By Heather Lindsey

When Marlene Ochoa was diagnosed with advanced colorectal cancer in April 2001‚ she wanted to participate in a clinical trial. “I figured I would be undergoing chemotherapy anyway‚ and that if I could take something else that could further contribute to my treatment‚ I should do it‚” explains the 53-year-old mother of two in Diamond Bar‚ California.

After talking to several physicians‚ Ochoa enrolled in a phase III clinical trial at the University of California‚ Los Angeles (UCLA)‚ Jonsson Comprehensive Cancer Center‚ and‚ in addition to standard chemotherapy‚ started taking the drug Avastin™ (bevacizumab). This agent stops the growth of new blood vessels that feed the tumor‚ cutting off the cancer’s blood supply and preventing its growth and spread.

“This is basically what I wanted‚” says Ochoa. “I felt that the tumors were taking energy from my body‚” adding that her abdomen was swollen and interfered with her eating and breathing. “I wanted to cut off how the cancer was being fed.”

Ochoa is taking part in one of the more than 60 clinical trials investigating drugs that help prevent angiogenesis—the development of new blood vessels for cancer tumors.

But‚ while angiogenesis sounds simple‚ researchers warn that it’s a much more complex issue than it appears. Antiangiogenic therapies are not the sole solution to cancer because the process of angiogenesis is complex‚ notes Lee Ellis‚ MD‚ a professor of surgical oncology and cancer biology who is researching angiogenesis at The University of Texas M. D. Anderson Cancer Center in Houston.

Dr. Ellis explains that many proteins regulate the creation of new blood vessels. Consequently‚ knocking out one protein‚ as many antiangiogenic drugs do‚ still leaves many other proteins that may stimulate angiogenesis.

“The biggest misconception about these drugs is that they are the magic bullet and people will be cured of their tumors by cutting off the blood supply‚”says Dr. Ellis.

Because angiogenesis inhibitors are still in the early stages of research‚ no data exist proving these agents can improve survival‚ cautions Lee Rosen‚ MD‚ director of the Cancer Therapy Development Program at UCLA’s Jonsson Cancer Center. However‚ he added that phase I and II studies support a trend in improved survival when patients are treated with angiogenesis inhibitors in combination with chemotherapy. Using this combination as a first-line therapy is now being tested in phase III trials.

Angiogenesis is Normally Healthy
In healthy adults‚ angiogenesis helps repair damaged tissue by supplying it with oxygen and nutrients. This process also occurs in women a few days each month during their menstrual cycle as new blood vessels form in the uterine lining.

“Normally‚ angiogenesis is a good thing that helps heal our wounds‚ protects our heart from lack of oxygen‚ and regulates menses‚ the ovulation cycle‚ and pregnancy‚” says Dr. Ellis.

However‚ in cancer patients‚ angiogenesis feeds tumors with oxygen‚ nutrients‚ and survival factors that enable them to invade and spread. Without their own blood supply‚ tumors can’t grow larger than a small pea‚ according to the Angiogenesis Foundation in Cambridge‚ Massachusetts‚ a nonprofit organization founded in 1994 by Harvard-trained physicians and scientists that facilitates the development and application of angiogenesis-based medicine through research and education.

Angiogenesis begins when cancer cells learn how to produce protein molecules that stimulate new blood vessel formation. One of the most important is vascular endothelial growth factor (VEGF).

“The body makes VEGF for a good reason‚” says David Johnson‚ MD‚ director of hematology/oncology and deputy director of Vanderbilt-Ingram Cancer Center in Nashville‚ Tennessee. Dr. Johnson explains that VEGF normally repairs cells that line the blood vessels or endothelial cells‚ but cancer takes this otherwise normal activity of the body and subverts it.

After cancer cells produce VEGF‚ they secrete the molecule into surrounding healthy tissue‚ where it binds to protein receptors on the cell surface. This process activates other cell proteins that transmit a signal to the cell’s nucleus to develop new blood vessels. Cancer cells can take hold in different parts of the body only if they receive oxygen and nutrients to grow. Angiogenesis inhibitors prevent cancer cells from receiving these nutrients.

Antiangiogenic drugs target these activators in a number of ways: by stopping the connection‚ plugging the connectors‚ or affecting the entire process. VEGF and its receptors are good targets because they are present in blood vessels in nearly all tumors. Drugs aimed specifically at VEGF are being tested in clinical trials‚ which include advanced lung‚ colorectal‚ breast‚ brain‚ kidney‚ and prostate cancers.

Cancer as a Chronic Illness
Antiangiogenic drugs cut off the blood supply to tumors instead of attacking the cancer directly like chemotherapy agents. But halting the growth means no new growth.

“Metastatic disease is what ultimately causes patients to die‚” says Nassim Usman‚ PhD‚ senior vice president of research and development of Ribozyme Pharmaceuticals‚ Inc.‚ which is creating a new antiangiogenic called Angiozyme.

“We’re not attacking the tumor but the metastatic process of the tumor‚” agrees Glen Justice‚ MD‚ medical director of the Orange County Regional Cancer Center‚ Fountain Valley‚ California. Dr. Justice and his colleagues are studying angiogenesis inhibitors‚ including Avastin.

William Li‚ MD‚ president of the Angiogenesis Foundation‚ says that viewing cancer as a chronic illness is a switch from the past 50 years when treating cancer meant wiping it out with high doses of toxic drugs.

