Mistakes can't get made. And if mistakes are made Research has advanced to the point where doctors may be able to get enough information from each different type of tumor? Slamon said there may be not one cure, but many cures for cancer based on what it broken.
The possibility, he said, is there. Panelist Dr. Paul Miller? Dennis Slamon talks about what he and his colleagues at UCLA have done in cancer research and how they are approaching cancer treatment differently. This scientist is finding out. All Sections. About Us. B2B Publishing. Business Visionaries. Hot Property. If there was one hero in the Her2-Herceptin story, it was Dr. It was through the efforts of Dr. Slamon that Genentech funded research leading to the development of Herceptin.
His struggles to develop and test Herceptin were ultimately depicted in a Lifetime movie named Living Proof. The trailer can be seen here. It is now , and despite all of the advances of the last decade, we have just arrived at the beginning. There are now at least six drugs that inhibit the Her2 gene. There are also chemotherapy drugs that have been chemically attached to Herceptin, along with similar targeted drugs that we should see in clinical use in the very near future.
Again, this is just the beginning. The EGF receptor is an oncogene. Viruses that carry the gene cause cancer in birds. To find human oncogenes Ullrich hunted for relatives of the EGF receptor gene.
If Ullrich had called it HIM2, it might have caused prostate cancer. HER2 does not require an external stimulus to cause cell division. The more HER2 in a cell, the more rapidly that cell divides. Gene amplification happens when cells divide. Errors in DNA copying cause regions of chromosomes to be duplicated. In most cases the duplication is deleterious to the daughter cell and it dies. If the duplicated region happens to contain a growth-promoting oncogene, that cell divides more rapidly than its neighbors.
Soon the duplicated region duplicates again and now the cell has 4 copies, then 8, then As the copies multiply, the cells become more malignant. Dennis Slamon entered the picture in There, William McGuire had assembled a bank of tissue from breast cancers. He found that patients with HER2 amplification had a much worse prognosis than the other cancer patients.
Sixty percent died within 3 years. At this point our third honoree, Michael Shepard, emerged. He, too, was a scientist at Genentech. His experiments with cancer cells convinced him that overexpression of HER2 causes drug resistance so he took an aggressive approach. In Shepard and Ullrich announced that they had produced a mouse monoclonal antibody that binds to the part of HER2 that is exposed on the cell surface. The antibody blocked the growth of human breast cancer cells that had HER2 amplification.
The mouse antibody was called 4D5. It eventually became Herceptin. Mouse antibodies cannot be used in humans because humans reject them as foreign. To convert 4D5 into a drug, Shepard took the bold step of humanizing it. He made mutations in the antibody that made it resemble a human antibody. The first humanized antibody was produced by Greg Winter in England, but no one else had done it successfully. Shepard humanized 4D5 and it became Herceptin. Slamon proposed to Genentech that he should lead clinical trials of Herceptin in women with Her-2 positive breast cancer.
There was much opposition in the company. Would a humanized antibody actually work in people? Why develop a drug that would be given to only 20 percent of women with breast cancer? With such a limited market, would the drug be profitable? Fortunately, Slamon, Ullrich and Shepard prevailed, and the trials were successful. The FDA approved Herceptin in In the initial trials Herceptin was given to women whose cancer had metastasized to remote locations.
Herceptin delayed progression but there were no cures. Genentech then developed a second antibody called pertuzumab that binds to a different region of the HER2 protein. The combination of Herceptin and pertuzumab plus an old-fashioned cancer poison produces dramatic results. When a breast biopsy shows HER2 positive cancer the combination treatment is given either before or after local surgery. After 3 years 93 percent of women have no detectable tumor and they appear to be cured even when the tumor had spread to regional lymph nodes.
Even when the tumor has metastasized to distant sites the Herceptin pertuzumab combination blocks tumor progression for an average of 5 years compared with one-and-a-half years before Herceptin. Herceptin broke new ground in four respects.
First, it validated antibody humanization. Second, it proved that cancer can be cured by antibodies against proteins produced by oncogenes. Third, it showed the benefit of treating subgroups of cancer patients, thereby ushering in precision medicine. Fourth, it established that companies can make a profit on a drug that is restricted to a subgroup. This encouraged other companies to develop drugs targeted at subgroups.
It is no accident that Herceptin was developed by Genentech. This is the second Lasker Clinical Award to Genentech scientists—the first went to Napoleon Ferrara for Avastin, an antibody that was also developed for cancer.
Who brought cancer to Genentech? Arthur Levinson, an early Genentech scientist, trained with Mike Bishop and he knew a lot about oncogenes. Levinson was head of research at Genentech during development of Herceptin and Avastin, and his influence was profound.
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