The return of the biochemists, but let's not forget selectivity

James Watson has an interesting op-ed in the NYT in which he advocates a return to biochemical methods for studying cancer. Watson thinks that while genetic studies of cancer will continue to provide important insights, we need to focus on the basic chemical reactions underlying cancer cell proliferation to come up with new therapies. I find this emphasis on chemistry gratifying, and others have also criticized the undue attention given to genetic studies of the disease. While such studies are and will remain undoubtedly important in elucidating the nature of cancer in individuals, it is only through detailed studies of the biochemical machinery of cancer cells that we can really find out the true nature of future targets for therapeutic intervention.

Watson also advocates emphasizing combinations of drugs instead of the largely single driver paradigm accepted currently. What is a little concerning for me that he does not really talk about toxicity and selectivity; there is usually a good reason why the FDA is loathe to approve combinations of chemotherapeutic agents that might cause lots of side effects. Watson seems to envisage an age when cancer, like heart disease and diabetes, might be able to be managed as a chronic disease. While this is a laudable goal, the nature of cancer compared to other chronic diseases is clearly different; it's far more invasive and involves a far trickier set of fundamental processes to understand and control (although diabetes is also not exactly the simple ailment it was initially thought to be)

Curiously, the example that Watson provides for emphasizing the biochemical basis of cancer seems to me to be potentially replete with selectivity issues. Consider this:

The idea that cancer cells may be united in having a common set of molecules not found in most other cells of our bodies was first proposed by the great German biochemist Otto Warburg. In 1924, he observed that all cancer cells, irrespective of whether they were growing in the presence or absence of oxygen, produce large amounts of lactic acid. Yet it wasn’t until a year ago that the meaning of Warburg’s discovery was revealed: The metabolism of cancer cells, and indeed of all proliferating cells, is largely directed toward the synthesis of cellular building blocks from the breakdown products of glucose. To make this glucose breakdown run even faster in growing cells than in differentiated cells (that is, cells that have stopped growing and taken on their specialized functions in the body), the growth-promoting signal molecules turn up the levels of the “transporter” proteins that move glucose molecules into cells.This discovery indicates that we need bold new efforts to see if drugs that specifically inhibit the key enzymes involved in this glucose breakdown have anti-cancer activity.

While this is definitely an interesting observation, I am not sure how productive in terms of selectivity and toxicity would targeting glucose metabolizing enzymes be. Glucose metabolizing enzymes constitute about as universal and fundamental a set of proteins as you could find in living organisms. Unless there are specific proteins with specific mutations present only in cancer cells, I can see a really big selectivity problem in targeting such proteins. Now of course we have had success in targeting all sorts of proteins that are expressed in both cancer and normal cells (consider kinases like VEGF), but still, it would be very interesting to see whether hitting such a basic part of the cellular machinery can actually provide tangible benefits.

In any case, the goals that Watson expounds on- a return to biochemistry, a balanced focus on pure and applied research, more flexible FDA guidelines for developing combination therapy, and the final goal of making cancer a chronic disease- are all sensible. The dream of winning a "war on cancer" is almost as unrealized today as it was in 1971, but maybe now we can feel confident that we are actually marching toward the front lines.