The past 30 years have produced an explosion of knowledge of the basic biology of cancer.

The past 30 years have produced an explosion of knowledge of the basic biology of cancer. We now know that cancer is a disease of the genome (our genes). Scientists around the world have identified hundreds of mutations in different types of cancers. These mutations can increase the activity of the products of certain genes (“oncogenes”), whereas the activity of other gene products (“tumour suppressor genes”) is decreased. 

Recently, we learned that some oncogenes and tumour suppressor genes also can be controlled in cancer cells by “epigenetic” mechanisms, which involve changes in the proteins that regulate chromosome structure. At least some epigenetic changes are potentially reversible, making them particularly attractive targets for new therapies. The combination of mutations and epigenetic changes in oncogenes and tumour suppressor genes in a given tumour determines its biological properties and behaviour: how fast the tumour will grow, whether it will invade local structures and if it will metastasize to other organs.

These features are more important than the appearance of the tumour under a microscope. We now know that two breast tumours can have dramatically different behaviour (including response to therapy), and we also know that tumours from different organs (e.g., some types of breast and ovarian tumours) can, be more similar to each other than to other types of same organ tumours.

We have also learned that all cells in a tumour are not equivalent. In many cancers, only a small fraction of tumour cells (tumour-initiating cells, sometimes called cancer stem cells) retain the capacity to infinitely self-renew. Although these cells have self-renewal capability, they often proliferate more slowly than the mass of cells within the tumour.  Consequently, they may be less sensitive to conventional chemotherapy, which targets rapidly dividing cells.
 
Durable cancer cures require the development of strategies to destroy tumour-initiating and bulk tumour cells. Owing to the central role of epigenetic regulation in both processes, we may learn much about normal stem cell biology by studying tumour-initiating cells and vice-versa. Such research may also help advance the field of regenerative medicine, in which scientists aim to use stem cells to repair damaged tissue. As for the foreseeable future, our patients will continue to be treated with agents (chemotherapy, radiation, surgery—even some targeted therapies) whose side effects damage normal tissues.

We also have learned that the immune system is constantly working to prevent tumour formation. Indeed, many emerging tumours probably never form because the immune system kills them before they grow to a significant size. Even in patients with a significant tumour burden, one can often isolate immune cells trying to fight the cancer cells.

Unfortunately, tumours use a variety of strategies to stymie the immune system and to disable anti-tumour immune cells. Tumours can even turn some immune cells into allies of the cancer. Luckily, we are beginning to learn how tumours subvert the immune system and to develop intelligent “immunotherapies”- drugs and cell-based therapies that re-activate and/or redirect anti-tumour immune response.

Finally, we know that many (although sadly not all) tumours develop through stages of increasing dangerousness. As a result, by detecting tumours when they are smaller we can often cure them. We have also seen dramatic advances in physics and computing power, which have enabled the development of extremely sensitive imaging devices. These techniques are now being supplemented by “molecular imaging,” in which novel agents that directly “see” features of the specific tumour can be used to detect remarkably small numbers of cancer cells.

These remarkable advances in cancer biology are just starting to reach the clinic—often to dramatic effect. Specific “targeted therapies”—drugs directed against the specific mutations that cause cancer—have been developed for several cancer-associated mutations.

The most dramatic example is Gleevec, which has substantially improved the survival of patients with chronic myelogenous leukemia, turning what had been a death sentence into a largely chronic disease. Other examples include Herceptin, which has dramatically improved the prognosis of (and in many cases, probably cured) patients with HER2 breast cancer, and Erlotinib and Gefitinib, which target specific mutations found in certain lung tumours. Biotechnology and pharmaceutical companies worldwide are developing a host of new targeted agents against cancer-associated mutant proteins. Some of these new agents target the epigenetic abnormalities in cancer cells, whereas others are believed to kill tumour-initiating cells. 

It is increasingly clear that in planning cancer therapy, the mutation is the message: consequently, the cancer medicine of the future will require us to rapidly define the precise mutational and epigenetic profile of each individual’s cancer cells and to select the appropriate combinations of targeted agents to kill—or at least control—them.