365drive various human cancers and will open up the possibility of personalized thera-
pies targeted to the molecular pathology and genomics of individual patients and
their malignancies. The new molecular therapies should be more effective and have
less-severe side effects than cytotoxic agents. To develop the new generation of
molecular cancer therapeutics as rapidly as possible, it is essential to harness the
power of a range of new technologies. These include: genomic and proteomic
methodologies (particularly gene expression microarrays); robotic high-through-
put screening of diverse compound collections, together with in silico and
fragment- based screening techniques; nanobiotechnology; new structural biology
methods for rational drug design (especially high-throughput X-ray crystallogra-
phy and NMR); and advanced chemical technologies, including combinatorial and
parallel synthesis.
Challenges for Developing Personalized Cancer Therapies
Two major challenges to cancer drug discovery are: (1) the ability to convert potent
and selective lead compounds with activity by the desired mechanism on tumor
cells in culture into agents with robust, drug-like properties, particularly in terms of
pharmacokinetic and metabolic properties; and (2) the development of validated
pharmacodynamic endpoints and molecular markers of drug response, ideally using
noninvasive imaging technologies.
Many variables besides genotypes of patients would need to be considered in
development of personalized therapies for cancer. An example of this is limitation
of genotyping for methylenetetrahydrofolate reductase (MTHFR), which plays a
central role in the action of 5-FU, an inhibitor of thymidylate synthase, by convert-
ing 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Two polymor-
phisms in the MTHFR gene (677C > T and 1,298 A > C) have been considered as
genomic predictors of clinical response to fl uoropyrimidine-based chemotherapy
(in combination with irinotecan or oxaliplatin). Results of studies on patients with
metastatic CRC who have undergone 5-FU-containing chemotherapy as a fi rst line
treatment indicate that the MTHFR genotype cannot be considered as an indepen-
dent factor of outcome.
Cancer Genome Atlas
The Cancer Genome Atlas (TCGA) is a coordinated effort to accelerate our under-
standing of the molecular basis of cancer through the application of genome analy-
sis technologies, including large-scale genome sequencing ( http://cancergenome.
nih.gov/ ). TCGA is a joint effort of the NCI and the National Human Genome
Research Institute (NHGRI), which are both part of the NIH. The Pilot Project
focuses on three types of cancers: brain (glioblastoma multiforme), lung (squamous
Future of Cancer Therapy