The medication landscape is constantly changing, in particular the cancer medication landscape. A strong emphasis on cancer research has yielded much new understanding that can be translated into new drugs. At the end of June 2014, the FDA Oncologic Drugs Advisory Committee will meet to discuss new drug applications, in particular PARP inhibitors (e.g. olaparib). This is one step in translating research results into clinical application. This PARP inhibitor case provides an example of why NGS sequencing has to replace Sanger sequencing or array-based tests, and why it will be wise to test multiple genes.
PARP, the acronym for Poly(ADP-ribose)polymerase, an enzyme involved in DNA repair, in itself will not repair DNA but it will help to recruit other molecules to the site of damage. The whole repair machinery is very complex so as to provide robust and reliable functionality. Normal cell functions, metabolism, chemicals, ultraviolet light, radiation, all with associated generation of free oxygen radicals and reactive intermediates are common factors in the generation of DNA errors. DNA repair is therefore a cardinal function in the cell for maintaining stability. However, when any of the more than 100 genes for DNA repair becomes mutated, mistakes begin accumulating everywhere and they can lead to cancer. This is what happens when cancer susceptibility increses as a consequence of alterations in BRCA1 and BRCA2 gene function in DNA repair.
So why PARP inhibitors in cancer treatment, since PARP is part of the DNA repair machinery of the cell? The other side of the story of cells with DNA errors is that from the moment it becomes too hard to repair the accumulating errors, it is better to hinder the cell from propagating them. The cell can do this by initiating apoptosis (programmed cell death) or by blocking cell division. The sooner a cell with DNA damage is flagged, the quicker it will be put out of the way. Therefore, inhibiting PARP in cells already showing impaired DNA repair will speed up the cellular sanitising process. PARP inhibitors have shown promising activity in patients with BRCA1/2 mutation-associated ovarian and breast cancers. The reason is not clear yet, but seems to be a consequence of the cumulative effect of the inhibitor of PARP and the altered BRCA functionality in DNA repair.
The link between BRCA1/2 and PARP inhibition exemplifies how companion diagnostics of biomarkers holds the promise of improving the predictability of the oncology drug development process and becomes an important tool for the oncologist in the choice of individual patient treatment. At the same time it highlights three further important points to note when planning genetic testing.
Gene function (e.g. BRCA1/2) as a whole is the critical issue and it cannot be estimated by looking only at some previously known variation spots in the gene. Instead, it is important to sequence the whole gene in order to identify any change that can have a bearing on function, hence medication.
Cellular mechanisms are overall very complex, and by setting clinical focus only on a few genes one might well miss important features of the personal genome that could be used to improve the treatment of the patient. PARP inhibitors will certainly turn out to be efficient also when other DNA repair steps fail,other than those managed by BRCA1/2.
Testing of cellular mechanisms require high-throughput sequencing and efficient data processing to provide comprehensive medical knowledge at an affordable price.
In conclusion, any medication will rely on information about many tens of genes, at the very least. Many of the genes are already know by scientists and can be tested by next-gen sequencing, even though they have not yet been evaluated by the FDA Oncologic Drugs Advisory Committee or any other similar medical body.
[For a review on BRCA1/2 and PARP inhibition see Lee, Ledermann & Kohn, Annals of Oncology 25: 32 – 40, 2014; doi:10.1093/annonc/mdt384]