Targeted Therapies — The Next Chapter

Within this blog, we have intermittently reviewed the concept of targeted therapies. To reiterate, these are classes of drugs that target specific pathways considered tumorigenic. Among the pathways initially targeted were the epidermal growth factor receptor and the closely related HER2. Shortly after the introduction of EGFr and HER2 directed therapies came the development of drugs that target another critical pathway, mTOR.

Hundreds of compounds are now under development intended to more accurately hone in on the pathways of interest in patients’ tumors. Regrettably, the medical community continues to apply old clinical trial methods to this newest era of drugs. While the selective application of drugs like: Tarceva for EGFR mutants, Herceptin for HER2 over-expressers, and Crizotinib for EML4-ALK mutants, are much more effective in patients with these gene expressions, these are a select few examples of linear thinking that bore fruit.

That is, this gene is associated with this disease state and can be treated with this drug.

Many, if not most cancers will prove to be demonstrably more complicated. Genomic trials can only succeed if we first know the gene of interest and second know that its (over) expression alone is pathogenetic for the disease entity. Even meeting these conditions is likely to result in comparatively brief partial responses due to the crosstalk, redundancy and complexity of human tumor signaling pathways — the “targets” of these new drugs.

To address these complexities, functional analytic platforms that examine outcomes, not targets, are needed. This bottom-up approach has now enabled my team to explore the activity of novel compounds. When investigators develop interesting “small molecules,” we examine the disease specificity, combinatorial potential and sequence dependence of these compounds in short-term cultures to provide meaningful insights that can then be addressed on genomic and proteomic platforms. This reduces the time required to take these new agents from bench to bedside. We cannot solve tomorrow’s questions using yesterday’s mindsets