I just came back from a Hopkins epigenetics meeting and heard a keynote talk from Bert Vogelstein. They have a robust way to finding real cancer drivers, which he believes is much smaller a set than other annotations. The rule is: > 5 interagency mutations, Tumor suppressor gene > 15% of mutations be inactivating, Oncogenes: > 15% recurrent activating mutations. Many well known cancer drivers have 80% mutations, so he believe this is a pretty reasonable criteria.
By this criteria, they only detected ~120 cancer drivers (~70 tumor suppressors and ~40 oncogenes). It is very hard to target lost tumor suppressors, so oncogenes are better drug targets. All rivers can be organized into 12 core pathways: TGF, Wnt, Hedgehog/GLI, HIF1A, JAK/STAT, NOTCH, G1/S transition, DNA damage, Apoptosis, Chromatin, PI3K/PTEN, RAS/RAF. Interestingly he believes that whole genome or exome sequencing are showing plateaux in terms of finding new driver genes, and many new drivers are related to epigenetics. The next step is to develop early detection method and understand what these drivers are really doing. In addition to understanding cancer drivers that his lab has been doing for years, they are recently looking sensitive biomarkers and techniques to detect early cancer mutations from blood, urine or stools.
Vogelstein mentioned that many cancer mutations that might cause drug resistance actually were already present when patients are first diagnosed with cancer, although they are only present a tiny percentage of cells. Some people call cells harboring these mutations tumor initiating cells or cancer stem cells, but they might just mean cancer heterogeneity (this is my interpretation). Unfortunately, most of cancer research is focused on treating patients at the last stage which is too late. He recommended the following about cancer treatment:
1. Treat tumors when they are as small as possible
2. Use combination agents
3. Is it ethical to use single agent drugs in Phase II/III trials? Phase I is OK, but Phase II/III with single agent would do patients harm, since patients are almost certain to develop drug resistance later.
I heard that Vogelstein rarely travels to present at conferences or seminars, and he refuses most of the meeting requests from speakers presenting seminars at Hopkins. He stays focused on important cancer research areas that he believes will make long term impact. But surprisingly when I email him to request reagents or information, he always replies by himself very quickly. I really admire this level of focus and science-driven curiocity. This was the first time I heard his talk (I unfortunately wasn’t there when he came spoke at DFCI in April 2012 when his postdoc trainee Nelly Polyak got tenured at Harvard) and I was totally inspired by his knowledge and dedication. I actually shed some silent tears afterwards and got a little distracted from Doug Higg’s talk afterwards which was also quite interesting (will have to read his papers to catch up). I hope we could do some solid cancer work deserving the inspiration he gave me.