There are many etiologies for segmental bone loss in the maxillofacial and mandibular regions, but the vast majority of defects that require bone grafting arise from ablative cancer surgery. Although advances in surgical technique and plate technology have improved the functional and cosmetic restoration of these patients, there are still significant limitations that make a novel approach using osteoinductive molecules quite appealing. Bone morphogenetic protein-2 and -7 (BMP-2, -7) are morphogens known to stimulate bone regeneration through endochondral ossification. These proteins are commercially available and FDA-approved for orthopedic applications based on randomized clinical trials proving equivalence to autologous bone grafts but with the added advantage of avoiding a donor site. Preclinical data and limited patient experience suggest that this approach will also successfully regenerate bone in maxillofacial bone defects and it is the Principal Investigator's long term objective to use BMPs rather than bone grafts to reconstruct these defects. Very little is known about the biologic effects of BMPs on cancer, however. Preliminary work using three oral squamous carcinoma (OSCCA) cell lines suggests that tumor cell proliferation and secretion of proangiogenic molecules are unaffected by treatment with BMP- 2 and -7. The purpose of this application is to follow up on these results and study whether these BMPs activate specific molecular pathways in oral cancer cells and the consequence, if any, on in vivo tumor growth.
Specific Aim 1 will establish the potential relevance of BMPs in tumorigenesis by determining which pathway-related molecules are being expressed and determining whether the pathway is functional by examining activation of a downstream target gene.
Specific Aim 2 will study the in vivo biologic effects of stimulating or inhibiting the BMP-pathway on OSCCA using an orthotopic nude mouse model of oral cancer. The primary endpoint will be tumor growth, with secondary endpoints of local invasiveness, metastasis, and survival also being studied. The impact of baseline BMP expression on the observed biologic effects will be determined by using cell lines identified in Specific Aim 1 with unique BMP expression profiles. Relevance to Public Health: Patients with bone defects in the maxillofacial and mandibular areas suffer devastating functional (speech, swallowing), cosmetic, and emotional consequences. The limitations of current reconstructive options will likely be overcome by rapidly emerging bone regeneration approaches using a growth factor molecule called bone morphogenetic protein. This study will form the necessary foundation for determining if this molecule can be used safely in patients with defects caused by removal of oral cancers without stimulating the cancer cells to grow or become more aggressive. ? ? ?
| Kokorina, Natalia A; Lewis Jr, James S; Zakharkin, Stanislav O et al. (2012) rhBMP-2 has adverse effects on human oral carcinoma cell lines in vivo. Laryngoscope 122:95-102 |
| Kokorina, Natalia A; Zakharkin, Stanislav O; Krebsbach, Paul H et al. (2011) Treatment effects of rhBMP-2 on invasiveness of oral carcinoma cell lines. Laryngoscope 121:1876-80 |
