War on cancer: update from the front

Some promising, and frustrating, data from the genomics revolution.

We might each very soon get our genomes sequenced, and this will provide a wealth of information about our ancestry as well as our susceptibility to many diseases and other conditions. This is quite static data ... get sequenced once, and your medical file is set for life- those basic facts are not going to change, even if our ability to interpret those genetic sequence facts is growing by the day and will continue to grow for decades, if not centuries.

But cancer is different- it is a genetic disease, a matter of mutations that waylay the normal course of cellular management from its what's-best-for-the-organism discipline to a descent into a mad Darwinian greed. To really tell what is going on, each cancer would have to be sequenced. Like HIV, whose mutations continue as the disease progresses, evading each drug hurled at it in turn, cancer mutations accumulate over time in cancer cells as well, making a dynamic genomic landscape.

Science magazine recently ran a magisterial, long, and unusually clear, review of cancer genomics. While sequencing individual cancers is not yet routine clinical practice, (other than for a few select markers), for research purposes it has been going on for some time, and we now have mountains of data. The authors made quite a few interesting points.

Sequence any cancer, and you get a mess. The tissues are heterogeneous, full of normal and mutated cells. The cancerous cells are a dog's breakfast of early and late cells, with some people theorizing that relatively few "cancer stem cells" are the real replicating drivers, and most of the other cells in the tumor in various stages of stasis or death. Even when you isolate the real, core, fastest-growing cells, they are again a mess, full of mutations that have nothing to do with the problem of cancer.

Indeed, the authors mention that genome sequences from highly mutagenized sites like lung cancers of smokers have ten times the number of mutations as those from lung cancers from non-smokers. Which gives you some idea of the incredibly mutagenic drive that smoking constitutes, and how much mutagenesis it takes to dramatically increase cancer incidence. It takes a lot of hits, and even then some smokers live to a ripe old age.

Tumors vary tremendously in their scale of gross mutation, from only a handful in an entire genome (common in pediatric cancers) to ten to a hundred in most types of tumors, up to a thousand or more in the most mutation-rich tumor of all, colorectal cancer.

So after a great deal of work, researchers have screened out all the noise and the garbage and come up with the genes that really drive cancer, out of our genomes of 23,000-odd genes. And this is the good news- there are only, roughly, 138 "cancer genes" responsible, in some mutated or altered state, for every known case of cancer that has been analyzed. Each tumor typically has a handful of these, which it has accumulated extremely slowly, over many years.

These genes tend to encode master controllers of the cell cycle, cell survival, cell differentiation, and DNA damage repair. For instance, ATM encodes a protein that senses DNA damage and halts the cell cycle in response. Obviously the kind of gene you want on your side, but one that gets in the way of cancer progression. It is frequently mutated in leukemias and lymphomas.

The 12 general classes of the 138 genes whose mutation or overproduction drives cancer growth. Some positively drive growth, while most are inactivated from their normal function of inhibiting cell growth.

The bad news is that few of these genes are easily targeted by drugs. The majority of these 138 drive cancer by virtue of being mutated into inaction, which is to say that they are tumor suppressors in their normal state. The typical gene mutation truncates these proteins- the remnant folds badly when it is made and is promptly tossed into the cellular recycling bin. There is little a drug can do for (or against) a protein that is not doing anything or is absent. Only when we have true gene therapy reliably injectable into these (highly inaccessible) cells would such a defect be truly fixable.

The ones that can be effectively targeted by drugs are oncogenic enzymes which are overproduced or specifically mutated into overactivity. The Ras kinase is a classic example, where a specific mutation of codon 12 or 13 from glycine to another amino acid renders this signalling protein deaf to upstream pathways that turn it off, by inactivating an enzymatic function that constitutes its "reset" switch. It becomes an always-on signaller, telling its cell (falsely) that external growth factors are always there, so go ahead and grow, grow, grow.

This is the kind of thing that can be targeted with drugs, not to turn the protein's reset switch back on, but to block its other actions so that it no longer does harm. This KRAS gene is mutated in about 30% of human cancers, so one can appreciate the usefulness to a cancer cell of having a good deal of mutagenesis going on, perhaps via another mutation in the DNA repair machinery, since this specific defect would otherwise be extraordinarily rare- much harder to come by than a truncating mutation.

The authors hold out hope that, since each of the un-druggable tumor suppressor gene products function in larger cellular pathways of control, other proteins can be found downstream from these inactivated tumor suppressors that might be usefully targeted by drugs:

"All of the known driver genes can be classified into one or more of 12 pathways (Fig. 7). The discovery of the molecular components of these pathways is one of the greatest achievements of biomedical research, a tribute to investigators working in fields that encompass biochemistry, cell biology, and development, as well as cancer. 

... 

We believe that greater knowledge of these pathways and the ways in which they function is the most pressing need in basic cancer research. Successful research on this topic should allow the development of agents that target, albeit indirectly, defective tumor suppressor genes. Indeed, there are already examples of such indirect targeting."

Unfortunately, the fact that there are so few core driver genes for cancer, itself militates somewhat against this view. If there were so many pressure points in the pathways of cellular control, we would see more of them reflected in oncogenesis. By all means, we need to gather all the knowledge we can, but magic bullets are going to be hard to come by.

The bottom line is that cancer, while far more complicated than the singular word naively indicates, still has an underlying "muta-genetic" pattern that can be used for definitive diagnosis in the coming molecular age, where genomes and individual cancers will be sequenced as a matter of routine. Once we devise maybe a couple hundred magic bullets to various oncogenes and related pathways, we may be able to treat cancer on an individualized basis much like HIV- with a customized cocktail of several drugs that, in combination, will forestall recurrence indefinitely. Currently, there are maybe twenty such drugs, many of which have poor efficacy or other issues, not to mention astronomical expense, so we have a long way to go.

A related point from this paper is that metastasis does not seem (at current knowledge) to involve novel or special mutations. The authors observe that cancer takes decades to develop, slowly accumulating its growth-promoting mutations, and that cancers slough off circulating cells in prodigious numbers, more so the larger they are. Thus a careful diagnosis of the original tumor, or any decendent, should suffice to characterize a cancer completely, and to stop it no matter how disseminated, given the specifically tailored and combined drugs that are envisioned above.

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