Alan Sandler, M.D., pulls up a slide on his computer screen that shows—in schematic fashion—the signaling pathways inside a malignant cell. At a glance, it looks hopelessly complicated. White arrows indicate the chain of communication between proteins; the arrows point here and there, crisscrossing the cell like strands of spaghetti left on a plate.
“I’ll give you a minute to jot this down,” Sandler quips, adding that this line draws chuckles when he uses it during lung cancer seminars.
The image is actually an oversimplification of the molecules and pathways that “drive” the cancer cell and which are targets for the newest generation of anti-cancer drugs. Seventeen blue boxes on the slide list 29 different “targeted therapies” that are already approved or still in development, and where in the cell they act.
“The explosion of new drugs that are out there to study in cancer is astonishing,” says Sandler, associate professor of Medicine and medical director of the Thoracic Oncology program at the Vanderbilt-Ingram Cancer Center. He recalls that in 1992, when he finished his fellowship, it was common not to even give chemotherapy to patients with metastatic non-small cell lung cancer because the benefit was still questionable.
Today, chemotherapy and targeted agents are extending life and offering hope to these very same patients.
“These are really exciting times in cancer therapy, especially for lung cancer,” says David Carbone, M.D., Ph.D., Harold L. Moses Professor of Cancer Research at Vanderbilt-Ingram. “Ten years ago we had extremely limited options.” Today, some of the new targeted therapies are “nearly miraculously effective.”
Carbone cites the effects of the drug imatinib (Gleevec) in patients with chronic myelogenous leukemia and gastrointestinal stromal tumors, and the drug erlotinib (Tarceva) in select lung cancer patients. “It’s like a Lazarus response,” he says.
But as the number of new drugs climbs, so do the challenges in designing clinical trials to test the new therapies, selecting the patients who will most benefit from them, managing the costs of these drugs—thousands of dollars per month—and moving forward to develop drugs aimed at different targets in the cancer cell.
A rare leukemia’s lesson
The concept of a “magic bullet” to treat disease dates to the late 19th century. Nobel laureate Paul Ehrlich, M.D., coined the term in reference to compounds that would seek out and destroy pathogenic microbes without harming the patient.
Targeted cancer therapies are envisioned as the “magic bullets” of cancer treatment. Ideally, they affect proteins and signaling pathways unique to malignant cells and leave normal cells alone.
While that ideal has not yet been achieved, the contrast to traditional chemotherapy is obvious.
“Chemotherapy drugs control the growth of cancer cells, but they do so in a way that’s kind of like using a hammer to kill a housefly on a table. If you bang the table hard enough, you destroy the fly and the table too,” says David Johnson, M.D., deputy director of Vanderbilt-Ingram and past president of the American Society of Clinical Oncology.
Likewise, surgery and radiation therapy can cause “tremendous collateral damage,” although recent technological advances have dramatically improved both of these approaches, he says.
Among the first of the new targeted therapies was Gleevec, whose behind-the-scenes development was described in the book Magic Cancer Bullet by Daniel Vasella, M.D., chairman and chief executive officer of the pharmaceutical company Novartis.
Gleevec bounded onto the world stage in 2001, with accelerated approval from the Food and Drug Administration for the treatment of chronic myelogenous leukemia (CML).
The abnormality that causes CML—the so-called Philadelphia chromosome (named for the city in which it was discovered)—was first described in 1960. It results from a translocation, a rearrangement that fuses two genes from different chromosomes together. This in turn produces an abnormal protein, a tyrosine kinase receptor called bcr-abl, which drives cells to become leukemic. Drugs like Gleevec can inhibit the activity of the aberrant receptor, and thus block cancerous growth.
“Imatinib surprised everyone,” says Mace Rothenberg, M.D., Ingram Professor of Cancer Research at Vanderbilt-Ingram. “Even the sponsor was surprised at how effective that drug was in causing complete hematologic and cytologic remissions, remissions where the Philadelphia chromosome disappeared.
“And this was done by a single pill whose main side effects were skin rash, some weight gain and some edema. This was remarkable.”
In the last five years, investigators have discovered how some patients develop resistance to imatinib, by acquiring additional mutations in the bcr-abl receptor that hinder Gleevec binding. A newly approved drug called dasatinib (Sprycel) is able to bind to the mutated bcr-abl, overcoming resistance to Gleevec in patients with such mutations.
“Suddenly we have two highly effective therapies for CML,” Rothenberg says. “This is like the grand slam home run.”
But CML appears to be a simple cancer, primarily driven by one genetic mutation, he adds.
