Drugs offer new approach to treating cancer
Researchers explore positive use for thalidomide
A generation ago, pregnant women who took thalidomide ended up with deformed babies. In future generations, cancer patients who take the same drug may end up with tumor-free bodies.
That's because researchers have found that thalidomide is an angiogenesis inhibitor, a new class of drug that works by inhibiting the growth of blood vessels a tumor needs in order to grow and spread to other parts of the body. With a slew of angiogenesis inhibitors now in clinical trials, the face of cancer treatment is changing.
"The next era of cancer drug development is angiogenesis inhibitors. When these drugs make it to the market, it will have a major impact on how we think about and treat cancer," says S. Gail Eckhardt, MD, associate director of clinical research at the Institute for Drug Development, Cancer Therapy and Research Center in San Antonio. "We now have drugs that affect the biology of the tumor rather than just causing the tumor to die outright. Most of us oncologists feel we've pretty much gone as far as we can with our current chemotherapy options."
Current cancer treatments kill any cell in the body that is dividing without concern for healthy cell growth such as in white blood cells and gastrointestinal tract cells. Enter angiogenesis inhibitors. The idea for these drugs surfaced in the 1970s but is now coming to fruition through advanced clinical trials. The drugs, including thalidomide, target a biological characteristic of tumors vs. normal tissue, Eckhardt says. That specific target means a patient can take the drug on a long-term basis with very few side effects. In fact, Eckhardt says, no major side effects have been seen at all in clinical trials with these drugs.
"There are a lot of patients we see with advanced cancer who are really on the edge in terms of how well they're feeling," Eckhardt says. "For the most part, we could give these drugs without a negative impact on quality of life. It's a therapy that is pleasant to present to patients. You know that compared to chemotherapy, you'll have hardly any side effects."
At first, researchers thought the drugs might inhibit normal processes such as wound healing that require new blood vessel growth. But Eckhardt says it turns out that wound healing occurs in a different way from tumor growth and that the latest generation of angiogenesis inhibitors is targeted specifically at tumors. Down the line, when more is known about the science of these drugs, it may be possible to match angiogenesis inhibitors to specific types of tumors. For now, the drugs are said to be broadly active against all kinds of tumors.
Angiogenesis inhibitors being tested include:
· Thalidomide, the sedative that caused fetal malformations in the 1960s. Researchers did a literature search, looking back for drugs that inhibited fetal growth. "The idea was that if the drug caused fetal malformation, it probably inhibited blood vessel growth," Eckhardt says. "It's exciting that something that was so detrimental and such a catastrophe of a drug in terms of giving it to pregnant women may in fact end up treating cancer."
· Matrix metalloproteinase inhibitors (MMPI), two of which are in advanced clinical trials. MMPIs target the enzymes specific to tumors that invade and destroy tissue. They also inhibit the growth of metastatic cells.
· Squalamine, a compound derived from the liver of the dogfish shark. Preclinically, the drug showed some effect on restricting the growth of breast tumors after chemotherapy in mouse models. It is currently in phase II clinical trials.
· Tyrosine kinase inhibitors, which stop proteins that stimulate blood vessel growth.
· Alpha V Beta 3 inhibitors, which inhibit specific adhesion molecules found in blood vessels in tumors.
One potential use, Eckhardt says, is in breast cancer patients who have a tumor removed but are at high risk for that tumor returning. "Now all we could do is give that patient chemotherapy, but soon we might be able to give an angiogenesis inhibitor after the chemo is finished," she says. "In the trials, what we'd like to see is that the chemo does the real shrinkage, and then the inhibitor prevents the tumor from spreading and alters the biology of the tumor."
With several drugs in advanced clinical trials, it's possible that some angiogenesis inhibitors will be on the market within five years, Eckhardt says. Just about every large pharmaceutical company has one of these drugs in development. The hitch is that it takes a long time to prove the drugs are working since they play mainly a preventive role.
"The traditional way we develop cancer drugs is that we look for tumor shrinkage, but we don't expect a lot of shrinkage with these drugs," she says. "These drugs are keeping the tumor from growing. We will probably see shrinkage over time, but the primary effect is halting growth. Some of these drugs get dropped in development because it takes so much money to get a drug on the market, and it's sometimes hard for people to get excited when the main effect is stabilizing patients with rapidly growing tumors instead of killing those tumors outright."
[For more information on angiogenesis inhibitors, contact Gail Eckhardt, MD, associate director of clinical research, Institute for Drug Development, Cancer Therapy and Research Center, 8122 Data Point Drive, Suite 700, San Antonio, TX 78229. Telephone: (210) 616-5834.]
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