Cancer Drug Development: New Targets for Cancer Treatment.
There is often a considerable lapse of time between the definition of what causes a disease in the laboratory and the development of successful therapy. However, the history of medicine teaches us that the need to understand the scientific basis of disease before the discovery of new treatments is both essential and inevitable. During the middle of the 19th century, the work of the great German pathologist, Rudolf Virchow, defined disease as having an anatomic or histologic basis. In the clinic, this scientific perspective would lead to increasingly effective and, often, increasingly aggressive surgical approaches to disease. Later in the 19th century, Koch's discovery of the tubercle bacillus (a discovery Virchow disbelieved and publication of which he thwarted, since he hypothesized that cancer, not microbes, caused consumption!), would define a microbiological basis for disease. With bacteria defined as a major cause of human suffering, the stage was set for the development of the discovery of effective antibiotics. In the early 20th century, the pioneering work of Banting, Best and others would show that disease can also have an endocrine or metabolic basis. This new body of scientific knowledge would lead not only to the specific discovery of insulin as an effective treatment for diabetes but also to a more general understanding of the role of hormones, vitamins and co-factors in human health and disease. Basic medical research and its successful translation into effective treatments has fundamentally altered the cause of human death. In the developed world, where access to the benefit of this work is available, infectious disease is not the problem it was in the days of Pasteur, Metchnikoff and Ehrlich. As we approach the millennium, science is now teaching us that diseases, particularly cancer, can have a molecular or genetic basis. Can successful application of this new knowledge be far behind? We are already seeing the application of this new knowledge in cancer drug screening and cancer drug development. At the NCI, for example, the old in vivo mouse screen using mouse lymphomas has been shelved; it discovered compounds with some activity in lymphomas, but not the common solid tumors of adulthood. It has been replaced with an initial in vitro screen of some sixty cell lines, representing the common solid tumors-ovary, G.I., lung, breast, CNS, melanoma and others. The idea was to not only discover new drugs with specific anti-tumor activity but also to use the small volumes required for in vitro screening as a medium to screen for new natural product compounds, one of the richest sources of effective chemotherapy. The cell line project had an unexpected dividend. The pattern of sensitivity in the panel predicted the mechanism of action of unknown compounds. An antifolate suppressed cell growth of the different lines like other antifolates, anti-tubulin compounds suppressed like other anti-tubulins, and so on. It now became possible, at a very early stage of cancer drug screening, to select for drugs with unknown-and potentially novel-mechanisms of action. The idea was taken to the next logical step, and that was to characterize the entire panel for important molecular properties of human malignancy: mutations in the tumor suppressor gene p53, expression of important oncogenes like ras or myc, the gp170 gene which confers multiple drug resistance, protein-specific kinases, and others. It now became possible to use the cell line panel as a tool to detect new drugs which targeted a specific genetic property of the tumor cell. Researchers can now ask whether a given drug is likely to inhibit multiple drug resistance or kill cells which over-express specific oncogenes at the earliest phase of drug discovery. In this issue of The Oncologist, Tom Connors celebrates the fiftieth anniversary of cancer chemotherapy. His focus is on the importance of international collaboration in clinical trials and the negative impact of unnecessary bureaucracy and regulation. As a student of Tom's in the 1970s in London, working on hepatoma-specific alkylating agents at Charing Cross Hospital in collaboration with his lab on the other side of town, I can attest to the fact that the regulatory hurdles to cancer drug development just twenty years later have added immeasurably to the effort and cost of cancer drug development. However, I look with optimism to the future of cancer diagnosis, prevention and treatment. It is a future where what we are learning now about the molecular and genetic basis of cancer will find their clinical outlet just as surely as the anatomic, microbial, metabolic and endocrine basis for disease has in the past. This new knowledge will provide new techniques in molecular diagnosis, which will allow us to predict which in situ cancers are destined for malignant behavior, and which can be safely watched without the need for intervention. Individual patient risk for particular cancers will be accurately predictable, so that patients can alter lifestyle habits or begin other prevention strategies. Oncogenes and growth suppressor genes give us new targets to inhibit or replace. Tumor-specific kinases will meet their inhibitors. The oncologist will play a leading role in understanding, applying and interpreting this new information in the clinic-an exciting and challenging future!
Curt
GA
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892-1904, USA. curtg@pbmac.nci.nih.gov