Next Era of Cancer Therapy Aims to Separate Cancer From Blood Supply

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 researchers at The University of Texas M.D. Anderson Cancer Center and other leading research institutions.

Teams of multidisciplinary investigators are working to understand the factors that bind blood vessels to cancer and then to perfect "anti-angiogenic" therapies that prevent further blood vessel growth.

They are examining the problem from all angles and situations. Tumor antiangiogenesis occurs when cancer cells begin sending signals to surrounding tissue, activating proteins that encourage the growth of new blood vessels - so researchers are investigating ways to shut down those signals to stop a tumor from becoming rooted.

They also are studying what to do if the cancer already has an established blood vessel network and how to give blood vessels themselves the power to resist a cancer.

M.D. Anderson's focus on the blood vessel-cancer paradigm has garnered scientific praise from around the world, as well as millions in funding for research - for example, $9.2 million was awarded to the institution in 2002 from the National Cancer Institute for anti-angiogenic research. That grant supports four different angiogenic research projects that provides a backbone to ongoing clinical research. Among other areas, researchers are examining markers of angiogenesis and the specific signaling pathways through which angiogenic proteins are controlled. They are developing 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 M.D. 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, M.D. 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 starve a cancer while sparing a patient.

Moving forward slowly

There is much interest in the development of anti-angiogenesis drugs. An estimated $4 billion has been invested in the research and development of angiogenesis-based medicines, according to The Angiogenesis Foundation, an information clearing house and think-tank for angiogenesis research. More than 60 different anti-angiogenesis compounds are in human testing around the world, and one estimate has it that at least 6,500 cancer patients worldwide have been treated with some form of experimental anti-angiogenic therapy.

While the development of drugs that inhibit angiogenesis as a means of controlling cancer is moving forward, the progress is slow, Ellis says. "Researchers are just beginning to understand this complicated process," he explains.

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 M.D. 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 M.D. 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 be going on, although that is a subject of debate. "We saw several tumors shrink for a short time, so it appears endostatin may be having an effect," says the study's co-leader, Roy Herbst, M.D., Ph.D., associate professor of medicine in the Department of Thoracic/Head and Neck Medical Oncology.

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 M.D. 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 M.D. Anderson have found that using an anti-angiogenesis inhibitor may initially increase 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."

Testing different types of drugs

One class of angiogenesis inhibitors being tested in cancer patients at M.D. Anderson are molecules designed to stop the growth of blood vessels cells. Included in this category is endostatin, but also 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 M.D. Anderson, thalidomide is being tested in a number of different cancers, including prostate cancer, multiple myeloma, brain and ovarian cancer.

Another group of angiogenesis inhibitors being tested in human clinical trials at M.D. Anderson are molecules that interfere with steps in the angiogenesis "signaling cascade" - the biochemical pathway that leads to new vessel development.

Included in this category are drugs that block the binding of the growth factor known as vascular endothelial growth factor (VEGF) to cells lining the blood vessels (also known as endothelial cells). VEGF is produced by tumor cells and initiates the process of angiogenesis, promoting the development of a new network of blood vessels that sprout and grow toward a tumor. By blocking the binding of VEGF, these drugs help deprive the tumor of necessary nutrients to grow.

Among such experimental drugs being tested at M.D. 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.

Another agent, bevacizumab (also known as Avastin, anti-VEGF, RhuMabVEGF), is undergoing extensive review at M.D. Anderson, in a variety of cancers - lung cancer, malignant mesothelioma, carcinoid tumors, myeloid leukemia and pancreatic cancer.

Like other molecularly targeted drugs, bevacizumab is designed to specifically interfere with a biological process that promotes tumor growth or survival. This drug is an antibody that neutralizes the VEGF protein by "sticking" to it, preventing it from triggering blood vessel growth.

Researchers are also investigating the power of a common arthritis medication to impede angiogenesis. They have already found that celecoxib (Celebrex) can reduce the number of colon polyps that develop in a rare genetic form of colon cancer - a discovery which led to FDA approval of the medication for that cancer therapy. Now, other ongoing M.D. Anderson clinical trials with celecoxib include studies on its effectiveness in prevention of Barrett's esophagus (a precursor to esophageal cancer), and superficial bladder cancer. It is also being tested with locally advanced lung cancer and cervical cancer, in combination with other treatments.

Bedside back to bench

Other M.D. Anderson researchers are going back to the lab to pick apart what works and what doesn't - and why. Using mouse models, O'Reilly is finding that the order in which new cancer therapies are delivered is crucial.

For example, chemotherapy has to get into cancer cells to be effective, but anti-angiogenesis drugs are designed to block off access to cancer cells - and may render chemotherapy ineffective if used first, he says. On the other hand, chemotherapy treatment may leave behind cells that are hard to kill with anti-angiogenesis therapy, O'Reilly says. "Sequencing matters, and that has been a surprise," he says, "But it helps us understand a lot about tumor biology."

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 M.D. 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, Ph.D., associate 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.

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."