Introduction: For head and neck cancer survivors, radiotherapy (XRT) improves survivorship at a cost of impaired quality of life. XRT-induced pathologic fractures (fxs) and associated nonunions are devastating iatrogenic sequelae associated with microvascular damage in bone, yet there are no pharmacologic strategies to prevent or treat these maladies. Deferoxamine (DFO), an FDA-approved iron chelator, has been extensively investigated for its ability to promote tissue vascularization through upregulation of the HIF-1α pathway. Our laboratory has previously demonstrated improved fx healing and prevention of nonunions in radiated bone utilizing localized DFO administration. However, the role of DFO in head and neck squamous cell carcinoma (HNSCC) tumorigenesis is currently unknown. While iron is essential for normal cell proliferation, excessive iron is associated with multiple oncogenic pathways. Thus, localized iron chelation may have beneficial antitumorigenic properties. Elucidating the role of iron metabolism and correlations between iron chelation and angiogenic signaling may offer opportunities for diagnostic and treatment purposes, while simultaneously improving tissue engineering efforts for HNSCC survivors.

Methods: We surveyed the UALCAN survivorship data base for iron-related genes in HNSCC. In vitro, established MDA1986 (HPV+) and UMSCC108 (HPV-) cell lines were grown in culture. The effects of DFO were probed on 3-D tumorspheres. HIF-1α was examined by IHC, and Western blot (WB) was used to elucidate iron mediators. In vivo, MDA-1986 buccal xenografts were developed in Nu/Nu mice. Control, DFO, and XRT groups were generated, and DFO and XRT were administered as previously described. IVIS imaging and tumor volumes were used to monitor growth. UALCAN data guided the selection of iron-regulatory proteins identified by WB in excised tumors.

Results: TFRC and FTH-1 were highly upregulated, suggesting that dysregulation of iron metabolism contributes to HNSCC development. In vitro, we observed a dose-dependent decrease in 3-D tumorsphere formation and no alterations in HIF-1α expression. WB demonstrated TFRC downregulation in response to 100µM DFO in both HPV+ and - cells. In vivo, a significant decrease in tumor growth and radiance was observed with DFO treatment (comparable to XRT) when compared to untreated controls. Excised tumor WB demonstrated downregulation of TFRC, identifying it as a pivotal indicator of response to iron-chelation therapy.

Conclusion: In vitro and in vivo studies reveal that DFO exhibits antitumorigenic effects, and suggest that HIF-1α is not affected by iron chelation in HNSCC cells. Moreover, TFRC was identified as a biomarker for indicating treatment response. Our findings signify that localized DFO may have antitumorigenic effects, in addition to the previously established regenerative therapeutic effects for the treatment of XRT-induced bone pathologies.

Citation Format: Alexis Donneys, Chitra Subramanian, Jeremy Lynn, Kevin Urlaub, Kevin Kovatch, Halil S. Uygur, Mark S. Cohen, Steven R. Buchman. The propitious dual roles of deferoxamine in head and neck cancer management [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2911.