Posted by Susan
(I promise this entry is less depressing than the title sounds.)
Over the past week, I've heard a few lectures from a researcher at Chicago (Mark Lingen) who's studying tumor angiogenesis--that is, the process by which tumors create blood vessel networks for themselves. For many years, angiogenesis was something of the redheaded stepchild of cancer biology--Judah Folkman, the "father of angiogenesis", worked on it for decades before being taken seriously (there's an interesting Nova program on Folkman's work here; among other things, it answers the eternal question of, "How can I obtain a large amount of mouse urine to use in protein purification?"*). Angiogenesis has become quite the hot field; there are a few dozen anti-angiogenic drugs in clinical trials, and one (Genentech's Avastin) has recently been approved by the FDA as a treatment for colon cancer after failing to work against breast cancer in 2002.
Targeting angiogenesis is radically different than conventional chemotherapy and represents a changing view on the curability of cancer that may completely revolutionize cancer treatment.
Most conventional chemotherapies are cytotoxic--that is, they kill cells, especially rapidly dividing cells. They affect cancer cells more than most healthy cells because the cancer cells divide more; however, healthy tissues that normally undergo a lot of cell division (such as bone marrow) are severely damaged by conventional chemotherapy. This is just from the intended effect of the drug; most chemotherapies also have severe side effects (ototoxicity from cisplatin, neurotoxicity and urotoxcity from ifosfamide, etc.) that are due to toxic metabolites of the drugs. The normal dosing schedule for conventional chemotherapy includes a period of very high drug dosing (in an attempt to obliterate the cancer) followed by a "holiday" to give bone marrow and other tissues a chance to recover from the damage.
By contrast, good anti-angiogenic drugs** are not terribly toxic to the patient. As you might expect, there are minor effects upon wound healing. I expect inhibition of angiogenesis would affect the female reproductive system, but I can't find any data on this presently. Also, the dosing schedule for anti-angiogenics is radically different than that of normal cancer drugs. It's called metronomic dosing; patients take a small amount of drug every day. No holidays. This should make sense intuitively; for anti-angiogenic therapy to work, it has to prevent the tumor from obtaining a blood supply by constantly preventing the growth of new blood vessels to the tumor. Using the "pound the hell out of it then give the patient a holiday" schedule would allow the blood vessels to grow back during the holiday.
The big difference between anti-angiogenic therapy and regular cancer therapy is that the latter is cytotoxic whereas the former is cytostatic. Cytostatic therapy doesn't kill cells in the same way that cytotoxic therapy does; rather, it prevents them from growing and dividing. So what's the point of cytostatic therapy? On one hand, it might be useful as an adjuvant therapy to normal cytotoxic therapy (though there are problems with this idea***). However, the revolutionary idea is that anti-angiogenics can be used as a long-term tolerable therapy to allow patients to live with cancer. This is a huge shift from normal ideas about cancer treatment. We're no longer talking about curing cancer but about taming it, turning it into a disease that can be managed for years--even decades--with drugs. It's not unlike the paradigm shift**** in AIDS therapy, and I'd venture to say that the saga of AIDS therapy will be helpful in identifying potential pitfalls in long-term cancer therapy.
An even more radical idea is the use of such drugs for long-term chemopreventative therapy; for example, people at high risk for head and neck cancer could take EGFR inhibitors even before they developed cancer to prevent any cancers that arise from initiating angiogenesis. Head and neck cancer is a particularly good candidate for this sort of scheme as these extremely aggressive cancers tend to activate angiogenesis very early in their development. Another example of chemopreventative therapy that I've heard of is the idea of using tamoxifen, raloxifene, or other synthetic anti-estrogens to reduce the risk of breast cancer in high-risk individuals.
Here's a few potential pitfalls to think about:
Different expectations of cancer drugs
I guess this is a bit obvious; a drug that you take for a short time to cure a disease is going to be different from a drug that you take for thirty years to manage a disease. I'll take the chemopreventative example of tamoxifen for breast cancers as an example. Tamoxifen acts as an anti-estrogen in breast tissue; it binds to the estrogen receptor and prevents it from being activated by estrogen. However, tamoxifen acts as a synthetic estrogen in other body tissues, like bone and uterine tissue. There is a (very small) increase in the risk of developing uterine cancer among women who are treated with tamoxifen. In the context of breast cancer therapy, this risk is negligible--the benefits of tamoxifen use in curbing the breast cancer far outweigh the small risk of the uterine cancer. However, in this scenario, we're talking about maybe ten years of tamoxifen therapy at max (women frequently take tamoxifen for the first five years that they're in remission). What happens when it's thirty years? What happens when the woman doesn't already have cancer? Is the risk of uterine cancer larger or more important in that case?
