Biology Reference
In-Depth Information
cells are alive and reactive, phosphorylation of
certain kinase substrates may transiently
increase due to the persistence of functional
signaling, activation by hypoxia, or some other
stress-response signal.
24,31
e
33
Although it is
now possible to extract proteins from formalin
long-term need for stabilizers that preserve of
post-translational modi
ed proteins and full
tissue diagnostic morphology without the need
for freezing.
RPMA Has Graduated to Use in Cancer
Clinical Trial Research
Patient clinical information, combined with
protein network data obtained from RPMA,
provides insights into the mechanisms of receptor
blockade, compensatory post-treatment receptor
activation, and overall differences in pathway
signaling between patients, and/or between
treatment arms. RPMA technology has been
successfully applied to the analysis of the state of
pro-survival, apoptosis, and mitogenesis path-
ways within microdissected human malignant
lesions, including comparisons to adjacent nor-
mal epithelium, invasive carcinoma, or host
stroma.
7,25,35,71,76,78,104,106
Preclinical data gener-
ated from RPMA performed following profes-
sional and federal laboratory standards (College
of American Pathologists/Clinical Laboratory
Improvement Amendments [CAP/CLIA]) has
propelled the technology into several clinical
research trials
25,78,106
(
Table 1
). Information
pertaining to the clinical trials was obtained
from the sponsor or from
Clinicaltrials
.gov
accessed from
http://clinicaltrials.gov/ct2/
fixed tissue,
6
formalin penetrates tissue at a vari-
able rate, reported within the range of mm/
hr.
28,38,95
Portions of the living tissue deeper
than several mm would be expected to undergo
signi
fluctuations in phosphoprotein ana-
lytes. A typical 16-gauge core needle biopsy is
7mm
cant
17.9 mm
3
). Even in
a relatively small core needle biopsy, it is clear
that the protein and nucleic acids in the depth
of the tissue will have signi
1.6 mm (volume
¼
cantly degraded
by the time formalin permeates the tissue.
28,72,73
Without stabilization,
imbalances of kinases/
phosphatases will
signi
cantly distort
the
tissue
s molecular signature compared to the
state of
in vivo
markers. Consequently, cellular
samples for RPMA kinase network analysis
require stabilization, or preservation, of the
kinases and phosphoproteins immediately post
tissue procurement.
24
e
26,71,72,74
'
Enabling tech-
nologies such as molecular
fixatives that arrest
both sides of the kinase/phosphatase balance
are currently being evaluated in clinical research
trials for their compatibility with RPMA.
26,71,72
This technology can address the important
TABLE 1
Example Clinical Trials Incorporating RPMA
Trial identier
a
Acronym
Conditions
Study Design
Phase
NCT01042379
I-SPY 2
Breast cancer
Open-label; interventional
II
Breast DCIS
b
NCT01023477
PINC
Open-label; interventional
I/II
NCT01074814
Side-Out
Metastatic breast cancer
Open-label; interventional
II/III
NCT00798655
N/A
Head and neck cancer
Open-label; interventional
II
NCT00952809
N/A
Lymphoma
Observational
N/A
NCT00867334
NITMEC
Colorectal cancer
Open-label; interventional
II/III
a
Clinicaltrials.gov identi
er accessed from
http://clinicaltrials.gov/ct2/home
,
provided by the U.S. National Library of Medicine, as of April 15, 2010.
b
DCIS
ductal carcinoma in situ
¼
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