The big medical news last week was that the US FDA revoked the use of the drug Avastin for the treatment of breast cancer. The reason was that any potential efficacy did not outweigh the side effects. Avastin is an anti-angiogenesis drug that blocks the formation of blood vessels by inhibiting the vascular endothelial growth factor VEGF-A. This class of drugs is a big money-maker for the biotechnology firm Genentech and has been used in cancer treatments and for macular degeneration where it is called Lucentis. Avastin will still be allowed for colorectal and lung cancer and physicians can still prescribe it off-label for breast cancer. The strategy of targeting blood delivery as an anti-tumour strategy was pioneered by Judah Folkman. He and collaborators also showed that adipose tissue mass (i.e. fat cells) can be regulated through controlling blood vessel growth (Rupnick et al., 2002) and this has been proposed as a potential therapy for obesity (e.g. Kolonin et al, 2004; barnhart et al. 2011). However, the idea will probably not go very far because of potential severe side effects.
I think this episode illustrates a major problem in developing any type of drug for obesity and to some degree cancer. I’ve posted on the basic physiology and physics of weight change multiple times before (see here) so I won’t go into details here but suffice it to say that we get fat because we eat more than we burn. Consider this silly analogy: Suppose we have a car with an expandable gas tank and we seem to be overfilling it all the time so that it’s getting really big and heavy. What should we do to lighten the car? Well, there are three basic strategies: 1) We can put a hole in the gas tank so as we fill the tank gas just leaks out. 2) We can make the engine more inefficient so it burns gas faster or 3) We can put less gas in the car. If you look at it this way, the first two strategies seem completely absurd but they are pursued all the time in obesity research. The drug Orlistat blocks absorption of fat in the intestines, which basically tries to make the gas tank (and your bowels) leaky. One of the most celebrated recent discoveries in obesity research was the discovery that human adults have brown fat. This is a type of adipocyte that converts food energy directly into heat. It is abundant in small mammals like rodents and babies (that’s why your newborn is nice and warm) but was thought to disappear in adults. Now, various labs are trying to develop drugs that activate brown fat. In essence they want to make us less efficient and turn us into heaters. The third strategy of reducing input has also been tried and has failed various times. Stimulants such as methampthetamines were found very early on to suppress appetite but turning people into speed addicts wasn’t a viable strategy. A recent grand failure was the cannabinoid receptor CB-1 blocker Rimonabant. It worked on the principle that since cannabis seems to enhance appetite, blocking it suppresses appetite. It does work but it also caused severe depression and suicidal thoughts. Also, given that CB-1 is important in governing synaptic strengths, I’m sure there would have been bad long-term effects as well. I won’t bother telling the story of fen-phen.
It’s kind of easy to see why almost all obesity drug therapies will fail because they must target some important component of metabolism or neural function. While we seem to have some unconscious controls of appetite and satiety, we can also easily override them (as I plan to do tomorrow for Thanksgiving). Hence, any drug that targets some mechanism will likely either cause bad side effects or be compensated by other mechanisms. This also applies to some degree to cancer drugs, which must kill cancer cells while ignoring healthy cells. This is why I tend not to get overly excited whenever another new discovery in obesity research is announced.