Pediatric Cancer: Bench to Bedside
Cancer treatments involve multiple agents, including the well-known options of chemotherapy and radiation. Most recently, drugs that target very specific parts of the cancer growth process have moved to the forefront of researchers' attention. Of these, a highly fruitful approach is one that blocks angiogenesis, the growth of the blood vessels, which in this case supply tumors.
Since 1998, Jessica Kandel, MD, R. Peter Altman Professor of Surgery & Pediatrics (in the Institute for Cancer Genetics), and Darrell Yamashiro, MD, PhD, Associate Professor of Pediatrics and Pathology & Cell Biology, have pioneered this field of research at Columbia University. They began with efforts to inhibit angiogenesis using one specific antibody. This antibody, which targeted a key protein involved in the development of human tumor blood vessels, vascular endothelial growth factor (VEGF), was synthesized by a biotechnology company and was called A4.6.1. "We were particularly interested in treating refractory tumors for which there were no good therapies available," says Dr. Kandel. Since that time, they have focused their research on finding new therapies for pediatric cancers that have failed currently available treatments, including:
- Resistant neuroblastoma, a tumor that usually begins in the adrenal gland or nerve tissue. Neuroblastoma is the second most common solid tumor in children (after brain tumor), at about 700 cases per year in the U.S.;
- Recurrent Wilms tumor, which begins in the kidney and occurs in about 500 children per year in the U.S.;
- Resistant hepatoblastoma, which begins in the liver and is relatively rare, at only 300 U.S. cases per year.
The team's early research in blocking VEGF using A4.6.1 proved highly successful. This agent became the forerunner to bevacizumab (Avastin), the first anti-angiogenesis therapy approved by the FDA to treat cancer. Today bevacizumab is widely used, along with chemotherapy, to treat cancer in adults. Results of the team's phase I trial in children were published in 2008.
Bevacizumab by itself is not a cure for cancer, but it can be used with chemotherapy to effectively treat some cancers, and in other cases to help extend patients' lives. It may have milder side effects than some chemotherapy, and is very well tolerated by children. It is gaining increasing use in a range of adult cancers, based on encouraging results so far in trials of adults with colon, breast, lung, and other tumors.
The effectiveness of bevacizumab varies depending on the type of tumor, according to Dr. Kandel, because the growth of blood vessels is not the same in all tumors. "Different tumors are more or less susceptible to being destabilized by bevacizumab than others," she explains. For instance, the drug is most sensitive in treating an experimental model of Ewing's sarcoma (a tumor of the bone or soft tissue), where it can block tumor growth by 90% in six weeks and significantly reduce the spread of cancerous cells (metastasis). In comparison, it may block tumor growth 40–50% in a model of resistant neuroblastoma. "Even in neuroblastomas with poor prognosis, the drug can have a positive effect," says Dr. Kandel.
Based on the success of bevacizumab, other anti-angiogenesis drugs (targeting VEGF and different proteins involved in angiogenesis) have been developed. Although these have been widely tested in adults, trials in children are still catching up. Recent and ongoing trials of these drugs in children include the following:
- phase I trials (to determine safety and dosage) of sorafenib and VEGF-Trap;
- A phase I trial of sunitinib in children;
- A phase II trial (to determine efficacy) of bevacizumab in children.
Although results to date have been promising, the duration of bevacizumab's effectiveness is somewhat limited, as tumors appear to adapt to its presence after sustained treatment. Observation of this phenomenon has led Dr. Kandel and colleagues to study the process by which tumors learn to grow when blood flow is restricted. "We already know that tumors are not usually cured by one drug, but by the use of multiple drugs to control several tumor processes. We believe that learning how tumors adapt may provide even more avenues for therapeutic options," says Dr. Kandel.