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or downregulation of the lipid transporter LRP1B emerged as a signifi cant correlate
of acquired resistance in the analysis. Functional studies showed that reducing
LRP1B expression was suffi cient to reduce the sensitivity of HGSC cell lines to
liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was
suffi cient to increase sensitivity to liposomal doxorubicin. Together, these fi ndings
underscore the large degree of variation in DNA copy number in spatially and tem-
porally separated tumors in HGSC patients. LRP1B is defi ned as a potential con-
tributor to the emergence of chemotherapy resistance in these patients and may
serve as a biomarker for such acquired resistance. Mapping the mechanisms that
confer resistance may enable prediction of whether some women are likely to
respond to a certain drug or not, and fi nd ways of reversing resistance.
Quantitative RT-PCR of 3 miRs (miR-484, -642, and -217) involved in angiogen-
esis is able to predict chemoresistance of ovarian cancer (Vecchione et al. 2013 ).
Additional analysis of miR-484 reveals that the sensitive phenotype is caused by a
modulation of tumor vasculature through the regulation of the VEGFB and VEGFR2
pathways. These fi ndings suggest that blockage of VEGF by use of an anti-VEGFA
antibody may not be suffi cient to improve survival in ovarian cancer patients unless
VEGFB signaling is also blocked. Alternatively, small compounds, such as func-
tionalized nanoparticles targeting the VEGFR1 and VEGFR2 receptors, could be
used as effective therapy in these patients, changing the course of prognosis and
treatment of ovarian cancer (Liu et al. 2011 ).
Pathway Targeted Therapies for Ovarian Cancer
Mouse ovarian epithelial tumor cell lines that contain various combinations of
genetic alterations in the p53, c-myc, K-ras and Akt genes have been used as model
for the molecular characterization of pathway-targeted therapy. Response to a par-
ticular anticancer drug can be related to the signaling pathway involved. Rapamycin
effectively inhibits the growth of tumors that rely on Akt signaling for proliferation,
whereas tumors in which Akt signaling is not the driving force in proliferation are
resistant to rapamycin. The introduction of activated Akt to the rapamycin-resistant
cells does not render the cells susceptible to rapamycin if they can use alternative
pathways for survival and proliferation. Therefore, the rapamycin-sensitive tumors
develop resistance to rapamycin when presented with alternative survival pathways,
such as the mitogen-activated extracellular kinase signaling pathway. The combina-
tion of rapamycin and the mitogen-activated extracellular kinase inhibitor PD98059
is required to diminish proliferation in these cell lines. These fi ndings indicate that
mammalian target of rapamycin inhibitors may be effective in a subset of tumors
that depend on Akt activity for survival but not effective in all tumors that exhibit
Akt activation. Tumors with alternative survival pathways may require the inactiva-
tion of multiple individual pathways for successful treatment. These results have
signifi cant implications for the use of pathway-targeted therapy in advanced human
ovarian cancers, which typically display numerous genetic alterations that are likely
to require impairment of multiple molecular pathways for successful treatment.
10 Personalized Therapy of Cancer