323Interruption of multiple specifi c biochemical pathways may be a promising
therapeutic strategy in ovarian carcinomas that exhibit resistance to an individual
targeted therapy. This strategy may be useful for developing personalized therapies
for ovarian cancer.
Human ovarian cancer stem cells (CSCs) have been characterized and shown to
have a distinctive genetic profi le that confers them with the capacity to recapitulate
the original tumor, proliferate with chemotherapy, and promote recurrence (Alvero
et al. 2009 ). CSCs identifi ed in ovarian cancer cells isolated form ascites and solid
tumors are characterized by cytokine and chemokine production, high capacity for
repair, chemoresistance to conventional chemotherapies, and resistance to TNFα-
mediated apoptosis. Chemotherapy eliminates the bulk of the tumor but it leaves a
core of CSCs with high capacity for repair and renewal. The molecular properties
identifi ed in these cells may explain some of the unique characteristics of CSCs that
control self-renewal and drive metastasis. The identifi cation and cloning of human
ovarian CSCs can aid in the development of better therapeutic approaches for ovar-
ian cancer patients.
Resistance to platinum therapy is a major obstacle that needs to be overcome in
the treatment of ovarian cancer patients. The high rates and patterns of therapeutic
failure seen in patients are consistent with a steady accumulation of drug-resistant
CSCs. A study has demonstrated that the Notch signaling pathway and Notch3 in
particular are critical for the regulation of CSCs and tumor resistance to platinum
(McAuliffe et al. 2012 ). Notch3 overexpression in tumor cells results in expansion
of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor
(GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to
platinum. Similarly, a Notch3 siRNA knockdown increases the response to plati-
num therapy, further demonstrating that modulation of tumor chemosensitivity by
GSI is Notch specifi c. Most importantly, the cisplatin/GSI combination is the only
treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicat-
ing that a dual combination targeting both populations is needed for tumor eradica-
tion. In addition, cisplatin/GSI combination therapy has a synergistic cytotoxic
effect in Notch-dependent tumor cells by enhancing the DNA-damage response,
G2/M cell-cycle arrest, and apoptosis. These fi ndings indicate that targeting the
Notch pathway signifi cantly increases tumor sensitivity to platinum therapy. Both
platinum-resistant and platinum-sensitive relapses may benefi t from such an
approach as clinical data suggest that all relapses after platinum therapy are increas-
ingly platinum resistant.
Two strategies for targeted therapy have emerged with promising results: poly
ADP-ribose polymerase enzyme (PARP) inhibitors and targeting angiogenesis, but
development of a convenient and accurate method to identify patients likely to ben-
efi t from these remains a challenge (Gómez-Raposo et al. 2011 ).
A catalogue of molecular aberrations that cause ovarian cancer is critical for
developing and deploying therapies that will improve patients’ lives. The Cancer
Genome Atlas project has analyzed mRNA expression, miRNA expression, pro-
moter methylation and DNA copy number in high-grade serous ovarian adenocarci-
nomas and the DNA sequences of exons from coding genes in most of these tumors
Personalized Management of Cancers of Various Organs