Doctors and scientists aim for cancer's weak spots with targeted therapies.
By Neil Osterweil
Reviewed By Charlotte Grayson
In 1971, just two years after the United States had fulfilled President Kennedy's vision of putting a man on the moon and returning him safely to Earth, Richard M. Nixon declared war on cancer. The "can-do" spirit that had propelled astronauts into the heavens and enabled one small step for a man would be put into the service of all humankind on mother Earth.
As other conflicts have flared and died across the globe over the last three decades, the war on cancer has been a constant struggle. Cancer is the second leading cause of death in the U.S. and accounts for the deaths of 1 of every 4 Americans. The American Cancer Society estimates that 556,000 Americans died from cancer in 2003.
Cancer is a tough opponent, fighting on many fronts and in many guises, and because it is not a single disease, we may never be able to claim that we have found a "cure." But today our knowledge of the enemy and its tactics has never been greater, and although the end of cancer is not in sight, specialists say, we may be starting to hold our ground.
Robert Romine -- "Bud" to his friends and family -- is a veteran of the war on cancer. In 1994, the retired railroad conductor went to his doctor for routine colon cancer screening because of a family history of the disease. A blood test came back with an elevated white blood cell count (often an indicator of illness), and further tests revealed not colon cancer, but chronic myelogenous leukemia (CML), a cancer of the white blood cells that starts in the bone marrow and can rapidly spread to the bloodstream, lymph nodes, organs, and nerves. "He was given three years," recalls his wife, Yvonne, in an interview.
Romine was started on a course of chemotherapy with hydroxurea, which stops cancers cells from reproducing, and interferon, which boosts the body's defenses against cancer. Neither drug is a cure, but they can help buy time for patients with CML -- at the cost of severe fatigue, flu-like symptoms, nausea, vomiting, and other serious side effects. "On a good day, I could make it from the bed to the davenport, and then I'd be through for the day," Romine tells WebMD.
But then the Romines read about the work of Brian Druker, MD, at the Oregon Health and Science University in Portland, not too far from their hometown of Tillamook. In their laboratory, Druker and co-workers had discovered that a compound developed by Novartis Pharmaceuticals had potential activity against CML. Romine became the first CML patient ever to be treated with the new compound, now called Gleevec.
Traditional chemotherapy works by blasting away at all fast-growing cells, which includes cancer cells but also healthy cells such as those that make up hair, skin, and mucous membranes. Gleevec, however, uses an entirely different strategy to fight cancer, by intercepting enzymes that are supposed to send messages telling cancer cells to divide and grow. Without the signals, the cells die.
"There's no question that targeting cancer cells is the correct strategy, but you have to make sure that you're targeting the right components in the cancer cell, and those are going to be elements that are critical to the growth and survival of the cancer cell," says Druker, professor of medicine and research program director at OSHU, in an interview with WebMD.
Because early human drug trials always begin with extreme caution, the first doses of Gleevec that Romine took were too low. But once he began taking the drug in the dosage that was found to be effective, the unheard of occurred: Within three weeks of starting on the adjusted dose in 1997, his white blood cell count returned to normal, where it has remained ever since.
"He was on his way out when Gleevec started working for him," Yvonne says.
From Shotguns to Smart Bomb
Gleevec, cancer experts say, is among the most promising of the new wave of targeted therapies -- drugs that are built from the ground up to attack specific types of cancer at their weak spots. Over the last few years, there has been a flood of new therapies based on improved understanding of what makes certain types of cancer tick and what's needed to throw a monkey wrench into the works.
"The fog is lifting from biology, and we're able to see sort of the 'wiring diagram' of cells, and then figure out where the short circuits are and start to develop a tool kit to really wire the cells back up properly. The strategies are different depending on what the target is," explains George Demitiri, MD, associate professor of medicine at Harvard Medical School and Director of the Center for Sarcoma and Bone Oncology at The Dana-Farber Cancer Institute in Boston.
