Tinker, Tailor, Soldier, Gene.

In very old movies (or so it is said), the good guys wore white hats and the bad guys black ones. This made it easy to sort out who was who and keep track of everyone's allegiances. In introductory classes, simplifications enable nice simple classifications: these are the enzymes of glycolysis, these are the Krebs cycle, etc.

The yearning for such simplicity remains, even in the face of far more complex situations. We want to have clean lists of pro-apoptotic or anti-apoptotic genes, but the reality is that some proteins play all the angles. Depending on the situation, their splice form, their translational state, etc., the protein can either push a cell towards or away from death. Similarly, we would like to classify proteins as either tumor promoting or tumor preventing and somehow alter the balance in the cancer patients favor, often by inhibiting the pro-tumor protein with a small molecule or antibody therapeutic.

One set of such molecular target are the Aurora kinases. Aurora was originally identified in the fruit fly and shown to be a serine/threonine protein kinase (an enzyme that adds a phosphate to the hydroxyl group on Ser or Thr). Later, 3 aurora homologs were identified in mammals, and the monikers Aurora A, B & C were eventually settled on. Aurora B and C are nearly identical, which has advantages since the exact role for C has been argued about a bit; from a pharmaceutical standpoint B and C are the same target, because it is probably impossible to generate a compound targeting the proteins which can distinguish them.

A number of pharmaceutical companies, including my past employer, have small molecules in development targeting either AurA or AurB/C or both; various arguments exist as to which specificity makes the most sense, and it can probably be only sorted out in the clinic. Vertex & Merck are, the last I heard, the most advanced with their compound (in Phase II), and in a stroke of luck it turns out to target another therapeutically interesting target, Jak2.

A lot of good biology has suggested that Aurora should make a good cancer target. Some of this is from various cell culture and xenograft (human tumor cells implanted in mice) studies, but there is also good evidence from clinical samples. Polymorphisms (e.g. this report) and amplifications (e.g. this one) in aurora genes have been observed in many human tumor samples. The fact that Merck/Vertex have taken their compound into Phase II suggests that they saw activity in Phase I, as only desperate biotech companies push a Phase I oncology drug candidate forward without some hint of efficacy.

An abstract in the most recent issue of Cancer Cell looks intriguing & food for thought. This report describes finding reduced Aurora A levels in several tumor models, with the reduction coming via gene silencing or deletion. Since many tumors are null for p53 function by one hook or crook, the idea that p53- tumors might benefit from lower Aurora A activity casts a bit of a question on Aurora A-targeting drugs, which might well include Aurora B targeting drugs as the two are too similar to truly avoid touching Aurora A to some degree.

It will be interesting to find out whether in the natural progression of some human tumors there is a phase where Aurora A is tumorigenic but a later phase where it is tumor suppressing. Perhaps, like many a spy in a Le Carre novel, AurA's reward for a job well done is a carefully arranged ambush when it has outlived its usefulness.