Report of a meeting: molecular basis of cancer therapy.
There has been an explosive increase in information relevant to the pathways that determine growth signal transduction, regulation of the cell cycle, mechanism of action of oncogenes and tumor suppressors, and mechanisms of programmed cell death (apoptosis). Additional information is needed to determine the targets for anticancer therapy that are most likely to lead to cancer cell death and/or growth cessation. Current experimental clinical approaches are directed toward killing cells with unique cancer-related phenotypes, such as cell surface antigens or growth factor receptors, or altering the host immune system to attack cancer cells. The following major therapeutic targets were identified during the course of this conference: 1) Reduce activity of gene products associated with stimulation of cell growth and increase activity of gene products that inhibit growth. The major principle here is that genes known to be sufficient for malignant transformation (such as Ras, Raf, and Bcr-Abl) and genes whose expression is necessary, but not sufficient, for malignant transformation (such as some cyclins) both may be important targets for anticancer drugs. The reason genes necessary but not sufficient for cell growth are targets is that progression through the cell cycle is based on a series of "on-off" switches whose activation depends on critical levels of specific kinases and phosphatases. Subtle differences in concentration or activity of these regulators, as may be found in cancer cells, could profoundly influence the position of the switch. There are many ways to affect activity of gene products, including use of anti-sense or ribozyme targeting of mRNAs; manipulation of regulatory controls (i.e., state of phosphorylation of Raf and p53; effect of SOS and GAP on Ras, etc.); alteration of essential covalent modifications (i.e., farnesylation of Ras which is essential for its association with the plasma membrane); and various forms of gene therapy to introduce genes (i.e., addition of wild-type p53) or to reduce activity of genes essential for growth (i.e., dominant negative receptor mutants). 2) Interfere with protein-protein or DNA-protein interactions that are needed for the activity of oncogenes and/or growth factors or the transcription factors essential for cell growth. This approach has been demonstrated to work in vitro to interfere with SH2-tyrosine phosphate interactions (i.e., Grb-2 and EGF receptor) and Ras-Raf interactions using specific peptides (J. Downward), but to be useful therapeutically it must be possible to introduce stable low-molecular-weight drugs into cells to affect these interactions.(ABSTRACT TRUNCATED AT 400 WORDS)
Gottesman
M M
MM
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
D000951:Antigens, Neoplasm; D017209:Apoptosis; D002453:Cell Cycle; D004351:Drug Resistance; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009857:Oncogenes; D015398:Signal Transduction
D000951:Antigens, Neoplasm