Blocking Cancer Pathways: PERSONALIZED MEDICINE AT MARY CROWLEY
"Almost all gene modifications can be classified in one or more of 12 signaling pathways."
In February 2001, the Human Genome Project published the 90 percent complete sequence of the three billion base pairs in the human genome containing approximately 30,000 genes. As a result of advances in sequencing technology (whole genome and whole exome), commercialization permitting wide-ranging access, and improved turn-around time, 138 mutated cancer driver genes have been identified to date. These cancer driver genes are defined as mutated genes that provide tumor cells with a selective growth advantage in one or more of the local, regional, and systemic environments. There are a significantly larger number of mutations that, although present in the cancer cells, occurred during the preneoplastic normal growth phase and, insofar as these mutations did not initially provide an adaptive advantage, are called passenger genes. Yet, these mutated genes can undergo exaptation that ex post facto describes the shift in their function due to changes in evolutionary pressures as a result of the functional rewiring. These changes are facilitated by the driver genes that result in a shift from neutral to cancer supportive activity. Additional perturbations in gene functionality can also be due to non-mutational changes in gene copy number, insertions and deletions (indels), fusions and epigenetic modifications (heritable non-structural changes primarily due to changes in methylation). Data encoded in the DNA, essentially a template, is transcribed into messenger RNA (mRNA), a bio-molecular mold, then translated into proteins (the product) which influence the reaction rates of metabolites (catalysis) (see figure 1). All of these –omic levels (genomic-transcriptomic (mRNA)-proteomic-metabolomic) can interact with and modify each other. To make matters more complicated, mRNA can undergo alternative splicing by means of which encoding sequences (exons) can be rearranged, resulting in more than one mRNA per gene, producing protein isoforms with different, even opposing, functions. Furthermore, differences in protein abundance can only be attributed to mRNA levels in 20-40% of cases.
Figure 1: The multilevel relationships between –omic levels
“In February 2001, the Human Genome Project published the 90 percent complete sequence of the three billion base pairs in the human genome containing approximately 30,000 genes…"
Figure 2: Cancer cell signaling pathways
Figure 3: Hallmarks of cancer: capabilities necessary for cancer cell growth and progression.
At first, the array and abundance of infrastructural changes that confer a selective growth advantage to cancer cells by enhancing adaptive fitness can seem staggering and almost beyond our ability to choose which one[s] to target. However, there is an underlying order to this diversity. Almost all of these modifications can be classified into one or more of 12 signaling pathways (see figure 2), which subserve one or more of the 10 hallmark functions necessary for cancer growth and progression identified by Hanahan and Weinberg (see figure 3).
“Almost all of these modifications can be classified into one or more of 12 signaling pathways, which subserve one or more of the 10 hallmark functions necessary for cancer growth and progression identified by Hanahan and Weinberg.”
Figure 4: High information transfer “bottleneck nodes".
The components comprising these 12 pathways interact with each other in a complex network made up of gene/protein nodes and connecting links, some of which are stimulatory and some inhibitory. The importance of any of these nodes to the operational efficiency of the network and, inversely, to error intolerance (the ability of the network to withstand one or more targeted damages to the nodes) is dependent on that node’s connectivity (the number of linkages to other nodes) as well as to which nodes it is connected. The linked nodes carrying high amounts of information between different clusters of nodes that are functionally distinct from each other are called “bottleneck nodes."
Figure 5: Targeting “bottleneck” verses “non-bottleneck” nodes
These key 'bottleneck nodes' are those genes/proteins that are essential to network function which, in turn, are necessary for maintenance of the malignant process. Looking at this in another way, these nodes are the most fragile component of the network and, therefore, the most vulnerable sites within the functional network comprising the cancer—appropriate targets for therapeutic attack (see figure 5).
“These key “bottleneck nodes” are those genes/proteins that are essential to network function which, in turn, are necessary for maintenance of the malignant process.”
Understanding Cancer Pathways
Insofar as a number of different genes/proteins can have rate limiting effects in a dominant signaling pathway, systems analysis can allow optimization of limited target pathway disruption. Further, given the cross-talk between pathways and that the robustness of the cancer network involves alternative and/or compensatory secondary pathway utilization, it is likely that more than one pathway needs to be targeted. For example, in non-small-cell lung cancer with an EGFR inhibitor sensitizing L858R mutation in exon 21, effective targeted therapy can be bypassed by upregulation of the cMet receptor and its downstream pathway. Mary Crowley has continued to offer a number of protocols with multiple node targeting—a major step in the development of Personalized Medicine.
Dr. Neil Senzer, Scientific Director