Use of Antiangiogenic Therapies in Pediatric Solid Tumors

Abstract

Cancer is an important cause of death in childhood. In recent years, scientists have made an important effort to achieve greater precision and more personalized treatments against cancer. But since only a few pediatric patients have identifiable therapeutic targets, other ways to stop the neoplastic cell proliferation and dissemination are needed. Therefore, the inhibition of general processes involved in the growth and behavior of tumors can be a relevant strategy for the development of new cancer therapies. In the case of solid tumors, one of these processes is angiogenesis, essential for tumor growth and generation of metastases. This review summarizes the results obtained with the use of antiangiogenic drugs in the main pediatric malignant solid tumors and also an overview of clinical trials currently underway. It should be noted that due to the rarity and heterogeneity of the different types of pediatric cancer, most studies on antiangiogenic drugs include only a small number of patients or isolated clinical cases, so they are not conclusive and further studies are needed.

Keywords: angiogenesis; antiangiogenic drugs; cancer; childhood; pediatric; solid tumors; therapy.

Figure 1

Main target signaling pathways of antiangiogenics. VEGF was the first signaling pathway inhibited by antiangiogenic drugs. Unfortunately, the benefits of anti-VEGF/VEGFR are limited and patients develop resistance. Therefore, drugs were developed that inhibit alternative signaling pathways such as FGF and PDGF. Multikinase inhibitors (MKIs) simultaneously target different components of these pathways. HGF and its receptor c-Met can also be inhibited by antiangiogenics. The angiopoietin pathway can be inhibited by preventing it traditional signaling through Tie2 or through integrins. There are also antiangiogenic drugs against TGF-β and its receptors ALK1 and endoglin.

Figure 2

Active clinical trials that use antiangiogenic drugs in childhood cancer. The ClinicalTrial.gov database has 359,094 registered clinical trials at the time of this submission. If these trials are filtered by condition or disease (cancer) and other terms (antiangiogenic), the number is reduced to 3839. If only trials involving children (child: birth–17 years) and those that are active are selected, there are 225 clinical trials. After manually eliminating trials that include only adults, that are not solid tumors, and that do not use antiangiogenic treatments, there are 38 trials. Most of these study brain tumors, but there are also trials that include soft-tissue sarcomas, bone sarcomas, neuroblastomas, or others. Seven of the 38 trials allow the inclusion of patients with different types of cancer. In relation with antiangiogenics used, most trials use bevacizumab combined with other treatments, but there are also others directed against alternative proangiogenic pathways such as sunitinib, sorafenib, and pazopanib. Metronomic therapy, thalidomide, and its derivatives are also studied in the current clinical trials.