“What we’re coming to realize is that the majority of cancers, especially solid tumors, tend to be polygenetic in origin,” he says. “It’s more than just a single dysregulated pathway, and so blocking a single pathway isn’t really sufficient in the majority of cases to cause true tumor regression.”
Signature response
It’s clear that the more specific a targeted therapy is—in terms of its target—the more restricted the patient population is that benefits from that drug, Carbone says.
“The reality is that lung cancer is probably 10, 15, 20 different diseases, driven by different molecular mechanisms and combinations that we’re just beginning to understand,” he says. “If we could find what subpopulations of tumors are driven by particular pathways, then we could find drugs to target those pathways and they’d be very effective in that subpopulation.”
Carbone’s laboratory was the first to identify a mutation in the epidermal growth factor receptor (EGFR) that predicts which lung tumors will respond to drugs such as gefitinib (Iressa) and erlotinib (Tarceva). In a manner similar to Gleevec, these drugs bind to and inhibit the receptor’s abnormal tyrosine kinase domain.
“We noted very early on at Vanderbilt that some lung cancer patients had a great response, but most patients didn’t,” Carbone says. The EGFR mutation that his group found in a patient’s tumor is found in about 10 percent of the U.S. patient population, and is “probably the best predictor of clinical response to these drugs.”
But the single mutation identifies only the “fantastic responders,” Carbone says. “Most studies are showing that there’s a much bigger set of lung cancer patients who will benefit from these drugs.”
Through the National Cancer Institute’s Strategic Partnering to Evaluate Cancer Signatures (SPECS) program, Carbone and his colleagues are searching for the “molecular signatures” that will predict which lung cancer patients will benefit from Tarceva.
They have found eight proteins in the blood that together “really seem to identify patients who will live longer when they are treated with erlotinib,” Carbone says. He presented the findings last June at the American Society of Clinical Oncology meeting in Atlanta.
These kinds of molecular signatures or “profiles” will be key to successfully using targeted therapies and moving them to earlier stages of treatment.
Clinical trials of new drugs start in the sickest patients—those with metastatic disease for which there is no known effective therapy. These patients have already endured the standard therapies, and the probability of anything working at that point is probably remote, Johnson says.
Unless the drug is tested first in patients in whom it is most likely to work.
This is what happened with the targeted therapy trastuzumab (Herceptin), which is directed against the HER-2 protein (a receptor similar to the EGFR). Herceptin first proved itself in clinical trials in the sickest patients whose tumors had high expression of HER-2.
It is now used as an adjuvant therapy—a treatment given usually after the main treatment, to boost its effectiveness—in breast cancer. Herceptin may never have reached that stage if patients in the early trials had not been “selected” for high expression levels of HER-2 in their tumors.
“If those initial trials had not been limited to patients with high HER-2 levels, it would have threatened the development of a drug that we know works as long as it is used against the right cancers,” says Carlos Arteaga, M.D., Vice Chancellor’s Professor of Breast Cancer Research at Vanderbilt. “Herceptin alters the natural history of women with breast cancer overexpressing the HER-2 protein (by increasing their chances for survival).”
Are they worth it?
Targeted therapies come at a cost.
“The presumption is that targeted therapies will only cause good things to happen and not bad things. Sadly, that is not the case,” Johnson says. He cites studies showing that long term use of both Gleevec and Herceptin can cause heart failure.
And then there’s the financial cost—up to $10,000 per month for the newest drugs.
“There’s no rhyme or reason for the cost of cancer drugs in this country,” Johnson says. “And what’s interesting is that the drug gets the blame for being ‘ineffective’ because it only offers a two-week survival advantage. I’m not praising the drug for giving you two weeks of survival, but each of us knows that used in a more appropriate way, we can get these huge benefits that were seen with Herceptin.”
The trouble, Johnson says, is the hype about the promise of these new drugs, which when apparently not met, creates disappointment and cynicism.
Carbone takes issue with the idea perpetuated in the lay press that the effectiveness of targeted drugs can be fully assessed by measures of median survival.
“It’s extremely misleading to say that a drug only gives you a six-week survival difference, without any additional explanation,” Carbone says.
Survival curves report a population average. About half of the patients will get no benefit at all and half will have “some benefit that’s very real: the tumor shrinks by a measurable amount, the patients feel better, and they live longer,” he says. About a quarter of the patients will have major shrinkage of the tumor, and in about 5 percent, the tumor will virtually disappear.
“For that 5 or 25 percent of patients, that’s a heck of a lot more benefit than a six-week survival difference tells you about,” Carbone says.
“The future is extraordinarily bright,” adds Johnson, “if we can stay focused on the real ultimate object of our research and that’s the human being—your sister, your husband, your mother, your child. That’s the target.”