Biology Reference
In-Depth Information
SIDE-OUT Metastatic Breast Cancer
Personalized Therapy Trial
The purpose of this trial, sponsored by TGen
Drug Development Services and funded through
the SIDE-OUT Foundation, is to employ molec-
ular pro
cannot provide information on the activated
(e.g., phosphorylated) state of signal pathway
proteins existing within a signal pathway tar-
geted by the kinase inhibitor; therefore, genomic
and immunohistochemical (IHC) data is being
used to choose chemotherapy regimens. Thus,
combining these two classes of molecular anal-
ysis covers both chemotherapy and molecular
targeted therapy.
Prevention of Invasive Breast Neoplasia by
Chloroquine (PINC) Trial
Prevention of Invasive Breast Neoplasia by
Chloroquine (PINC) is a new neoadjuvant
therapy trial for patients with breast ductal carci-
noma in situ (DCIS) sponsored by Inova Health
Systems (
Table 1
). The human DCIS neoadjuvant
therapeutic target is the autophagy pathway and
the proposed treatment is oral Aralen (chloro-
quine phosphate). The therapeutic strategy is
based on data from Espina et al. that supports
the hypothesis that cellular autophagy is
necessary for the survival and propagation of
DCIS neoplastic cells.
25
The novel design of the
study provides immediate molecular and biolog-
ical feedback regarding the treatment impact on
the neoplastic cell target. The clinical study will
examine the safety and effectiveness of Aralen
(500 mg/week) administration for a four-week
period to patients with low-, intermediate-, and
high-grade DCIS. Patients who are ER negative
(expected to be approximately one-half of the
high grade DCIS cases), or ER positive, will
receive Aralen. Magnetic resonance imaging
studies will be performed on each patient at
enrollment and just before surgical therapy after
the twelve-week treatment. All patients will
receive standard of care surgical therapy:
mastectomy or lumpectomy, depending on the
size and con
ling to individualize therapy for
patients with refractory, metastatic breast cancer
(
Table 1
). In order to assess whether individual-
ized therapy can change the clinical course of
disease, a growth modulation index (GMI) will
be calculated for each patient. The GMI is calcu-
lated as the ratio of progression-free survival
(PFS) under the individualized therapy to the
time to progression (TTP) for the most recent
regimen on which the patient has progressed.
Biopsies of the metastatic tumors are analyzed
using immunohistochemistry, transcript arrays,
and RPMA. For the RPMA portion of the study,
biopsies are subjected to laser capture microdis-
section and the activated state of selected signal
pathways is scored compared to a series of cell
line derived calibrators printed on each array.
The RPMA generated value for a selected set of
endpoints is compared to a previously gathered
reference set of data from a variety of primary
and metastasis samples from a number of
different tumor types. The purpose of this
comparison is to determine whether an indi-
vidual patient falls in the top or bottom quartile
compared to the reference population. Only
patients whose tumors are found to have
activation states in the top quartile of activation
are categorized as
Data from immu-
nohistochemistry, transcript arrays, and RPMA
analysis is used to select therapy for each indi-
vidual patient. Genomic and proteomics data
correlations are being assessed in this trial
because the optimal therapy, as predicted by
the molecular analysis, may be chemotherapy
rather than molecular therapy. For this trial,
the RPMA data is being used to suggest
FDA-cleared and commercially available molec-
ular targeted therapy such as kinase inhibitors
(e.g.,
“
activated.
”
uence of the primary DCIS lesion.
Effectiveness in this study will be measured in
two ways directly at the molecular level in the
DCIS tissue before and after treatment. Using
RPMA technology, the activated state of 100
signal
pathway
proteins
associated with
imatinib, ge
tinib, sorafenib). Genomics
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