John C. Reed, M.D., Ph.D.,
Professor, Apoptosis and Cell Death Research
Donald Bren Executive Chair
Cancer cells want to live forever and have developed ways to escape their own cell death programs. They rev up anti-death genes, which are normally kept in check, throwing off the equilibrium between cell life and death. As a result, tumor cells survive for long periods and can often withstand the harshest chemotherapy.
The first anti-death gene discovered wasBcl-2, which is hyperactive in about half of all human cancers. Dr. John Reed found that Bcl-2 renders cancer cells resistant to essentially every anti-cancer drug available, a veritable death sentence for patients whose tumors contain excessive amounts of the Bcl-2 protein.
To overcome Bcl-2, Dr. Reed devised short, synthetic pieces of modified DNA into a drug that prevents production of the Bcl-2protein. He showed that this DNA-based drug restores mortality to cancer cells, either triggering the natural cell death program or making them more sensitive to conventional chemotherapy.
This prototype therapy became the drug candidate Genasense® (Oblimersen sodium), which recently completed successful clinical trials for leukemia in patients whose cancers withstood standard chemotherapy. Genasense is built on antisense technology, which uses molecules that interact with complementary pieces of DNA to change how the genes function. One of the first DNA-based drugs to target a major disease, Genasense works by shutting down the gene that creates the Bcl-2 protein. It is the first DNA-based drug to prolong patient survival. While more studies may be required before Genasense is approved to treat relapsed/refractory chronic lymphocytic leukemia, these promising results show that a path to other successful cancer therapies has been laid by Dr. Reed’s pioneering work at Sanford-Burnham.