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Time to Rethink Cancer Therapy?

In an earlier post, I wondered a bit about the ultimate causes of cancer. For the last several decades cancer has been labeled as a genetic disease, an idea which we have chased with great fervor. Yet, It feels to me sometimes as though the evolving story of the causes of cancer is like a hall of mirrors in an amusement park in that there seems to be an ever receding chain of causal genetic alterations fueling cancer’s inexorable progression.

The most visible of these alterations are in the growth modulating molecules of the cell. Over expressed growth factor receptors or transcription factors, mutant signaling molecules, etc. How did these components come to be broken? Genetic insults of various kinds have been discovered, studied, and labeled as causes of cancer. We are actually getting pretty good at intervening in some of these malfunctioning growth pathways that have been co-opted by cancer. For example, antibodies that block the activity of HER2, the human epidermal growth factor receptor that seems in some cases to drive breast cancer proliferation are quite effective.

Yet, even when we do intervene with seeming effective tools, such as trastuzumab for HER2 over-expressing breast cancer, the cancer seems in most cases to rebound by activating still other pathways of growth. It has come to be reminiscent of the proverbial leaky dike and us with not enough fingers to plug the leaks.

The genomic instability that is so characteristic of most cancers seems to be the driver of genetic diversity that provides resistant variants. It appears that cancers “evolve” to a state of significant heterogeneity and the genomic instability seems to be a player in that process. But, where does the genomic instability come from? We can then propose a change in cells that causes genetic instability. But, where then does that come from? See what I mean?

This genetic, linear causation idea is the foundation on which our cancer therapy strategy is built. Naturally, our combat strategy is direct. Cut it out. If you can’t cut it out, hammer it with chemicals or radiation. If a little doesn’t work, then try a lot. Too much cell division and DNA replication? Inhibit DNA replication. Too much RAF signaling? Inhibit RAF signaling. Battle this problem where it occurs: inside the cancer cell itself. This strategy has produced some remarkable results; however, for most cancers, the fact remains that some cells inevitably escape destruction to arise as an even more fulminant tumor later.

The feeling of frustration in chasing cancer up the path only to have it resurrect out of seemingly nowhere still further upstream is a signal to me. I have sensed in this frustration a signal to think about cancer pathogenesis and treatment in new ways, like I’m sure others have. Recently I have been gratified to hear a number of researchers propose new views of what cancer is and new strategies for treating it.

I have been a member of a tumor microenvironment interest group for a while, mostly to keep an ear to the ground in that area. Having spent many years trying to grow cancer cells in various ways, it is clear to me that they depend heavily on their microenvironment to survive.

Over the summer I noticed a few publications (see this news story in Nature Medicine for more details) suggesting that resistance to chemical therapy may be mediated by more than just the response of the tumor cells. These studies suggest that the tumor microenvironment may provide protection from anti-cancer agents by secreting of growth factors from stromal cells intermingled with the tumor cells. In one study, WNT16B growth factor secretion was induced in stromal fibroblasts, which in turn protected the cancer cells from programmed cell death. In another pair of studies (here and here), stimulated secretion of hepatocyte growth factor from stromal cells attenuated the sensitivity of melanoma cells to BRAF inhibitors, one of our newest targeted therapeutic classes. It seems that the effects of treatment are more complicated than we had thought. Our cell-autonomous approach to drug development is probably too simplistic. In retrospect, it seems obvious that we should account for the effects of other cells that, with the tumor cells, create the environment in which the cancer develops.

Rethinking cancer therapy has been proposed by Robert Gatenby and colleagues for some time now (see, for example, their article in Cancer Research in 2009). Over the summer, Gillies, Gatenby, and colleagues published another paper describing how these concepts impact targeted therapy as progress in cancer therapy. These folks have brought concepts from evolutionary biology and the control of invasive species to bear on cancer therapy.

Gatenby and colleagues describe a model for how evolutionary dynamics operate in the tumor microenvironment: phenotypic diversity, courtesy of genetic instability, provides the substrate for selective forces, provided by cytotoxic drugs, resulting in selection of tumor cells that can survive almost any insult. Under this scenario, toxic drugs will select for some variant that will then proliferate to fill the niche vacated by the cells killed by the therapy. Adaptive therapy is described as a potential solution to this problem. In essence, adaptive therapy uses interventions that strategically impose a substantial evolutionary cost on cancer, thereby reducing its fitness to survive and ability to adapt to its new environment.

A high evolutionary cost means that interventions are difficult to evolve around. To illustrate what these might be like, they draw examples from control of invasive species. Might cancer be better handled as if it were an invasive species? Two points that they make are 1) that eradication is often not possible and control of population size is the goal; and 2) the high-evolutionary cost interventions are often biological.

Although the cancer genome is an important component of the disease, it is becoming clear that there are additional facets of the disease, such as the interaction of the cancer genome with genomes in its environment. Consideration of the role of tumor microenvironment modulation of therapy is a welcome expansion of how we think about cancer and our response. Likewise, radically new strategies for cancer therapy, possibly like adaptive therapy, are welcome, as well. Incorporating these new concepts into our view of cancer helps put us on the path to effective new treatments.