293its many downstream players, such as PTEN or AKT. There is a lot of crosstalk
between the PI3K pathway and other pathways, a lot of feed-forward and feedback
loops. Central nodes between these intersecting circles can be effectively targeted
with drugs.
Only one PI3K pathway inhibitor is in use to date but others are increasingly
being developed and tested. At least 20 different companies have recognized the
importance of the pathway in breast cancer and are trying to develop drugs that
target it.
In the future, breast cancer tissue samples from newly diagnosed patients can be
tested for their specifi c PI3K pathway abnormality in order to fi nd a drug that zeroes
in on what may be that particular cancer’s vulnerable point. Using those drugs in
combination with other treatments such as chemotherapy may signifi cantly advance
breast cancer care.
Rational Drug Design for Breast Cancer Capecitabine (Xeloda, F. Hoffmann-La
Roche) is an example of a rationally designed cytotoxic treatment. It is designed to
generate 5-FU preferentially in tumor cells by exploiting the higher activity of the
activating enzyme thymidine phosphorylase in tumors compared with healthy tis-
sues. Tumor-specifi c activation has the potential to enhance effi cacy and minimize
toxicity. Proof of this principle is provided by clinical trial results showing that
capecitabine is effective and has a favorable safety profi le in the treatment of meta-
static breast cancer. Breast cancer treatment thus will be determined by tumor biol-
ogy as well as patient characteristics. Improved molecular characterization and
greater understanding of tumorigenesis will enable more individualized treatment.
Developing Personalized Drugs for Triple-Negative Breast Cancer Triple-
negative tumors, i.e. hormone receptor- and ERBB2-negative, account for 15 % of
all breast cancers and frequently harbor defects in DNA double-strand break repair
through homologous recombination, such as BRCA1 dysfunction. Whereas target-
specifi c drugs are available for treating ERBB2-overexpressing and hormone
receptor- positive breast cancers, no personalized therapy exists for, triple-negative
mammary carcinomas. The DNA-repair defects characteristic of BRCA1-defi cient
cells confer sensitivity to poly(ADP-ribose) polymerase 1 (PARP1) inhibition,
which could be relevant to treatment of triple-negative tumors. AZD2281, a PARP
inhibitor, was tested in a genetically engineered mouse model (GEMM) for BRCA1-
associated breast cancer (Rottenberg et al. 2008 ). Treatment of tumor-bearing mice
with AZD2281 inhibited tumor growth without signs of toxicity, resulting in
strongly increased survival. Long-term treatment with AZD2281 in this model
resulted in the development of drug resistance, caused by up-regulation of Abcb1a/b
genes encoding P-glycoprotein effl ux pumps, which could be reversed by co-
administration of the P-glycoprotein inhibitor tariquidar. Combination of AZD2281
with cisplatin or carboplatin increased the recurrence-free and overall survival, sug-
gesting that AZD2281 potentiates the effect of these DNA-damaging agents. These
results demonstrate in vivo effi cacy of AZD2281 against BRCA1-defi cient breast
cancer and illustrate how GEMMs of cancer can be used for preclinical evaluation
of novel therapeutics and for testing ways to overcome therapy resistance.
Personalized Management of Cancers of Various Organs