In spite of these difficulties, effective cures using anticancer drugs (alone or in combination with other treatments) have already been found for some formerly highly lethal cancers, including Hodgkin’s lymphoma, testicular cancer, choriocarcinoma, and some leukemias and other cancers of childhood. Even for types of cancer where a cure at present seems beyond our reach, there are treatments that will prolong life or at least relieve distress. But what prospect is there of doing better and finding cures for the most common forms of cancer, which still cause great suffering and so many deaths?
Traditional Therapies Exploit the Genetic Instability and Loss of Cell-Cycle Checkpoint Responses in Cancer Cells
Anticancer therapies need to take advantage of some molecular peculiarity of cancer cells that distinguishes them from normal cells. One such property is genetic instability, reflecting deficiencies in chromosome maintenance, cell-cycle checkpoints, and/or DNA repair. Remarkably, the most widely used cancer therapies seem to work by exploiting these abnormalities, although this was not known by the scientists who first developed the treatments. Ionizing radiation and most anticancer drugs damage DNA or interfere with chromosome segregation at mitosis, and they preferentially kill cancer cells because cancer cells have a diminished ability to survive the damage. Normal cells treated with radiation, for example, arrest their cell cycle until they have repaired the damage to their DNA, thanks to the cell-cycle checkpoint responses discussed in Chapter 17. Because cancer cells generally have defects in their checkpoint responses, they may continue to divide after irradiation, only to die after a few days because the genetic damage remains unrepaired. More generally, most cancer cells are physiologically deranged to a stressful degree: they live dangerously. Even though the cells in a tumor have evolved to be unusually tolerant of minor DNA damage, they are hypersensitive to the much greater amount of damage that can be created by radiation and by DNA-damaging drugs. A small increase of genetic damage can be enough to tip the balance between proliferation and death.
Unfortunately, while the molecular defects present in cancer cells often enhance their sensitivity to cytotoxic agents, they can also increase their resistance. For example, where a normal cell might die by apoptosis in response to DNA damage, thanks to the stress response mediated by p53, a cancer cell may escape apoptosis because its p53 is lacking. Cancers vary widely in their sensitivity to cytotoxic treatments, some responding to one drug, some to another, probably reflecting the particular kinds of defects that a particular cancer has in DNA repair, cell-cycle checkpoints, and the control of apoptosis.
Radiotherapy and traditional cytotoxic drugs are rather weakly selective: they hurt normal cells as well as the cancer cells, and the safety margin is narrow. The dose often cannot be raised high enough to kill all the cancer cells, because this would kill the patient, and curative treatments, where achievable, generally require a combination of several cytotoxic agents. The side effects can be harsh and hard to endure. How can we do better?
An ideal treatment is one that is cell-lethal in combination with some lesion that is present in the cancer cells, but harmless to cells where this lesion is absent. Such a treatment is said to be synthetic-lethal (from the original sense of the word synthesis, meaning “putting together”): it kills only in partnership with the cancer-specific mutation. As we become increasingly able to pinpoint the specific alterations in cancer cells that make them different from their normal neighbors, new opportunities for such precisely targeted treatments are coming into view. We end this chapter with some examples of new treatments of this type that are already being put into practice.