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pathway revealed that what are believed to be protein and phosphoproteomic
signatures of PI3K activation did not correlate with PI3K mutations, but did corre-
late with the loss of negative regulators of that pathway, like loss of INPP4B or loss
of PTEN. Thus there is a discrepancy between the information from mutation and
phosphoproteomics. The challenge now is to fi gure out which of these many differ-
ent genetic events or protein signatures are going to be biomarkers of responsive-
ness to drugs like PI3K or mTOR inhibitors. This work is ongoing and the researchers
are currently reanalyzing the genetic data based upon protein and phosphoproteomic
endpoints.
Understanding Tumor Diversity in Mouse Mammary Cancer Model
Using a fi nding that the genetic complexity of tumors in mice parallels that in
humans, researchers are conducting trial studies in mice similar to human clinical
trials to evaluate whether an understanding of tumor diversity can improve cancer
treatment. Analysis of tumors arising in the MMTV-Myc model of mammary carci-
nogenesis reveals substantial heterogeneity, seen in both histological and expression
phenotypes (Andrechek et al. 2009 ). One of the MMTV-Myc mammary tumor sub-
groups exhibits metastatic capacity and that the signature derived from the subgroup
can predict metastatic potential of human breast cancer. Together, these data reveal
that a combination of histological and genomic analyses can uncover substantial
heterogeneity in mammary tumor formation and therefore highlight aspects of
tumor phenotype not evident in the population as a whole.
Personalized Management of Ovarian Cancer
Epithelial ovarian carcinoma (EOC) is the most important cause of gynecological
cancer-related mortality in Western societies. High-grade serous ovarian carcinoma
(HGS-OvCa) accounts for 60–80 % of the ~35,000 women diagnosed with EOC in
the US and ~40,000 in Europe annually. Known risk determinants for the develop-
ment of ovarian carcinoma include BRCA1/BRCA2 mutations, family history, nul-
liparity, oral contraceptive use, tubal ligation, pregnancy, and lactation. A common
treatment regimen consists of tumor debulking, followed by administration of plati-
num and taxane-based chemotherapy. Due to presentation of disease at advanced
stages and development of resistance to therapy, the 5-year survival rate is <40 %.
Early diagnosis, identifi cation of nonresponders and patients with primary platinum
resistance is an important step toward achieving greater life expectancy for EOC
patients. Gene expression profi les have been established that are associated with
overall survival and response to platinum therapy. Despite those encouraging devel-
opments, no biomarkers for prediction of response to therapy are yet in clinical use.
New approaches for early diagnosis as well as treatment are, therefore, required to
improve outcome in this disease.
10 Personalized Therapy of Cancer