Working with Pharma
Biomarkers help clinicians identify which patients will best respond to a targeted treatment. Development of a drug begins with finding a molecular target that plays a strong pathological role. Recently, key regulators of DNA Damage Response (DDR) pathways have become targets for successful cancer drugs.
Inhibition of the molecular target by a drug is often measured by the diminished activity of the target and of its downstream pathway. In the context of DDR targeting, a major indicator of DDR pathway inhibition in cancer cells is an increase in the level of DNA breaks, as multiple DNA repair pathways are no longer available to mitigate DNA damage. This eventually leads to cancer cell death.
DNA damage is commonly measured by assays that visualize chromosomal breaks and abnormalities under the microscope or that identify broad regions of DNA damage-sensing and repair proteins that accumulate on the chromosomes. However, these methods are unable to directly identify where DNA double-strand breaks occur with high resolution. Without this, such assays lose critical information on the precise DNA sequences that strongly correlate with and contribute to breakage.
Could the identification of DNA break sites provide unique information? Many studies have probed the genome and found certain sequences that play a key role in disease (such as expanded triplet DNA repeats in Huntington's disease and Fragile X syndrome). Some studies have discovered that regulatory, repetitive, and structure-forming DNA sequences become fragile when critical stress responses in the cell are compromised. The fragility of these sequences contributes to breakage at these sites and to the instability of the diseased cell.
These studies lend mechanistic insights on how certain response pathways affect the stability of distinct parts of the genome. Vulnerable DNA sequences revealed by the therapeutic targeting of these response pathways can serve as potential biomarkers of response to these drugs.
Assays that seek to identify biomarkers of drug response are limited to mutations and abnormalities present in expressed genes. However, through the identification of genome-wide DNA breaks caused by DDR drugs and other similar targeted therapeutics, it is possible to similarly look for mutations and regions of vulnerabilities across non-coding regions of the genome. This information can complement current assays that identify biomarkers of drug response within genic regions by adding the contributing effect of non-coding and repetitive DNA sequences on disease pathology and drug intervention.