New gene targets for cancer therapy identified

Using data recently made available from the human genome, researchers have identified 57 genes involved in the growth of human tumor cells. Some of these genes appear to affect tumor cells only, making them potential targets for new chemotherapeutic agents, scientists report in the July 22nd issue of Cancer Cell.

Specifically, the investigators found that monoclonal antibodies against neural cell adhesion molecule (L1CAM) kill cancer cells that express L1CAM on their surface, but do not affect cultures of normal cells.Dr. Igor B. Roninson, of the University of Illinois at Chicago, and colleagues developed a new method of identifying potential anticancer drugs, in which they select genetic suppressor elements (GSEs) that inhibit genes required for cell proliferation. GSEs are short cDNA fragments that inhibit the function of their cognate gene, they explain.They first transduced highly malignant breast cancer cells with fragments of complimentary DNA. To isolate GSEs, they incubated cells with IPTG, a transcription inducer, and BrdU, which causes suicide of cells that are replicating their DNA. Cells containing IPTG-inducible growth inhibitory GSEs do not replicate their DNA and survive exposure to BrdU. Dr. Roninson’s group identified 57 genes that gave rise to growth-inhibitory GSEs. Of the 52 that had previously been identified, 33 are recognized as regulators of cell growth or neoplastic transformation. These included proto-oncogenes and genes that are amplified in cancer cells. One of the GSE-associated genes encodes neural cell adhesion molecule (L1CAM), which is expressed primarily in the brain, but is also observed in normal tissues and in several types of cancer. They found that the L1CAM GSE induces the formation of filopodia and focal adhesion plaque formation on cells, and increases frequencies of fragmented or lobulated nuclei, which are associated with tumor cell death.L1CAM antibodies inhibited the growth of colon, breast, and cervical cancer cells that express L1CAM, but normal cells were not affected.”These findings suggest that anti-L1CAM monoclonal antibodies or their derivatives may potentially be used as anticancer agents,” the scientists write.To confirm the tumor specificity of L1CAM and other GSE-cognate genes, they engineered knockout mice. Mice null for 13 such genes were viable, although limited developmental abnormalities were observed, suggesting that gene inhibitors may not be growth-inhibitory for most normal tissues.”The genes we have identified clearly have the potential to serve as targets for novel therapeutics in the fight against cancer,” Dr. Roninson commented in a press statement.Dr. Roninson said his group plans to use the same process to select GSEs from other cancer cell lines and from normal cells. “I have no doubt that we will find more, but how many more I can’t predict,” he told Reuters Health. However, he believes the number of such genes will be similar in other types of cancer.”We also want to work with the targets we have identified so far,” he added, “especially trying agents that are already available to perturb these targets.” He pointed out that anti-L1CAM monoclonal antibody is commercially available, and that this treatment approach is “worthwhile,” given the success already achieved using Herceptin (trastuzumab), an antibody used to treat HER2 (human epidermal growth factor receptor-2)-positive tumors.(Source: Cancer Cell 2003;4:41-53: Reuters Health: Karla Gale: July 25, 2003: Oncolink)