by Tobey MacDonald, M.D., Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA
In 1971, Dr. Judah Folkman, then surgeon-in-chief of Children’s Hospital Boston, reported in the New England Journal of Medicine that solid tumors are dependent on “angiogenesis”, the formation of new blood vessels, for survival and growth. He proposed that a chemical secreted by the tumor helped it to increase its blood supply, and that if that chemical could be blocked, then the tumor would regress and die. Dr. Folkman, and other labs working on angiogenesis, subsequently identified a number of these chemicals (e.g. vascular endothelial growth factor, VEGF) in the mid to late 1980s, and with that, drug discovery to inhibit these chemicals began. In 1991, the first inherent human angiogenesis inhibitors were discovered: angiostatin and endostatin. And in 2004, the first angiogenesis inhibitor, bevacizumab (Avastin), was approved by the FDA for the treatment of colon cancer.
At that time there was a flurry of excitement in the adult and pediatric oncology communities surrounding this drug, and others to follow in the same class of angiogenesis inhibitors (AIs), given the promising early clinical results and the lack of severe toxic effects typically seen with standard chemotherapies. The FDA has since approved a number of AIs for the treatment of various cancers, with most of these targeting VEGF. A number of these, including Axitinib, Sorafenib, Sunitinib, Pazopanib, Cabozantinib, and Regorafenib, to name a few, have recently been found to significantly improve survival in specific adult cancers such as thyroid, colon and renal cell carcinoma. Unfortunately, the same success of AIs has yet to be demonstrated in brain tumors, especially pediatric malignant brain tumors. The first group-sponsored pediatric brain tumor trial with an AI was conducted by member institutions of the Pediatric Brain Tumor Consortium (PBTC) in early 2000. This was phase I trial with the VEGF blocking compound, SU5416. PBTC also completed an Avastin trial for refractory malignant glioma in 2010, but neither drug was approved for further clinical development in this setting due to a lack of significant responses. However, Avastin and similar drugs are continuing to be investigated and used for the treatment of pediatric brain tumors in certain conditions. Although the original enthusiasm for AIs in the treatment of pediatric brain tumors has dampened over time, the jury remains out whether these drugs can be combined with other new biological therapies, immunotherapies, or conventional chemotherapy and radiation, to improve the survival of children with brain tumors. Thus this “old frontier” remains a current frontier for pediatric brain cancers with the hope that a better understanding of AIs will eventually lead to a successful new treatment regimen for clinical investigation.
How AIs work—Angiogenesis inhibitors are unique cancer fighting agents because they block the growth of blood vessels that support tumor growth rather than blocking the growth of the tumor cells directly. In normal tissue, new blood vessels are formed in response to signals generated during tissue growth and repair (wound healing) during the normal female reproductive cycle and during the development of the fetus in pregnancy. Many protein “chemicals” are now known to activate new blood vessel growth. Of these, the most potent is called vascular endothelial growth factor (VEGF). Other important ones include fibroblast growth factors (FGF), epidermal growth factor (EGF), placental growth factor (PIGF), platelet derived growth factor PDGF), and tumor necrosis factor alpha (TNF-alpha), to name a few. In cancerous tissue, tumor cells produce their own VEGF and other chemical signals that induce the existing blood vessels in the surrounding tumor environment to make new blood vessels for the growing tumor. Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels. In response to these chemical signals, endothelial cells divide and grow, breakdown their surrounding tissue barriers and migrate toward the tumor to form a connection to the body’s blood supply. In general, the most clinically effective AIs have been found to block the chemical signaling pathways that lead to the stimulation of endothelial cells to form new blood vessels. In fact, all of the FDA approved AIs for the treatment of cancer thus far attack multiple arms of these signaling pathways simultaneously.
AIs in clinical trials for pediatric brain tumors—At one point between 2000-2010, about 20 different angiogenesis inhibitors were being tested in adult and pediatric brain cancer trials. Today, in the US, there is only one active pediatric brain tumor trials with an AI, pomalidomide, for children with refractory brain tumors according to the website ClinicalTrials.gov. This drug was developed as a more potent AI with immune therapy effects, after it was found that similar AI class of drugs, thalidomide and lenalidomide, appear to have some anti-tumor effects in children with progressive brain tumors, especially in low-grade glial neoplasms. A phase I trial of lenalidomide and radiotherapy for children with diffuse intrinsic pontine glioma and high-grade glioma was recently completed in April 2019, but the results have not yet been reported. Similarly, a Phase II study of Avastin and a biologic therapy targeting EGFR, lapatinib, for refractory ependymoma was completed in 2015. Avastin was also combined with radiotherapy in one arm of the last completed COG study for pediatric high-grade glioma, but showed no difference in treatment with radiation and temozolomide chemotherapy. Previous clinical trials have shown some limited benefit of Avastin and irinotecan for the treatment of progressive low-grade gliomas or the same regimen plus temozolomide for progressive medulloblastoma, and thus many centers will use these combination therapies as a salvage therapy in these specific conditions and settings. Finally, multiple trials are underway using innovative correlative imaging or investigation of biological samples to better visualize and understand angiogenesis so that AIs can be optimized for future investigation and clinical utilization.
AI side effects—Because of the effects of AIs on new blood vessel formation and the existing vasculature, there are potential risks of hemorrhage, clots in the arteries (with resultant stroke or heart attack), hypertension, impaired wound healing, and leaky vessels in kidneys leading to loss of proteins into the urine. These effects still appear to be relatively infrequent. Another rare side effect is perforation of the GI tract. However, in general, AIs appear to be very well tolerated.
Conclusion–In summary, AIs continue to offer an “old” new approach to the treatment of childhood tumors. It is hoped that because of the important benefits of AIs over standard chemotherapy, such as the lack of resistance to therapy and the lack of significant side effects on other normal tissues, with a better understanding of angiogenesis that these agents will continue to be investigated, especially in combination therapy. Only time will tell if the original great promise of AIs will be met.
Tobey MacDonald, M.D. is a pediatric oncologist and Director of Neuro-Oncology in the Aflac Cancer Center at Children’s Healthcare of Atlanta. He is also Professor Pediatrics at Emory University School of Medicine in Atlanta, GA. His research interests include childhood central nervous system tumors and interactions important to CNS tumor invasion and angiogenesis. He also finds time to serve on the Medical/Scientific Advisory Board of the Childhood Brain Tumor Foundation.
January 2020.