Cancer is such an old disease that it has even been found in dinosaur bones.  So many years have passed and we still don’t have a cure. It looks like the mortality from cancer has decreased only ~10% in the last 10 years.  Metastasis and resistance continue to be the biggest problem.

We definitely have lots more information about what causes cancer than how to cure it. Why is this? Sure, we have very fancy labs and more technology and specialized people evaluating many different mechanisms, and we have tons of tools to help make “our jobs easier”! But are all these technologies really helping us or are they derailing us from the simple straight-forward approach use of pure logical thinking that was utilized by the people who discovered the original chemotherapy agents?

If doctors like Goodman, Gilman, Rosenberg, Hitchings and Elion hadn’t been there at the precise “eureka moment” we probably wouldn’t have many therapeutic agents in our current chemotherapy arsenal.  I don’t think those compounds would have been approved or even made in current times either, because they are too toxic and have very poor drug-like properties; however, the majority is still being used or has been used as leads to develop somewhat less toxic agents.

While reading some oncology literature*, I scribbled in my pad the most important factors related to “chemistry design” where I believe there is much room for improvement.  These seem to be the most relevant causes for unsuccessful discovery of new cancer therapies in recent years:

1. The selection of a chemical starting point molecule that is not amenable to optimization of drug properties including solubility, stability, potency, pharmacokinetic exposure and selectivity.
2. The premature selection of a candidate drug because of deadlines, funding, etc.
3. The feeling that “we are done” and nothing else can be done.
4. Thinking that developing SAR (structure activity relationship) is a simple task in cancer research.  We are dealing with very complex biologic systems and it is presumptuous to reduce it exclusively to simple SAR terms…what if the biological response is a result of inhibition of an unrelated target?
5. The use of the inadequate preclinical models to test new therapies that don’t reflect real life scenarios. This goes more for pharmacology; however this is the most important point where chemistry and pharmacology come together.

This line of reasoning made me think: what would I wish for if I found a genie in a bottle who offered three work-related wishes?… (although to a chemist this genie would probably come in a beaker or an Erlenmeyer flask) the first thing I would do is probably to ask for few more wishes….but seriously, I think the following breakthrough necessities for the cancer discovery process would be a reasonable request:

1. Wisdom and sharp eye to weed out faulty hypotheses and irrelevant data (presumably abundant in recent years).  Can you imagine after years of research to realize that a pathway thought to be critical in the disease process is not the main reason of cancer and the real reason is because the target is in the middle of a very complicated pathway system that is almost impossible to understand?
2. A device that will reveal the molecular genetic profile, including the connection with other pathways of a patient tumor, and what mechanism we should “switch off” in order to selectively target the tumor over healthy tissue. We are in an era where we are making more and more target-based therapies.  Presumably in the future we wouldn’t care much about the organ of origin but rather of the molecular genetic profile of the tumor.   Based on the genetic alterations, every tumor would be different even if they are in the same tissue.
3. A device that will clone that particular tumor of a patient and will program a predictable model that would: 1) translate from laboratory to clinic to tell us right away if a particular therapy would be efficacious in “killing” the tumor of interest and 2) serve to reflect the mutation character and resistant profiles.

Now, my question to you is: what would you wish for?

*Recommended reading: Cancer Drug Design and Discovery by Stephen Neidle and Chemistry and Pharmacology of Anticancer Drugs by David E. Thurston.