Part 2: The obstacles in the race to cure cancer
In the last hundred years, medical advances have allowed us to cure and even eradicate diseases such as small pox and polio. With all the time and money surging into the fight against cancer, why haven’t we cured it yet?
The first issue is that unlike bacterial or viral pathogens, cancer cells are not foreign molecules. Cancer cells are our own cells. Antibiotics have been so successful against bacterial infections because they target a specific bacterial protein essential to a bacteria’s survival. Without this protein, the bacteria die. We cannot use the same approach with cancer because destroying a protein essential to the cancer’s survival would also kill us.
Even though cancer cells are human cells, there are some differences between cancer cells and normally functioning human cells. Mainly, cancer cells grow and divide extremely rapidly. De-regulation of certain molecular pathways allows this rapid proliferation. So, one approach to curing cancer is to reign in these de-regulated pathways.
Unfortunately, there are a huge number of ways pathways can become de-regulated. For example, let’s look at just one step in one specific proliferation pathway. Epidermal growth factor receptors (EGFRs) are located on the outer membrane of a cell. Their job is to bind growth factors that are released by distant cells. When a growth factor binds, the EGFR activates a signaling pathway that results in cellular growth and proliferation. Normally, the amount of growth signal is limited and is only present at the appropriate time. Thus, cell growth is regulated.
EGFRs are often de-regulated in cancer cells. One way this can happen by the cell producing it’s own growth factors and continuously releasing them. This causes EGFRs to be continually activated. Alternatively, a mutation in the EGFR gene can yield EGFRs that are activated without the growth factor actually binding to the EGFR. Or, a different mutation could yield EGFRs can lack the growth factor binding domain and remain continuously activated.
All three of these de-regulating alterations to EGFR cause increased cell proliferation and promote tumor formation. Each EGFR alteration would require a different therapy. If the cancer cell was creating it’s own growth factor, as described in the first scenario, a drug could be made to block the manufacture or export of the growth factor. But, this drug would not be effective against cancer cells described in the second and third scenarios, which have growth factor-independent EGFR activation.
The problem becomes more complex because it’s not just the EGFR that can become de-regulated. There are numerous downstream molecules in this pathway that can become de-regulated in a variety of ways. To add to the problem, there are multiple signaling pathways that can de-regulated and cause cancer. A person could have a normally functioning EGFR pathway, yet still develop cancer due to mutations in other pathways. There will likely be no single cancer cure because there is no single cancer cause.
Technological advances have allowed us to identify exactly which pathways and even which processes in these pathways have been de-regulated. This has allowed for personalized medicine in which a drug is prescribed to a person based on the characteristics of their cancer.
One example is the drug Gleevec, which was approved in 2001. It’s used treat certain cancers including chronic myelogenous leukemia (CML). Gleevec inhibits a protein called tyrosine kinase receptor (TKR). Briefly, TKR acts similarly to EGFR. It sits on the outer surface of the cell membrane and binds growth factors. Just as in the case of EGFR, cells can produce their own growth signals and activate the TKR, resulting in cell proliferation. Gleevec inhibits the TKR receptor, thereby preventing the activation of the TKR proliferation pathway.
Gleevec was remarkably effective in individuals with CML (albeit it expensive~ $65,000/year). Many patients saw their cancer go into remission while taking the drug. However, after two years of treatment the cancer would return. Researchers realized that, in these patients, cancer cells had developed a mutation in a different part of the TKR receptor. While the drug had probably eliminated 99.9% of the cancer cells, a small number remained which harbored the TKR mutation offering drug resistance. Over time, this small population grew and eventually the cancer returned.
This example highlights two problems. One, cancer cells are very good at mutating their DNA and adapting to their environment. Two, like any living organism, cancer cells follow Darwinian selection. That is, the cells that are best able to survive and divide are selected for and eventually the entire population is made up of cells containing the essential mutation.
The ability to rapidly mutate DNA, as seen in cancer cells, is known as the “mutator phenotype.” If cancer cells did not have this phenotype, it would not be possible for so many people to develop cancer in the course of a human lifetime. The mutator phenotype is the result of mutations in the machinery the copies and proofreads DNA. Some of these mutations are genetic (such as BRCA1/2 in breast cancer) and others arise by chance. The mutator phenotype allows cancer cells to become drug resistant by rapidly changing the design of their proteins.
In summary, cancer can be caused in a wide variety of ways, all necessitating different treatments. When a drug is developed to target a specific subset of cancers, cells often mutate and become resistant to the drug. These resistant cells then proliferate and create a new population of cancer cells. This is why cancer is so difficult to permanently cure.
Hopefully this article has shed some light on why cancer has not yet been cured. In my final piece to this series, I’ll write about new findings that are changing our understanding of cancer and where cancer research is headed.