Anti-angiogenesis: Next Era of Cancer Therapy Aims to Separate Cancer from Blood Supply
MD Anderson Backgrounder 03/14/06
With cancer, it's all about the body's bounty of blood.
If all the blood vessels in the body were lined up end-to-end, they would form a line that could circle the earth twice. Yet the body produces still more blood vessels on demand, such as to heal wounds or grow embryos. This task of forming new blood vessels, a process called angiogenesis, is also critical to the development of cancer. In order for a rapidly growing tumor to maintain its growth, a tumor "signals" already existing blood vessels to sprout new branches to feed it and new tiny vessels develop in short bursts. Given the thousands of miles of blood flow already in place in a human body, vessels usually don't have far to grow to hook up to a tiny tumor that cries for blood. But scientists know that unless a tumor connects to a supply of blood, it will grow to a mere 1,000 cells and then stop. Separating cancer from its blood supply, or keeping them from linking in the first place, is the goal of clinicians and investigators at The University of Texas MD Anderson Cancer Center and other leading research institutions.
Teams of multidisciplinary scientists have been working for years to understand the factors that bind blood vessels to cancer and then to perfect "anti-angiogenic" therapies that prevent further blood vessel growth. These therapies are now at the forefront of cancer treatment. Avastin, a drug already approved to treat colorectal cancer, is showing benefit in breast and lung cancer, and two new therapies have recently been put in the medical tool kit. In December, 2005, the FDA approved Nexavar for advanced kidney cancer, and one month later, approved Sutent, also to treat kidney cancer as well as gastrointestinal stromal tumors (GIST). Many other experimental agents are expected to come up for approval soon.
In 2004, approximately 1,000 laboratories around the world were studying angiogenesis, and more than 300 biopharmaceutical companies were developing drugs and technologies to control new blood vessel growth, according to The Angiogenesis Foundation, an advocacy group. Such research has led to clinical studies underway in North America, Europe, Asia, and Latin America. Researchers at MD Anderson have also moved significantly forward from the day when they were first to test the then fledgling drug Avastin with chemotherapy for treatment of advanced lung cancer. At MD Anderson, an alphabet soup of experimental agents that includes AMG 706, AGO 13736, AZD 2171, PTK 787, AEE-788, IMC 1C11, AE 941, and others, are now being studied in the labs or through clinical trials, or both. “It’s not just a dream any more, but a reality,” says Roy Herbst, of the notion that oncologists now have access to a new medical kit of anti-angiogenesis agents with which to help prolong the lives of their patients.
And while much attention is also paid to targeted therapies known as EGFR inhibitors, drugs designed to attack specific proteins on cancer cells, Herbst predicts that anti-angiogenesis therapies will prove to be in the future strong and dependable workhorses of next-generation therapies. “Drugs that target EGFR generally work in only a subset of patients, and they can stop working due to mutations and resistance that develops in the cancer,” he says. “On the other hand, every tumor needs blood vessels, and targeting those vessels is a ubiquitous approach that might be useful for all cancers. “We are seeing activity from these inhibitors in the majority of cancers, but we have yet to figure out why they work better in some cancers than in others,” Herbst says. “The bottom line is that anti-angiogenesis has become a new modality for treating cancer.”
Moving forward slowly
It has taken a world of research to move anti-angiogenesis treatments into the limelight it now enjoys. Tumor angiogenesis occurs when cancer cells begin sending signals to surrounding tissue, activating proteins that encourage the growth of new blood vessels, so researchers at MD Anderson thought that if they shut down those signals a tumor will not become rooted.
And if it had an established blood vessel network, researchers believed these agents would give blood vessels the power to resist a cancer. As one of the first institutions to focus heavily on anti-angiogenesis, MD Anderson's work on the blood vessel-cancer paradigm has garnered scientific praise from around the world, as well as millions in funding for research. For example, in one year alone (2002), the National Cancer Institute (NCI) awarded MD Anderson more than $9 million for anti-angiogenic research. That grant supported four different angiogenic research projects that provided a backbone for ongoing clinical research. Among other areas, researchers examined markers of angiogenesis and the specific signaling pathways through which angiogenic proteins are controlled. They developed methods, including non-invasive imaging, to detect tumor cell death and blood vessel damage from new anti-angiogenic therapies.