“This new strategy to treat cancer is viewed not as an incremental step but as a monumental leap forward in controlling cancer‚” says Dr. Li.

While researchers look for an ultimate cure‚ patients could be managing their cancer with antiangiogenic drugs in combination with other treatments‚ says Dr. Ellis‚ just as those with other “chronic diseases” such as diabetes‚ hypertension‚ or Parkinson’s.

Clinical Trials
A number of antiangiogenic drugs are in phase III studies. Although the end goal of inhibiting angiogenesis is the same among the many trials‚ the mechanism by which these agents work tends to vary.

Avastin‚ a monoclonal antibody that is given intravenously‚ is being evaluated in patients with lung‚ colorectal‚ and metastatic breast cancer. The drug is being studied in combination with Xeloda® (capecitabine) and with Taxol® (paclitaxel) for the potential treatment of metastatic breast cancer. Avastin is an antibody that seeks out VEGF‚ binds to the protein‚ and prevents it from attaching to its receptors on the surface of endothelial cells‚ explains Dr. Ellis.

Earlier studies conducted by Dr. Johnson and his colleagues found that patients with non—small-cell lung cancer who received Avastin in combination with chemotherapy had better response rates and somewhat longer survival than chemotherapy alone‚ he says.

Although results from phase III trials are not yet available‚ Ochoa started to feel better just two or three weeks after beginning therapy. “I could actually breathe‚”she says. “I started eating full meals.”She also began walking 2.5 miles in the morning to get her physical endurance back. Additionally‚ since the start of her therapy‚ her tumors have shrunk by about half.

A number of new drugs‚ including SU6668‚ PTK787‚ and ZD6474 are being developed to directly block the function of VEGF.

Instead of binding to the VEGF protein like Avastin‚ these drugs attach to the VEGF receptor‚ inhibiting its activation and blocking the response to VEGF‚ explains Dr. Ellis. This action blocks the signaling pathway that spurs angiogenesis.

“It’s like putting some chewing gum inside the lock so VEGF can’t get in—the gum is the drug and the receptor is the lock‚” says Dr. Rosen‚ a primary investigator of the agent.

Side Effects of Angiogenesis Inhibitors
Phase I and II trials have shown that antiangiogenics have relatively few side effects since healthy tissue does not contain growing blood vessels.
“We have found that angiogenesis inhibitors are safe agents that can be given orally or intravenously‚”says Dr. Justice.

But‚ as with all drugs‚ there are side effects to be considered‚ the most notable being hemorrhaging‚ says Robert Catalano‚ PharmD‚ vice president of regulatory affairs for the Eastern Cooperative Oncology Group based in Philadelphia‚ Pennsylvania‚ adding that patients need to be monitored carefully.

Hemorrhaging has occurred in earlier studies of Dr. Johnson’s patients who had lung cancer. “The truth is we don’t know why it occurred‚” he says. The side effect does appear to be more common in squamous cell carcinoma‚ a form of lung cancer that appears in the central portion of the chest. Patients with adenocarcinoma‚ which occurs in the lungs’ periphery‚ experienced hemorrhaging far less frequently.

Lung cancer patients often bleed from their lungs‚ notes Dr. Johnson. Blood vessels that feed a cancer are not strong and well developed. “They’re more leaky‚” he says. “They don’t possess the muscle that normal blood vessels do and are more prone to bleeding.”

Additionally‚ giving a patient an antibody against VEGF can inhibit the body’s ability to repair damaged blood vessels‚ and pregnant women should not take the drugs because angiogenesis is needed for fetal development.

In other words‚ antiangiogenic therapies are not for everyone. “Patients hear tons of information about new drugs‚” adds Dr. Johnson. “All of that is exciting at times but has the potential to turn into tremendous disappointment.”

What if Results from Phase III Trials are Negative?
Recent phase III studies with Semaxanib (SU5416) in patients with advanced colon cancer showed no benefits‚ so further studies with the drug have been terminated.

Unfortunately‚ negative study results tend to make investigators abandon their research‚ says Dr. Johnson.

“But we didn’t move from the Wright brothers’ plane to a 747 in a year‚” he says. “Learning how to fly is a skip in the park compared to learning the complexities of a cancer cell. It’s an ongoing process that never stops.”

Studies with negative results aren’t necessarily a bad thing‚ says Dr. Rosen. Research might generate negative results because certain types of cancers might not respond to a particular drug or because researchers need to investigate the drug in earlier stages of the disease.

Other drugs‚ such as endostatin and angiostatin‚ which have had disappointing study results‚ might actually work in a select group of people‚ says Catalano. “We need to become more knowledgeable about what receptors these drugs have an affinity for‚” he says.

Ochoa encourages participation in clinical trials. “I believe that when you’re in a life-or-death situation‚ you really have nothing to lose‚” she says.

She recommends trying to remain as informed as possible about how angiogenesis inhibitors and other drugs are performing in studies and to openly discuss treatment options with your doctor. —It also helps to have your doctor say‚ “We’re going to try to make everything work for you‚” she notes.

She approaches her own treatment and her continued participation in the trial with a positive pragmatism. “I truly believe some people can take the drug and some people can’t. This is a two-year program‚ and as long as it’s working and I’m not having side effects‚ I’ll continue.”

“I have my bad days and good days‚” she adds. “But I always felt this would work well with me.”

Editor's note: CURE is glad to honor the memory of Marlene Ochoa who passed away in 2002.