Axitinib sensitization of high Single Dose Radiotherapy

Abstract

Background and purpose Single Dose Radiation Therapy (SDRT) provides remarkably high rates of control even for tumors resistant to fractionated radiotherapy. SDRT tumor control depends on acute acid sphingomyelinase-mediated endothelial cell injury and monoclonal antibodies targeting Vascular Endothelial Cell Growth Factor (VEGF) signaling radiosensitized tumor endothelium when delivered immediately prior to irradiation. Here we evaluate the ability of the oral VEGF receptor inhibitor, axitinib, to sensitize tumor endothelium and increase tumor control with SDRT. Methods and materials Axitinib was added to primary cultured endothelial cells, or administered orally to Sv129/BL6 mice bearing radiosensitive MCA/129 sarcoma or radioresistant B16F1 melanoma flank tumors, followed by SDRT. Endothelial apoptosis was assessed by TUNEL assay or bis-benzamide staining. Mice with irradiated tumors were followed for 90 days to evaluate the impact of axitinib on SDRT tumor control. Results Pre-treatment with axitinib increased acute endothelial cell apoptosis following SDRT in vitro, and in vivo for both MCA/129 and B16F1 tumors. Axitinib correspondingly increased SDRT tumor growth delay and complete response rate (by 40%) for both tumors. Administration precisely 1 h before SDRT was critical for radiosensitization. Conclusions Axitinib radiosensitizes tumor endothelial cells and enhances tumor cure with SDRT, which may permit dose de-escalation and significantly expand the range of clinical indications for SDRT.

HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas

“…Whereas for heavy ion irradiation and hyperthermia in combination with photon irradiation the clinical results are promising [33,36], the efficacy of combined radiochemotherapy is controversially discussed and comes at the costs of accumulating side effects [37,38]. Additionally, molecularly targeted approaches of radiosensitization with protein kinase, mammalian target of rapamycin (mTOR), and histone deacetylase (HDAC) inhibitors have been developed in preclinical studies and are currently undergoing clinical evaluation [39][40][41][42][43][44]. HSP90 inhibition in general appears as a very attractive means of radiosensitization, since it can target multiple HSP90 client proteins orchestrating radioresistance and other characteristics of the malignant phenotype, including angiogenesis, invasiveness and metastasis, at the same time [28,30,45,46].…”

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

“…Rao et al [49] explored axitinib with single-dose RT in vitro and in vivo; an increased tumor growth delay and complete response was recorded mainly when axitinib was given 1 h before RT to treat sarcoma or radioresistant melanoma cells.…”

Outcomes and toxicity of radiotherapy for refractory bone and soft tissue sarcomas

“…Targeted agents, including vascular endothelial growth factor inhibitors, were recently reported to show efficacy in sarcoma when combined with RT (22,23). Doses >10 Gy likely produce secondary cell elimination due to enhanced vascular damage (20,21).…”