We need to move from the primacy of therapeutics to the primacy of diagnostics, from “companion diagnostics” to “companion therapeutics”. Drug discovery greatly benefits from being based on correcting biological markers of disease. Once you have such markers, you can identify drugs that modulate them individually, or modulate the biological pathways they are in, or modulate in opposite direction the gene/phene expression signature of a panel of top markers.
The later approach is probably the best, as most diseases are complex, and by modulating a biosignature you are more likely to be more efficacious as well as more specific for the disease. For example, using a gene expression biomarkers signature, “dry lab” approaches such as connectivity map, or “wet lab” approaches such as de novo screening of compounds in cells or model organisms, may yield useful compounds. Using several low dose combinations of such compounds in subsequent clinical trials may synergize their abilities and minimize their liabilities, resulting in a broad-spectrum therapeutic with favorable side effect profile. The biomarker signature can be monitored as a primary measure of response to treatment, providing real-time feedback.
After the clinical trials are successfully completed, in subsequent actual clinical practice, tailoring the compounds in the combinations and their dosages based on the profile of biomarkers in a particular patient may yield additional benefit. Again, the biomarker signature can be used to monitor not only the efficacy and make any needed adjustment in dosages, but also as a way of gaining additional insights about stratification in a wider context, taking into account gender, possible subtype of disease, age, ethnicity, and, importantly, environmental factors.
Alexander B. Niculescu, III, MD, PhD