Another concern along these lines is that most anti-cancer agents affect fertility. Anti-angiogenics are especially bad in this respect--two drugs with anti-angiogenic effect, retinoic acid and thalidomide, are best known for their ties to birth defects. When you actually have cancer, childbearing isn't as much of a concern. However, if you're going to be on a chemopreventative or long-term chemotherapeutic agent for thirty years or so, the circumstances are quite different.
Are at-risk groups differentially sensitive to the chemopreventative agent?
As you probably know, cancers have a number of environmental and genetic causes. Obesity and smoking will increase your risk of practically every cancer. There are some concerns in how one identifies at-risk groups to be treated with chemoprevention. Some easily-identified at-risk groups for specific cancers--for example, women who carry mutations in the tumor suppressor gene BRCA1, who are at a much higher risk of developing breast and ovarian cancers--have different treatment requirements than most people with that cancer. In the case of breast cancer, BRCA1-positive (i.e. mutant) women are significantly less likely to respond to tamoxifen therapy (because their tumors are less reliant upon estrogen) than women with mutations in BRCA2 or women with spontaneous cancer. These women would not respond well to tamoxifen treatment. On the other hand, people who face an increased environmental risk of cancer--such as users of chewing tobacco, who have an increased risk of oral cancer--would be much better candidates for chemopreventative trials as their cancers are unlikely to be different from the average cancer of that type.
Taking chemotherapy home--patient compliance
Presently, chemotherapy is administered by hospitals. This is obviously impractical for lifetime therapy. If long-term chemotherapy becomes a real method of treatment, doctors are going to have to impress the importance of drug compliance upon their patients. This is especially true of anti-angiogenics, which require constant dosing to effectively prevent blood vessel growth.
Cost is going to be an issue. Cancer treatment isn't cheap now--lifetime therapy could be staggeringly expensive.
It's an interesting prospect. I'm especially curious to see how the field of chemopreventative agents progresses; it'd be really nice if we moved beyond exhortations to eat tomatoes to prevent prostate cancer or whatever. I guess realistically the best chemoprevention is weight loss and not smoking (with limiting sun exposure, not drinking rotgut whiskey, not living in Love Canal, and not getting HPV somewhere behind there). It is pretty cool to hear about clever drug therapies, though. I'll close with one of my favorites--Charlie Rudin (formerly of Chicago, now of Hopkins) is involved with the development of an attenuated adenovirus that is selectively cytotoxic to cells deficient in the tumor suppressor gene product p53 (i.e. cancerous or precancerous cells). His group is specifically targeting oral cancer, and the virus is administered as a mouthwash. How cool is that?*****
*Answer: feed mice unlimited sugar water and they'll produce their body's weight in urine every day.
**There exist bad, or at least less good, anti-angiogenic drugs. Thalidomide is a good example--it's a small-molecule inhibitor of angiogenesis (molecular mechanism unclear) that also causes immune system depression (through interactions with the NFkB pathway), neuropathy, and horrible birth defects. On the up side, it prevents nausea and is effective against leprosy. Very interesting drug.
***Anti-angiogenics seem to work synergistically with radiotherapy (RT); the idea is that the anti-angiogenic therapy, if given shortly before RT, can stabilize the leaky, abnormal tumor-induced vessel that feeds the tumor and make the tumor more oxygenated. Oxygen-rich tissue is the ideal target for RT, which exerts its cytotoxic effects through the reactive oxygen species it creates in damaged cells. However, the idea of combining anti-angiogenics with cytotoxic chemotherapy has some problems; most importantly, many cytotoxic agents target DNA and work best in rapidly dividing cells. If you stem cell division with anti-angiogenics, the cytotoxics won't work as well.
****I hate you, Thomas Kuhn.
*****Answer: SO COOL.Posted by Susan at April 26, 2004 05:09 PM