Nearly every child that is exposed to radiotherapy for the management of pediatric head and neck cancer develops some degree of craniofacial hypoplasia (bone growth inhibition). This is a devastating, deforming disease that has lasting implications on quality of life and social adaptation. Reconstructive surgery remains the only corrective option for these children. However, these operations are exceedingly challenging due to the unwanted iatrogenic damage that radiation exposure imparts on adjacent tissues. While it is commonly known that radiation imparts its injury to bone through mechanisms of vascular diminution, cellular depletion and osteoblast injury, no pharmacologic interventions currently exist to help remediate these processes. The goal of this proposal is to specifically address vascular diminution in the formation of craniofacial hypoplasia. Radiation disrupts neovascularization (new blood vessel formation) and existing bone microvasculature causing vessel thrombosis, decreased vascular density and obliteration of small blood vessels that progressively worsens over time. Radiated bone demonstrates reduced mechanical strength and atrophy due to increased bone resorption and decreased osteogenesis.
Our central hypothesis is that vascular diminution occurring during the development of craniofacial hypoplasia can be quantified and restored utilizing pharmacotherapeutics that stimulate neovascularization.
Aim 1. We will quantify the degree by which radiation impedes angiogenesis in vitro, and elicits microvascular diminution in vivo. In vitro we will utilize angiogenic live cell imaging to quantify endothelial cell (HUVEC) differentiation and tubule formation after sequentially increased radiation dose exposure. In vivo we will utilize a clinically-relevant model of radiation-induced craniofacial hypoplasia in the infant rat exposed to three sequentially increased doses of radiation. Bone growth inhibition and microvascular diminution will be quantified with longitudinal µCT imaging and microangiography after vessel perfusion.
Aim 2. We will determine whether therapeutic stimulation of angiogenesis can promote neovascularization and prevent craniofacial hypoplasia in the aftermath of radiation injury. Radiation damages existing vascularity; hence we believe that targeting new blood vessel formation will facilitate osteogenesis despite the effects of radiation. Three angiogenic therapies with varying mechanisms of action will be observed in vitro in irradiated HUVECs, and in vivo in our animal model as previously described.
While radiotherapy is a necessary component for nealy all pediatric head and neck cancers, its unwanted negative effects on bone development last a lifetime. Successful completion of these studies will demonstrate whether targeting angiogenesis is a viable therapeutic option for preventing deforming craniofacial hypoplasias secondary to radiation exposure.