The traditional approach to treating cancer has been what scientists call "empiric" therapy, which is essentially trial and error. "The old model was to take an extract of a berry found in the Amazon or whatever -- something that looked interesting because it killed cells in the laboratory -- then give it to a whole bunch of cancer patients and hope that some subset of them benefited. Sometimes you get lucky and sometimes you don't, and if you don't you really haven't learned that much. The real excitement about the new biology and the new therapies is that we should be able to do our work much more rationally and figure out why something's not working," says Demitiri in an interview with WebMD.
Sometimes, what works against one form of cancer may work against other, unrelated diseases. Gleevec, for example, has also been found to be effective against a rare form of stomach cancer.
Like Gleevec, Velcade, which was approved in 2003 for treatment of advanced, difficult-to-treat cases of the blood-cell cancer multiple myeloma, also disrupts enzymes that cancer cells need to replicate, but it does it in a different way, by targeting a protein complex that cells usually use for housekeeping operations. Velcade is currently being investigated for possible effects against other cancers such as non-Hodgkin's lymphoma and some forms of leukemia.
Cutting Supply Lines
"I do think that we really, in the last couple of years maybe, have turned a corner: Instead of fantasizing about rational therapy of patients rather than empiric therapy, I think we're getting tools now that will allow us to truly tailor our therapy," says Alan P. Venook, MD, professor of clinical medicine and director of the University of California at San Francisco/Mt. Zion Cancer Center Clinical Research Office.
Venook is one of many researchers throughout the U.S. working with a promising new class of drugs called angiogenesis inhibitors. One drug in this category, Avastin, just received FDA approval for treatment of advanced colon cancer. These drugs, which work by preventing the growth of new blood vessels and choking off a tumor's blood supply, were the brainchild of Judah Folkman, MD, professor of pediatric surgery at Harvard Medical School and a cancer researcher at Children's Hospital in Boston.
When Folkman first proposed the idea more than 30 years ago, he was met with scorn and derision by many of his colleagues, but his persistence and dedication to the concept are finally beginning to bear fruit. In addition to Avastin, at least a dozen angiogenesis inhibitors are in late-stage testing for cancer and other diseases such as "wet-type" macular degeneration, a vision-robbing disease of the eye's retina.
William Dahut, MD, who conducts clinical studies with angiogenesis inhibitors at the National Cancer Institute's Center for Cancer Research, tells WebMD that "we're really encouraged by the amount of activity that Avastin has shown, particularly when given in combination, and it seems like that's where we most likely will be. All of these targeted therapies work best, and probably the anti-angiogenic agents in particular, when they're combined with other therapies."
In clinical trials, Avastin combined with standard chemotherapy significantly prolonged the life of patients with advanced colon cancer that had spread to other organs. Unlike other chemotherapy drugs, however, Avastin caused few side effects, meaning that it can be added to standard therapy with few problems.
"It's a matter of finding the right target and then figuring out whether you go after it with a single drug or a cocktail of drugs. We're smart enough to know that one blockbuster [drug] is almost certainly not going to be sufficient to really cure cancer," says Demitiri. "We can't cure the most drug-sensitive cancers that we treat -- testicular cancers -- with one drug; we need a cocktail of at least three."
An Ounce of Prevention
The improved understanding of what causes or contributes to certain types of cancer, whether it's genetics, environmental factors, or lifestyle choices such as smoking, has also revealed the importance of understanding which factors specific to individual patients can affect how they will respond to a particular type of cancer treatment.
For example, women with breast cancer tumors that contain high levels of a gene called Her2/neu are more likely to benefit from a class of drugs called selective aromatase inhibitors than other women, and less likely to respond to tamoxifen, which is frequently prescribed for preventing cancer recurrence but has been shown to be effective only for a maximum of five years.
