Clearing a path to cancer cures
Since it was first approved in 1998, the breast cancer drug Herceptin — developed by Dennis J. Slamon and his colleagues at the UCLA Jonsson Comprehensive Cancer Center — has saved the lives of hundreds of thousands of women.
Dennis Slamon. - Photo by Reed Hutchinson
Hailed for his steel-hard persistence in finding new therapies, Slamon, director of clinical/translational research and head of the Revlon/UCLA Women's Cancer Research Program at the Jonsson center, has won numerous major awards for his breast cancer research. The search for funding, however, continues, and Slamon works tirelessly to find financial support for the center's programs.
Slamon and two colleagues, Edward Garon and William Tap, both assistant professors of hematology-oncology at the Geffen School of Medicine, recently described where they stand in this complex battle against cancer to approximately 40 of the center's friends and donors at the Faculty Center.
Golden era or dark day?
One important discovery that led to the development of Herceptin, Slamon said, was the realization that breast cancer is not just one disease, but many. "There is a molecular diversity of human cancers that has largely gone unappreciated, and it's gone unappreciated because we've lumped things together," he said.
He told the story of Vincent DeVita, a staff investigator at the National Cancer Institute (NCI) in 1961. At the time, Hodgkin's disease was incurable. Patients were responding to therapy after receiving a single drug, but in almost all cases, the cancer would recur within 12-18 months. If given the same drug again, they wouldn't respond, and if given a different drug, the tumor would shrink, but the cancer would come back in six to eight months.
DeVita wondered what would happen if the drugs were combined up-front rather than given one at a time, Slamon said.
Professor Edward Garon.
Because of that research, Hodgkin's disease became curable; 80% of the patients who would have died were cured by combination chemotherapy. Yet even though this led to the so-called "golden era" of medical oncology, Slamon remarked that it was also a dark day.
"Why would I say something that crazy? Because the problem was that everyone assumed this approach would work for all the major diseases," he said. It did not, yet "the field just kept going alphabet soup, mixing and matching chemotherapies."
Over the next 45 years, another problem developed. Researchers used a "one-size-fits-all" approach, Slamon said. If a patient had lung cancer, he received one set of drugs; if he had colorectal cancer, he received different drugs; and if she had breast cancer, she got a third set. Everyone assumed that each of those cancers was one individual disease.
"Nothing could have been further from the truth, and we should have known this," Slamon said. The traditional approach — surgery, radiation therapy and systemic therapy — cures patients half the time. "But half the time, they do not," he said. "The premise is, cancer is not a single disease. Even within a given organ, it is not a single disease."
Zeroing in on the target
Slamon and his colleagues set out to find ways to target their treatments. They took breast cancer cells and mimicked what was happening in their patients, looking at genetic alterations in the genes that regulate growth. One of them was a gene called HER-2, human epidermal growth factor receptor No. 2.
The researchers saw that women who had the HER-2 alteration weren't doing as well because they had a more aggressive tumor. That made it a logical target. Slamon's group found that when they added an antibody to the receptor that the gene made when it mutated, the tumor growth rate dropped dramatically.
Professor William Tap.
The process of identifying the target and validating it in the laboratory worked not just for breast cancer, but for other major malignancies, he said. The UCLA researchers developed models for several cancers, seeing which antibodies worked and which didn't.
"We were using the right therapy for the right patients, dramatically increasing the effectiveness and significantly decreasing the toxicity," Slamon said.
Within the next three to five years, he predicted a revolution in the way cancer is treated. "There are going to be more genetically identified driving alterations that we can target."
The search for more cures
Garon and Tap, Slamon's colleagues, talked about the progress they are making in finding ways to treat other cancers.
Garon has been studying lung cancer patients who have mutations of a particular gene in their tumors, called ras mutant tumors. He presented a slide showing the cell lines of 43 different patients taken during a clinical trial. The slide revealed which cell lines were sensitive to a test drug and which ones were insensitive.
"If it takes less of a drug to stop cancer cells from growing, that means that the target is more effective in that particular setting," he said. "So instead of going forward with this drug, why don't we figure out whether or not patients have this mutation before treating them? If they have the mutation, we will treat them; if they don't, we won't treat them with the drug.
"We have, in fact, spoken with AstraZeneca, who owns this compound, and we are going to be part of an international study. The enrollment of this study will be limited to patients who have mutations of this particular gene in their [ras mutant] tumors," Garon said.
Tackling a rare cancer
Tap described his work with patients suffering from sarcoma, a rare form of cancer that strikes approximately 15,000 people in the United States each year. Yet with more than 80 different types, sarcoma is very difficult to study, he said.
In one type, Ewing's sarcoma, an aggressive tumor invades bone and is formed when pieces of chromosomes, in the act of dividing in a cell, break off and attach themselves to other chromosomes, Tap explained. When that happens, two genes that aren't supposed to be together are placed next to each other. In some cases, genes that are important for the cell to grow are placed next to genes that turn on that growth factor.
Each cell has hundreds of "antennae" that receive signals from around the body, telling the cell when it needs to grow, Tap explained. In an abnormal cell, the number of antennae increases; suddenly, the cell has thousands and thousands of antennae that continually tell it to grow.
Drugs have been developed that actually go into the cell and "cut the cord" between the antennae and the cell's nucleus, shutting the cell off, Tap said. "We were really excited, after years and years, to have these new compounds," he said. "We've been putting patients in this big international trial now for about a year."
Tap has been trying to figure out why only certain patients respond to this drug. What he and his colleagues have discovered is that cancer cells are finding ways to get to these blocked receptors. Other pathways get turned on, and the cells continue to grow. But they don't happen in everybody, he said, and based on the research they've done, they can often identify which patients will or won't respond to the drug.
"The key is to continue from what we've learned in the past," Tap said. "As we get new information, our job is not done. We really have to figure out how to apply it to the patients. This is one score on which I think we're moving along."
For more information about the Jonsson center and the groundbreaking work of Slamon and his colleagues, visit www.cancer.ucla.edu