One of the challenges of scientific conferences, at least the ones I attend, is that the investigators have a tendency to rush through a high volume of highly interesting slides at a fast pace, meaning ones notes end up looking like a chicken scratched them out and then a spider with wet feet ambled over them for good measure. Teasing out the nuggets is sometimes a challenge, "what was I thinking when I scrawled that?"
And so it was with the plenaries at the American Association of Clinical Research meeting in DC this week. Looking at the notes from Charles Sawyers and Bert Vogelstein's plenary talks on the prostate cancer and the cancer genome, respectively, is particularly apt as you can see in the photo on the right!
Every time I listen to one of Prof Vogelstein's talks I learn something new and the last lecture makes more sense too. He noted that 78 cancer exomes have been published to date. The exome is the 1% of the human genome that is functionally relevant for phenotypic changes. Exomes are comprised of short segments of DNA called exons, and provide the genetic blueprint for proteins.
The question is how many genes are altered in a typical solid tumour?Vogelstein showed that this varies by tumour type. For example, in pancreatic cancer, there are an average of 44 non-silent mutations, while for more complex cancers such as melanoma and lung cancer, there are 100-200, 30-80 in breast, colon and brain cancers. The lowest are seen in leukemias and medulloblastomas, at around 10.
Most mutations in a cancer are actually passengers though, so the big needle in the haystack question is working out which are the drivers?
The other interesting fact I learned was that approx. 90% (263) of drivers are actually suppressors, as in tumour suppressor genes, and virtually all are found in 12 key pathways (eg NOTCH, PI3K/mTOR, RAS/RAF etc) and only 10% (33) are actually oncogenes.
However, the elephant in the room, as Vogelstein accurately alluded to is tumour heterogeneity. It is the very diversity that makes it difficult to understand, describe and target appropriately with therapeutics to improve outcomes in humans. After all, with respect to tumour suppressors, Vogelstein's pithy statement:
"You can't target something that isn't there!"
Rings very true, which is frustrating to say the least. Much progress has been made in cancer research to date, but we still have a long way to go.
The confluence of basic research, applied research, clinical trials, and therapeutics at this AACR meeting at least reassured me that the time from bench to bedside is improving, as are the technologies and strategic thinking based on a deeper understanding of the underlying biology. There was an urgency here in DC that I hadn't noticed before. Long may it continue.