Dynamical Analysis of Drug Efficacy and Mechanism of Action Using GFP Reporters

Introduction

Target identification and validation are critical components of the targeted drug discovery (Bleicher2003, Hoelder 2012, Dahlin 2015). Predicting drug effectiveness through potential target is typically via a bottom-up conceptualization of tumor function. It assumes that sufficient knowledge regarding cellular processes can be gathered through genomic, proteomic, and metabolic profiling projects. Such knowledge can then be used to recognize tumor vulnerabilities, screen potential drugs and construct effective targeted therapies (Lee 2009, T.C.G.A. Network 2008). For this constructivist approach to succeed, the vulnerabilities must be based on simple linear relationships, in which inactivating a particular target will be sufficient to control the tumor.

To illustrate the kind of special situation that contributes to a direct correlation between therapy and disease control, we consider two cancer types, chronic myelogenous leukemia (CML) and acute promyelocytic leukemia (APML), in which substantial improvements in patient outcomes have been achieved by targeted therapy. In these cancers, a single type of translocation fusing parts of two genes is a pathognomonic indicator of the disease and an excellent biochemical target for therapeutic targeting (Chen 1991, Druker 2001, Nowell 1960, Rowley 1977). These cases seem to be fairly extreme outliers from the bulk of cancer types in two ways.

The first is the striking uniformity of CML and APML tumors. Significant homogeneity of particular, discriminating patterns of gene expression in a particular subtype of tumor is rare, yet both of these tumors show exactly this characteristic (Dong 2010, Nowiki 2003). It appears that such tumors arise from a specific partially differentiated precursor cell that exhibits most of the characteristics of a cancer and that those missing cancer characteristics occur as a consequence of a single genomic alteration (Pear 1998). This behavior is in stark contrast to the considerable heterogeneity of molecular pathologies that appear to arise from various differentiated precursors in many cancers, such as breast cancer (Perou 2000). Also consider melanoma, which originates from a single, highly-differentiated cell, the melanocyte, and has yet to be sub-classified into clinically useful groups on the basis of molecular pathology. The second way in which CML and APML differ from most cancers is that, as opposed to CML and APML, tumors arising from highly differentiated cell types appear to have to breach more types of controls opposing oncogenesis. Even when starting from a single differentiated type, they appear to break these controls in a wider variety of ways.