One aromatase inhibitor, called Femara, has been shown in a large clinical trial to cut the risk of recurrence of breast cancer almost in half among postmenopausal women who were treated for the disease and have finished a five-year course of tamoxifen. Femara lowers levels of the female hormone estrogen in breast cancer tumors by preventing conversion of a hormone produced in the adrenal gland into estrogen-related hormones.
Anne Schafer, finance director for a local Girl Scouts Council in Somerset County, N.J., took part in the trial. She was diagnosed with breast cancer at the age of 42, despite having no family history of the disease. "I thought I was pretty young, and the news got worse, because I had my surgery and found out that I had 17 or 18 positive lymph nodes, and there was extracapsular extension, which means that the cancer had actually burst out of at least one of the lymph nodes into the surrounding tissue. It's like being hit by the proverbial bus, and then hit by a train."
She underwent a mastectomy and reconstructive surgery and also had high-dose chemotherapy, followed by a course of tamoxifen. But because her tumor expressed high levels of Her2/neu, it was less responsive to tamoxifen, and after the five years were up, she was faced with a dilemma.
"I started thinking, what do I want to do? Do I want to do nothing? Did I want to stay on tamoxifen?" She learned through her participation in an Internet support group about the promise of Femara and other aromatase inhibitors, and she decided that it was better to be proactive than to sit around hoping that the cancer wouldn't come back.
Finding the Right Targets
In addition to the treatments described above, there are several other targeted cancer therapy strategies in use or under active development. These include:
- Monoclonal antibodies. The human immune system makes antibodies in response to various invasive organisms such as viruses and bacteria, but monoclonal antibodies are specially bred in the laboratory to attack cancer, either by latching on to cancer cells to mark them as targets for the immune system, or as carriers for other drugs or radioactive particles that can kill cancer cells. Seven monoclonal antibodies are currently approved for treatment of cancer in the U.S., including drugs targeted against colon cancer, non-Hodgkin's lymphoma, breast cancer, and leukemia.
- Vaccines. Many different research teams are working on vaccines that prime the body to attack cancer cells by recognizing various parts unique to tumor cells, such as docking sites or tumor DNA.
- Antisense therapy involves the use of bits of DNA sequences matched up with specific areas of cancer DNA to prevent unwanted genes from being activated and causing cancers to spread.
While cancer specialists are cautiously optimistic about the prospects for targeted therapies, they are also pragmatists who realize that in cancer therapy there is often a huge leap between promise and practice.
"As we've learned over the years, cancers are deceitful diseases and they really have figured out how to resist therapies by developing multiple pathways and multiple physiologic mechanisms to escape from inhibition," says UCSF's Venook. "I think it's incredibly exciting, but I think truly at the end of the day these are, all of them, incremental therapies, and the real trick, the challenge in research is going to be not to treat 100 patients to help the 10. Admittedly many of these are less toxic than conventional chemotherapy, but still, wouldn't you be better off targeting patients who are likeliest to benefit?"
Druker says that target identification alone isn't enough. "We have all sorts of therapies that can target things, but we're not always sure whether what they're targeting is what's actually broken, and it's going to be a matter of evolution in terms of our understanding of what are the critical abnormalities that drive the growth of each and every cancer, so we can develop a Gleevec for each and every cancer. Patients will come in with a disease -- cancer -- we'll identify what's driving the growth of that cancer, and we'll have drugs to shut that down. It's matching the right patient with the right drug or combination of drugs."
Published Feb. 26, 2004.
SOURCES: Robert "Bud" and Yvonne Romine. Anne Schafer. Brian Druker, MD, Oregon Health and Science University, Portland. George Demitiri, MD, Harvard Medical School and Dana-Farber Cancer Institute, Boston. Alan P. Venook, MD, University of California at San Francisco/Mt. Zion Cancer Center Clinical Research Office. William Dahut, MD, National Cancer Institute's Center for Cancer Research. "Cancer Facts and Figures 2003," American Cancer Society. National Cancer Institute. Wingo, P.A. Cancer 2003; vol 97(11 Suppl): pp 3133-3275.
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