (USA) for patients with stage II/III
breast cancer. I-SPY 1 completed enrollment,
and I-SPY 2 is currently recruiting (
Table 1
).
A primary objective of I-SPY 1 was to establish
a systems biology-oriented research infrastruc-
ture for combining imaging, comparative
genomic hybridization (CGH), gene expression,
New Individualized Therapy Trial for
Metastatic Colorectal Cancer (NITMEC)
Trial
RPMA are
flexible assays in the sense that the
arrays can be probed with any given panel of
validated antibodies, essentially providing
a custom pathway network pro
le based on
the disease, drug target(s), patient population,
or pathway. An urgent clinical need exists to
identify new drug targets for metastatic lesions,
particularly in late stage disease which has the
poorest prognosis. RPMA data may be of
tremendous
importance
for
personalized
fluorescent in situ hybridization, immunohisto-
chemistry, and RPMA data that were generated
at independent research centers. Within this
infrastructure, data sharing portals were devel-
oped at the National Institutes of Health
1
to
integrate information from the research sites,
2
determine molecular predictors of response
and outcome to standard neoadjuvant therapy,
3
as well as the development of noninvasive
(magnetic resonance imaging) markers of
response. I-SPY 1 was the
therapy and patient strati
cation because the
metastasis cell signaling network is different
from the primary tumor due to the microenvi-
ronment tumor niche.
57,69
The extent of cell signaling changes associ-
ated with metastasis, and insights into the rela-
tive role of the
in patients
with primary colorectal cancer concomitant
with hepatic metastasis, was the basis for
developing a score to stratify patients for
a Phase I/II study (NITMEC,
Table 1
)ofimati-
nib alone or in combination with panitumu-
mab. The score was developed based on
RPMA data from a population of colorectal
cancer hepatic metastases and patient-matched
primary colorectal cancer tumors, which indi-
cated that a high percentage of liver metastasis
with wild type K-RAS had high levels of phos-
phorylated c-KIT ABL, and PDGFR, thus
implying that the liver metastasis may be sensi-
tive to imatinib, which speci
“
seed
”
and
“
soil
”
first clinical trial in
which the reverse phase protein microarray
analysis of frozen core needle biopsies was
reduced to practice in a CAP/CLIA compliant
laboratory.
106
CAP/CLIA provide professional
and U.S. federal guidelines for clinical labora-
tory analysis.
In conjunction with laser capture microdissec-
tion and RPMA analysis of signaling networks
in microdissected breast
tissue, Wulfkuhle
et al. con
rmed the lack of concordance and
diminished protein signaling levels in non-
microdissected whole tissue lysate samples com-
pared to microdissected samples,
91,92,104
af
cally targets all
three of these kinases. Investigators in the NIT-
MEC pro
led hepatic metastasis
samples
rm-
ing the requirement for microdissection to
obtain an accurate portrait of the tumor cells.
The success of I-SPY 1 has lead to the establish-
ment of I-SPY 2, in which an adaptive trial
design will be used to correlate response and
procured by laser
capture microdissection,
rather than pro
ling the primary colorectal
tumor, to evaluate the feasibility of a prede
ned
lab score based on proteomic data and whether
it can predict which patients will respond to
imatinib treatment.
7
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