"Founded on the hypothesis that interim measures will enable early and accurate clinical assessment of anti-angiogenic therapies, this program is an important example of the outstanding translational research being conducted," says Waun Ki Hong, M.D., head of MD Anderson's Division of Cancer Medicine. "We must move beyond conventional approaches, combining targeted therapeutic strategies with established regimens of chemotherapy, radiotherapy, and surgery to develop effective cancer treatment and cancer prevention strategies." "Compared with the world's leading institutions, MD Anderson probably has the strongest integrated program translating findings in the research laboratory to the care of our patients," says Lee Ellis, M.D., a professor in the Departments of Surgical Oncology and Cancer Biology. The key, he says, is close collaboration across disciplines on a shared goal, finding smart ways to affect tumor blood flow while sparing a patient. While the development of drugs that inhibit angiogenesis as a means of controlling cancer is now moving forward rapidly, progress had been slow in the past, Ellis says. Many of these "baby steps" have to do with the nature of the treatment. Most traditional cancer treatments, like chemotherapy, exert a toxic punch on cancer cells, and therefore their effect can be readily measured; either tumors quickly shrink or they don't. Biologic drugs, like anti-angiogenesis agents, however, are designed to rather quietly interrupt a molecular process that leads to cancer development or growth. It can be hard to know if the drugs are working, they may not shrink a tumor immediately but slow its growth, or stop it from spreading. And that is difficult to measure, especially in comparison to the short-term timeframe used to evaluate chemotherapy effects. Such is the case with endostatin, the naturally occurring protein known to inhibit tumor growth in animals. It was discovered by Michael O'Reilly, M.D., an assistant professor in radiation oncology at MD Anderson, when he was a researcher at Harvard Medical School in the 1990's. Endostatin was one of the first specific anti-angiogenic drugs to be tested and MD Anderson was one of three centers chosen in 1999 to conduct a clinical trial using the agent, which had received wide publicity even before it had ever been tested in humans. But results of that trial, published in September, 2002, show endostatin, although safe to use, is only minimally effective when given as a single agent in the treatment of advanced cancer. Still, extensive testing hinted that some biologic activity may have been going on, although that is a subject of debate. "We saw several tumors shrink for a short time, so it appeared endostatin was having an effect," says Herbst, the study's co-leader.
The fact that endostatin didn't show dramatic clinical activity is not unusual, says James Abbruzzese, M.D., professor and chairman of the Department of Gastrointestinal Medical Oncology at MD Anderson. It takes time to understand how a new agent, especially a biologic drug, may be working, and then to tweak it, he says. "For first-generation drugs, progress is often incremental, but research should go on," says Abbruzzese.
As an example of how difficult it is to test these new drugs, Ellis and other colleagues at MD Anderson have found that using an anti-angiogenesis inhibitor may initially improve the efficiency of blood flow to a tumor rather than decrease it. "Ironically, it may reduce leakiness in blood vessels, and allow small vessels to open up," he says. But as the agent works over time, a tumor may shrink or stop growing. "We are into testing the third generation of anti-angiogenesis therapies," says Ellis. "The agents are constantly being refined to be more effective." In addition, recent studies have shown that angiogenic factors, originally thought to only affect blood vessels, may also have a direct effect on tumor cell function, he says. “Again, these findings are novel, and one must keep an open mind when doing translational research in this field,” says Ellis.
“Endostatin didn’t work as we wanted it to,” says Herbst. “But it turned out to be one of the building blocks for the success we are now having.” Recent studies in China with a newer formulation suggest that this drug might return to the clinic in the near future, he added.
