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autophagy, hypoxia, adhesion apoptosis, and
p53-mediated cell survival will be measured
before and after therapy within the microdis-
sected epithelial and stromal compartments. In
parallel, DCIS living organoids and DCIS
progenitor cells, pre and post treatment, will be
harvested and studied
1
for
ex vivo
invasive
potential in human breast stroma,
2
progenitor
cell yield and growth,
3
and the tumorigenicity
and invasion following NOD/SCID (nonobese
diabetic/severe
cascade. Lapatinib, a small molecule inhibitor,
is a dual tyrosine kinase inhibitor that blocks
both EGFR (ErbB1) and Her2 (ErbB2) by binding
to the ATP pocket. In addition, lapatinib can
inhibit truncated forms of the receptor,
68
and
trastuzumab, a monoclonal antibody, binds
directly to the Her2 extracellular domain.
30
Despite numerous studies, we still don
'
t under-
stand the mechanism or signi
cance of ErbB
blockade, particularly for an individual patient.
Molecular pro
cient)
murine transplantation.
25
Full-genome molec-
ular cytogenetics will be performed on the
microdissected DCIS cells.
Phase II Trial of Trastuzumab and/or
Lapatinib Plus Chemotherapy for Her2
þ
Breast Cancer
The U.S. Oncology 05-074 /GlaxoSmithKline
LPT109096 sponsored trial,
combined immunode
ling provides a means to individ-
ualize therapy for tyrosine kinase inhibitors used
in combination or as monotherapy.
This is the
rst
in vivo
proteomic monitoring
trial of signal pathway targets before and after
mono or dual therapy. HER2
breast cancer
patients are treated with lapatinib alone, lapati-
nib plus trastuzumab, or trastuzumab alone
for two weeks, before chemotherapy with
FEC75
þ
Phase II random-
ized trial of neoadjuvant Trastuzumab
30
and/or
Lapatinib
68
plus chemotherapy in women with
ErbB2 (HER2/neu) over-expressing invasive
breast
“
12.
Reverse phase protein microarrays are being
used to: identify kinase signal pathway activa-
tion states in microdissected tumor cells
collected prior to therapy (biopsy 1), or during
therapy (biopsy 2), which predict later clinical
response following standard of care chemo-
therapy and surgery
1
; and identify kinase
pathway interconnections in the cancer cells
that are altered in response to therapy.
2
Changes
in compensatory or interconnected proteins
could indicate off-target effects or provide
insights for new combination therapies.
Phase II Trial of Radiation, Cisplatin, and
Panitumumab in Head and Neck Cancer
The University of Pittsburgh
e
sponsored trial
(NCT00798655;
Table 1
) for squamous cell carci-
noma of the head and neck will evaluate
progression-free survival of patients undergoing
post-operative chemoradiotherapy with panitu-
mumab. Patient inclusion criteria include status
post surgical resection, with stage III/IVa tumors,
without any prior chemotherapy or EGFR
pathway inhibitor therapy. RPMA are being
used in baseline archival paraf
4 followed by weekly paclitaxel
cancer,
”
recently completed patient
accrual (
n
100). RPMA are providing quantita-
tive cell signaling data related to the
in vivo
effects of molecular targeted therapy before
and after therapy. This multisite trial has estab-
lished a proteomic work
¼
ow for breast core nee-
dle biopsy collection, preservation, and shipping
without the need for dry ice or frozen sample.
Core needle biopsies are placed immediately in
a phosphoprotein/kinase preservative that
retains sample antigenicity and morphology
and is compatible with laser capture microdis-
section and frozen section preparation.
24,72
Two important questions related to molecular
targeted therapy are being addressed via RPMA
data in this clinical trial
1
: Does mono or combi-
nation Her2 inhibition therapy improve
complete patient response?
2
and Can we
prospectively identify responders to Her2 tar-
geted therapy?
Lapatinib and trastuzumab have different
modes of action on the Her2/EGFR signaling
n-embedded
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