Cancer Therapy Has a Hopeful but Challenging Future

At the clinical level, the explosion of knowledge about the molecular and cellular basis of cancer has had only modest effects on the diagnosis and treatment of most types of cancer.

First, the accumulation of mutations, along with the differences in this process from individual to individual, means that single molecular markers have not proved very useful in refining diagnosis. For example, assessing the different mutations occurring in such important genes as ms or the p53 gene in breast cancer have had conflicting results in predicting disease outcomes. Presumably this is because these mutations have differing effects, depending on the other mutations involved in the cancer and their interaction with the normal alleles of the individual patient. As a result, it appears that multiprotein/multigene molecular “signatures” will be needed. If such signatures can be developed as body fluid or other relatively noninvasive tests, it could lead to major improvements in treatment, insofar as diagnosing cancer as early as possible is crucial for a favorable prognosis.

The second common theme is that the multiple types of genetic damage and selective processes required for cancer also function to cause resistance to treatment. That is, the unstable and abnormal genetic status of cancer cells that produce the growth abnormalities also lead to abnormal responses to drugs and other interventions. A vivid illustra­tion of this is, ironically, one of the notable successes of tar­geting particular molecular processes in treating cancer. Chronic myeloid leukemia (CML) is known to begin with a specialized mutation (a particular chromosomal translocation) that disrupts the gene for a specific tyrosine kinase, Abl, so that it becomes an activated oncogene.

In addition to outright mutations leading to cancer, we have mentioned several examples in which changes in gene expression of normal proteins stimulate cancer development. This also applies to drug resistance, and this mechanism underlies another, broader example of the obstacle to treatment presented by the genetic status of cancer cells. Multiple-drug resistance (MDR) is a phenotype in which cells develop resistance to many current, initially effective, chemotherapeutic agents for a wide variety of cancers. This is the result of the expression, or overexpression, of a pump protein that causes the efflux of the drug from the cell. As with the selection among cancer cells for continued ability to proliferate, administration of the drug selects for those cancer cell variants that have changes in gene expression, such that the efflux pump reduces the effectiveness of the drug. Thus, new drug development must contend not only with the genetics of cancer, but also the genes and gene expression involved in drug resistance.

The third common theme identified as an obstacle to molecular cancer treatments is that, as discussed, cancers reflect physiological dysfunctions at a particularly funda­mental level. Il is not easy to interfere with these functions without compromising other functions, or interference engages compensatory mechanisms normally serving as “backup” to crucial functions. Al the simplest level, interventions that alter these basic mechanisms of cellular life and death often prove to be too disruptive to the physiology of some normal cells to be useful. Many inhibitors in the growth factor/MAP kinase pathway (see Figure 2-5) that showed promise on cultured cells and in mice proved to be too toxic for therapeutic use.

Other results indicate that effective treatments will need to resemble the normal molecular biology of the cell very closely. Experiments attempting to target p53 are noteworthy in this respect. Because mutation of one p53 gene will predispose to cancer (if the other copy were lost, an important checkpoint would be lost), activation of the remaining normal copy might protect against cancer. Such enhanced p53 activity did protect against cancer in mice, but the mice also showed notably shortened life span and visible signs of early aging. As shown by this unexpected role of p53 in aging, the central roles played by proto-oncogenes and tumor suppressor genes means that they often have multiple roles that complicate development of therapies. In experiments in which expression of activated p53 was limited to mammary tissue, mice were again protected against cancer, but at the cost of inhibiting lactation and mam­mary development. The best anticancer results obtained from experimentally manipulating p53 expression has come from experiments in which whole artificial chromosomes with the p53 gene and all its normal control elements were introduced into mice.

Finally, the importance of these normal genes and proteins to cell function means that they often have redundant mechanisms of control. This seems to apply to that other “usual suspect” in cancer, Ras. Evidence that association with the plasma membrane via lipid “tails” was required for Ras activity (similar to the alpha subunit of the heterotrimeric G protein, see Figure 1-14) led to the development of drugs, farnesyl transferase inhibitors (FTIs), that block addition of the lipid tail. Although FTls have proved clinically useful against some types of cancer in some patients, their effects are highly variable. One idea is that the FTIs only inhibit one pathway for Ras membrane association. Used alone, these drugs showed only modest effects on tumors, but in combination with standard chemotherapeutic drugs, FTls worked relatively well on some cancers. However, it was puzzling that some cancers importantly involving ras mutations, such as lung cancer, were not affected by the inhibitors. Further, some ms-independent tumors were just as susceptible to FTIs. It now seems that these drugs may not be acting only through Ras membrane association.

It should be noted that standard chemotherapies and radiation therapies are highly toxic by the usual standards of clinical practice. Cancer therapy is a prime medical example of “drowning men grasping at straws.” Thus the modest clinical advances accompanying significant basic science advances in understanding cancer are widely regarded as being hopeful. The enormous success in treating infectious diseases with antibiotics and vaccines may be an unrealistic model for chronic diseases generally, and cancer in particular. Currently, much work is directed al developing “cocktails” of tumor inhibitors that would be both more specific and less toxic than current treatments.