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
