Right, in my previous post I wrote a bit about why treating cancer is such a bitch, given that there are so many ways in which cells can drive phenotypes that are associated with cancer. However, in some cases, the pathology of a certain kind of cancer may be very invariant (not much variation) in which case the problem of heterogeneity isn’t as big a headache.
Once an invariant target has been identified a process of rational drug design can be carried out. Rational drug design means that you use evidentially supported principles and methods to develop drugs. Once a target has been identified, its structure can be deduced and its function studied. If preventing that target from working efficiently can knock out the disease phenotype it contributes to, it can be considered as a potential target for therapy.
Chemists can then use computational tools and their intuition to design drugs, either small molecule drugs which are completely synthesized from chemicals, or biologics, where biological sources of molecules that can knock out our target are sought.
This post features the poster boy of targeted therapy against cancer, called Gleevec, or Imatinib mesilate. This is different from traditional, non-specific chemotherapy because it only targets proteins whose overproduction is a feature of cancer cells, whereas traditional chemotherapy tends to hit all fast growing cells, normal or cancerous.
The Pathology of Chronic Myelogenous Leukaemia & What Gleevec Targets…
Now Gleevec is a blockbuster drug that has been most successful with a particular type of Leukaemia, called Chronic Myelogenous Leukaemia (CML), in which there is rapid and uncontrolled proliferation (aka cancer) involving a class of White Blood Cells and their precursors called Granulocytes.
This aberrant growth happens due to a mutational event that involves the fusion of two genes with aberrant regulation, namely the BCR gene from Chromosome 22 to the ABL gene from Chromosome 9, giving rise to a fused chromosome popularly known as the Philadelphia Chromosome. (This name comes from the documentation of the disease by two scientists from Philadelphia in the American state of Pennsylvania)
This fusion gene produces a new protein that is a tyrosine kinase (it can add a phosphate group to an amino acid called tyrosine on proteins that interact with it) which is transcriptionally active (the mutant cells keep making the BCR-ABL fusion protein without needing any external signal) and this fusion protein can halt DNA repair and get cells to really hurry up while dividing. This is what drives mutant cells on the path to cancer, aided no doubt by the fact that DNA repair, once stopped, enables large scale mutations to happen as a consequence of genomic instability.
Now notice that the protein produced by the fused gene is capable of triggering things like proliferation, cell survival, increased motility et cetera, in other words, cancer. To sum up, this gene, Bcr-Abl is central to the pathology of CML, and as a consequence is an excellent drug target, since you can knock out all the cancer phenotypes it can trigger by knocking it out.
Now here is the smart bit involved in targeted therapy, Imatinib was selected because it is a competitive inhibitor of BCR-ABL fusion protein, that is, instead of the proteins with which this tyrosine kinase interacts Gleevec goes and binds to the active site, thereby preventing BCR-ABL from triggering the signalling pathways that lead to the formation of cancer phenotypes. It is like filling a box up with something that is harmless to prevent something harmful from getting in and being able to use the box. It is like playing a prank on someone who needs to empty their bladder desperately by occupying the bathroom without needing to urinate, and what Gleevec does is the biochemical equivalent of that.
It also helps that it binds specifically to this kinase and not a lot of kinases in general which could have otherwise had detrimental effects on normal cells.
Gleevec is the chemical equivalent of a sniper that can take out a target without hitting anybody innocent, and if evidence is to be trusted then it has done wonderfully well. Not only is it used as the first line of attack against CML but is also used against some other forms of cancer, such as Gastrointestinal Stromal tumours that act using the KIT pathway, if I recall correctly. This is because it is also capable of blocking c-KIT, which is another protein that can drive cancer.
Most importantly, it provides validation of the concept that it is possible to account for heterogeneity provided we have enough information, that it is possible to selectively take targets out, and that it is possible to develop high class chemotherapy that doesn’t suffer from the abhorrent side effects of traditional chemotherapy. In other words, it is the drug that has made it possible for oncologists and oncopharmacologists to dream, even if CML is just one of many cancers around.
Here is a video on Gleevec’s mechanism of action.
Here is a long scientific lecture/presentation on the development of Gleevec and how it went from bench to bedside.
Happy learning 🙂