Integrating “Omics” Data for Quantitative and Systems Pharmacology in Translational Oncology - Bioanalysis Advanced Materials Methods and Devices - page 182

12.1 Introduction

We are entering an important era where cancer medicine is being transformed into
personalized medicine. This transformation has been primarily driven by the
development of new technologies and powerful computational algorithms to
sequence and characterize genomes. These high-throughput and scalable
technologies have enabled researchers to acquire and analyze measurement of
tens of thousands of “omic” data points across multiple levels (e.g., DNA, RNA,
protein) from a single tissue in a reasonable time frame. These massive “omic” data,
when analyzed and interpreted by powerful computational methods, reveal new
information and knowledge that can be translated to disease treatment and manage-
ment. Indeed, the application of such technologies in the field of oncology has
changed the paradigm of cancer treatment in a manner previously not possible.
Large-scale cancer genome projects such as the Cancer Genome Atlas Research
Networks (TCGA) [ 81 , 82 ] and the International Cancer Genome Consortium
(ICGC) [ 38 ] have identified genes and pathways that drive the initiation in some
cancers [ 81 ]. Numerous studies have demonstrated that some cancers are dependent
on these oncongene driven signals for survival and maintenance [ 90 ]. Understand-
ing of these oncogenes is key for developing novel small molecules to inhibit the
activity and function of these oncogenes. Targeted cancer therapies have exploited
this “oncogene addiction” concept [ 90 ] leading to several successful genotype-
directed clinical applications of targeted therapies. One of the “best success”
examples of exploiting the “oncogenic addiction” concept was the development
of Imatinib Mesylate (Gleevec TM ) in chronic myelogenous leukemia (CML) [ 19 ].
CML can be genetically characterized by the formation of the Philadelphia chro-
mosome, which is a result of reciprocal translocation between the long arms of
chromosomes 9 and 22 [ 65 ]. Consequently, this translocation generates the fusion
protein BCR-ABL, a constitutively activated tyrosine kinase, which drives this
disease and can be detected in all CML patients. Multiple in vitro and animal model
experiments (“bench”) have demonstrated that BCR-ABL alone is sufficient to
cause CML [ 15 , 35 , 49 ]. Further mutational analysis has established BCR-ABL
protein oncogenic activity is driven by the tyrosine kinase activity. Therefore,
efforts have been made to develop an inhibitor of the BCR-ABL tyrosine kinase,
with the expectation that this therapeutic should be an effective and selective
treatment for CML. Imatinib Mesylate (Gleevec ® , Novartis, Inc.), a novel tyrosine
kinase inhibitor of BCR-ABL, began Phase I clinical testing (“bedside”) in June
1998. The dramatic results obtained from the clinical trials in CML patients led to
rapid US Food and Drug Administration (FDA) approval in May 2001 as the first-
line treatment for this disease. The success of Imatinib provided the framework for
future targeted drug development such as the recent approval of Crizotinib for
ALK + patients in non-small cell lung cancer [ 11 ] and Vemurafenib for patients
with BRAF mutations in advanced melanoma [ 23 ].
Over the past decade, DNA-based microarrays have been the assays of choice
for high-throughput studies to quantitate and characterize gene expressions.