Chemotherapy boosts benefit
Within the last several years, there has been a flurry of positive clinical trials in colorectal cancer, renal cell carcinoma and lung cancer at MD Anderson using anti-angiogenesis inhibitors, says Ellis. "Although we still have a tremendous amount to learn, researchers have begun to understand this complicated process,” he says. One huge advantage has been the recent understanding that anti-angiogenic therapy works best when combined with chemotherapy and vice versa. “We know now that anti-angiogenic therapy improves the effects of chemotherapy in colorectal and lung cancers,” Ellis says. But this is an apparent paradox, as it was originally thought that anti-angiogenic would “starve a tumor of oxygen and nutrients,” and the same mechanisms could possibly prevent delivery of chemotherapy. “Although these agents may inhibit blood vessel growth, more research must help us understand some of the other functions of these anti-angiogenic drugs,” he says. Herbst also knows first-hand about the additive power of chemotherapy. MD Anderson researchers have a long history of studying Avastin in a variety of cancers, lung cancer, malignant mesothelioma, carcinoid tumors, myeloid leukemia and pancreatic cancer. But his first studies of Avastin in patients with advanced lung cancer were unsuccessful until chemotherapy was added to the treatment. “What changed in the field is that we originally thought these agents could be used alone, and we have come to realize they can’t. Cancer uses too many redundant systems and one agent isn’t enough to hit all those molecular targets,” Herbst says. Now he and other MD Anderson researchers are testing use of Avastin not only with chemotherapy but also in combination with other targeted therapies. In the April 10, 2005 issue of the Journal of Clinical Oncology, Herbst reports that use of Avastin with Tarceva, an EGFR inhibitor approved for use in lung cancer, has shown encouraging anti-tumor activity. Herbst is now leading a national phase III clinical trial testing Avastin and Tarceva, versus Tarceva alone, to treat lung cancer in 800 patients.
Testing different types of drugs
Most of angiogenesis drugs being tested today fall into the class of large monoclonal antibody molecules, like Avastin, or small molecules, known as tyrosine kinase inhibitors, that block the signals that cancer cells send out to lure blood vessels to grow to them. All of these agents are “indirect” inhibitors of the angiogenesis process because they don’t work directly on blood vessels. “They impede molecules that stimulate blood vessel growth, like blocking a stream of water so that the grass won’t grow,” says Herbst. Different classes of angiogenesis drugs are those that are designed to directly “kill” the blood vessels that feed tumors. Among such experimental drugs being tested at MD Anderson is AE-941 (Neovastat), a naturally occurring product extracted from shark cartilage. Charles Lu, M.D., an assistant professor in Thoracic/Head and Neck Medical Oncology is leading a nationwide, Phase III trial of Neovastat in advanced lung cancer. That trial is now closed and results are expected in the next few years.
And then there is thalidomide, a drug developed in Germany which was marketed in the 1950's as a sleep aid and reliever of morning sickness, until it was realized that thalidomide inhibited limb development during the first trimester of pregnancy. Although a widely feared drug, thalidomide is currently used as an anti-inflammatory agent, particularly to treat some symptoms of leprosy. It also has been reported to be beneficial as a treatment of skin lesions and some diseases associated with AIDS. In the mid-1990's, researchers wondered if the very qualities that damaged the growth of limbs in neonates, angiogenesis, might be helpful in preventing tumors from promoting blood vessel formation. Today, at MD Anderson, thalidomide is being tested in a number of different cancers, including prostate cancer, multiple myeloma, brain and ovarian cancer.
Bedside back to bench
What researchers are discovering about anti-angiogenesis is helping them put together the pieces of a grand plan, a way to deliver anticancer drugs efficiently and effectively to a single tumor site in the body and nowhere else. Just as the post office uses street addresses and zip codes to deliver a letter to one home out of millions, researchers at MD Anderson have discovered that blood vessels have a vascular address system of their own. That's how blood cells circulating in the blood stream know where to go, according to the researchers who made the discovery, Renata Pasqualini, Ph.D., and Wadih Arap, M.D., Ph.D., professors in the Department of Genitourinary Medical Oncology and Cancer Biology. "Scientists have long thought that blood vessels are uniform and generic, much like plumbing in a house," says Arap. "Recently, we recognized that blood vessels that feed various organs are actually strikingly different, and blood vessels in tumors stand out as being particularly unusual," adds Pasqualini.
This diversity, signified by different vascular zip codes, can be used to target the delivery of diagnostic and therapeutic agents to specific organs and to sites of disease such as tumors and metastasized cancer cells, says Pasqualini. Arap and Pasqualini have also recently found that blood vessels are also needed to support the growth of adipose tissue (found in body fat), much as it happens with tumors. In a study reported in the journal Nature Medicine last year, they found a zip code in fat vasculature, and they successfully used the address to selectively eliminate a storehouse of fat in mice. “The implications of this go beyond the control of obesity, given that body mass appears to influence the progression of prostate and breast cancer,” says Pasqualini. Physicians in the future may be able to deliver a cornucopia of anti-angiogenesis drugs, each of which works in different vascular zip codes, says Abbruzzese. He adds it may even prevent cancer development in susceptible patients using these agents. "We still have much to learn," says Abbruzzese. "But with such promising research, we now have some real opportunities to make progress."