Targeted Therapy: Woe Unto Thee!

After a brief haitus dedicated to continued success in medical school, the blogkove is back. With a vengeance.

Intrepid reader Henry sent me this article (continued here) about the tribulations of a B-Raf inhibitor trial. My executive summary of the situation is as follows: the good Dr. Flaherty took part in a trial of a new inhibitor that halts growth in melanoma in a promising way, both theoratically and practically. However, the melanoma, ever the wily contender, switches its signalling pathway to avoid utilizing the now-inhibited B-Raf, and thus is able to complete its evil mission of "grow ad infinitum." The oncologists and patients, needless to say, were shocked at how after 6 months or a year of successful treatment, the melanoma suddenly turned deadly again, laughing in the face of the targeted drug therapy.



This is no novelty. Prior to my matriculation at MCG, I worked for several years in the laboratory of Dr. Jack Arbiser, whom I consider a professional and personal mentor. He is an astute researcher, with a strong grasp of cancer biology. However, his ideas on cancer therapy have been dismissed by some of his colleagues for several reasons. Some feel uncomfortable with his conclusions on tumor growth and signalling because he hasn't beaten them over the head with data. The problem is he is almost always correct in his assertions. Also, he has a bit of a fetish for phytopharmaceuticals, and the current thinking of oh-so-many-drug-developers is that the best drugs come out of labs, not from plants, and that the most efficacious ones are gigantic molecules of inordinate complexity, not the simple honokiol, MW 266, of which I personally took part in the development thereof (I also wrote that wiki article). I have a feeling that the FDA's and many researchers' obsession with targeted-therapy has much to do with the successes of Gleevec in the treatment of CML. Gleevec is a targeted therapy that has done wonders for CML, but it is illogical, considering the diversity of tumor subtypes, to apply that paradigm to all tumors. We already know better (and more) than that.

Dr. Jack has spent a great deal of his professional career characterizing the dynamic nature of melanoma signalling: how melanoma will switch pathways to avoid  an insult (a drug, in this case). Here is a good paper penned by him on the issue. He has stood up at conferences and made the very point that a B-Raf inhibitor alone would not be curative of melanoma, but alas it fell on deaf ears. At Harvard, Jack studied under Judah Folkman, who himself was mocked by the grey-beards because of a revolutionary idea that made sense, was true, but would stand in the face of the "established way." He would hold the fresh hot tumors being pulled out of kids, and he just knew that they were establishing a new blood supply. They had to be. They were so warm, so alive. Of course, many of the researchers of his time thought that angiogenesis, the development of new blood vessels and supply, could only play a marginal role, if any, in cancer growth, and rather like the economy, it was growth, growth, growth that drove the process. So they continued for years with the cytotoxic drugs, and have created the classic cancer victim: bald, jaundiced, sick. For some cancers, it is more worth it to forgo chemotherapy, because certainly it would kill you before the cancer could. Folkman knew, as many innovators do, that limiting angiogenesis would slowly strangle a rapidly growing cancer. He then set out characterizing the process and simultaneously developing angiogenesis inhibitors (in an act of shameless self-promotion, here is an article I wrote on Dr. Folkman's first angiogenesis inhibitor, fumagillin). And my, how things have changed. Now angiogenesis is taught in schools, and it is steadily becoming "the way." Folkman went from being forced into a basement office to being a tenacious hero, cancer's nemesis. His discoveries were so great, they surely would have won him the Nobel Prize, as his research has contributed to a new understanding of cancer that has amounted to a paradigm shift in the way we approach tumors. He was never awarded The Prize, perhaps because too-innovative ideas aren't what the Nobel Committee is looking for, they want something that is good but not great, nothing that shakes foundations or upsets the current balance. Dr. Folkman died of a heart attack in early 2008. I drove him to the airport after a talk at Emory shortly before he passed away; he was a very gentle, kind, and modest man.

Currently we have nothing approved: resection is curative, and there is one adjuvant therapy, interferon, which has many untoward side-effects, and is essentially intolerable. Yet we use a multi-drug cocktail for the treatment of HIV, called Highly Active Anti-Retroviral Therapy (HAART), the success of which is a testament to the successes of modern drug design. People can now live a long time with HIV. When someone walks into the clinic with the signs and symptoms of community acquired pneumonia, they are started on empirical antibiotics: broad-spectrum coverage, to kill every bug you can, and once you have culture results, you can then dial back your treatment to a more bug-specific antibiotic. Why, when we have so many growth inhibitors, and such a sophisticated understanding of tumor signalling, are we focused on hitting just one target. It only makes sense to use a multi-drug approach. When someone walks in with angina, they walk out with a beta-blocker, a statin, an ACEI/ARB, plavix/ASA, and nitro. Under the B-Raf Trial paradigm, when someone comes in with melanoma, they get 1 drug. So all the tumor has to evade is 1 stinking target. Now, obviously, cytotoxic chemotherapy is steadily becoming the way of the past, but in doing so, let the therapies keep up with our understanding. It was predicted after Folkman's discovery of angiogenesis' role in tumor growth that cancer would be cured in 2 years. Now we can inhibit angiogenesis, block signalling via multiple predictable pathways, and pulse the tumors with cytotoxic drugs; how is it that we still are struggling?