221for enhancing L-ASP activity by combining it with antagonists of ASNS, such as
siRNAs, antisense nucleotides, antibodies or small-molecule inhibitors for treat-
ment of cancer (Lorenzi et al. 2006 ). Reducing or suppressing the expression of
ASNS potentiates the growth inhibitory activity of L-ASP four- to fi ve-fold. Tissue
microarrays confi rmed low ASNS expression in a subset of clinical ovarian cancers
as well as other tumor types. Overall, this pharmacogenomic/pharmacoproteomic
study suggests the use of L-ASP for personalized treatment of a subset of ovarian
cancers (and perhaps other tumor types), with ASNS as a biomarker for selection of
patients most likely to respond to L-ASP treatment. The technology is currently in
the preclinical stage of development. With respect to L-ASP treatment of patients
with solid tumors, phase I clinical trials have been initiated using L-ASP in combi-
nation with gemcitabine.
Oncogene GOLPH3 as a Cancer Biomarker
Genome-wide copy number analyses of human cancers have identifi ed frequent
5p13 amplifi cation in several solid cancers, including lung, ovarian, breast, prostate
and melanoma. Using integrative analysis of a genomic profi le of the region, a
Golgi protein, GOLPH3, was identifi ed as a candidate targeted for amplifi cation
(Scott et al. 2009 ). Gain- and loss-of-function studies in vitro and in vivo validated
GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi
network and interacts with components of the retromer complex, which has been
linked to target of rapamycin (TOR) signaling. GOLPH3 regulates cell size,
enhances growth-factor-induced mTOR (also known as FRAP1) signaling in
human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus,
genomic and genetic, biological, functional and biochemical data in yeast and
humans establishes GOLPH3 as a new oncogene that is commonly targeted for
amplifi cation in human cancer, and is capable of modulating the response to
rapamycin, a cancer drug in clinical use. A protein made from GOLPH3 may serve
as a biomarker for tumors that can be effectively treated with the rapamycin: tumors
with a high level of the protein are more apt to shrink in response to the drug than
those with low levels.
Predictive Biomarkers for Cancer
Unpredictable effi cacy and toxicity are hallmarks of most anticancer therapies.
Predictive markers are factors that are associated with response or resistance to a
particular therapy. Currently, the only recommended predictive markers in oncology
are estrogen receptor (ER) and progesterone receptor (PR) for selecting endocrine-
sensitive breast cancers and HER-2 for identifying breast cancer patients with meta-
static disease who may benefi t from trastuzumab. For malignancies other than breast
cancers, validated predictive markers are not available as yet.
Impact of Biomarkers on Management of Cancer