TY - JOUR T1 - Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1239 LP - 1245 DO - 10.2967/jnumed.115.157362 VL - 56 IS - 8 AU - Vessela Vassileva AU - Vineeth Rajkumar AU - Mario Mazzantini AU - Mathew Robson AU - Adam Badar AU - Surinder Sharma AU - Erik Årstad AU - Daniel Hochhauser AU - Mark F. Lythgoe AU - Geoffrey M. Boxer AU - Rosmund Barbara Pedley Y1 - 2015/08/01 UR - http://jnm.snmjournals.org/content/56/8/1239.abstract N2 - Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized 131I-labeled anti-carcinoembryonic antigen antibody (131I-huA5B7), with cetuximab in colorectal cancer (CRC). Methods: Three human CRC cell lines—SW1222, LoVo, and LS174T—were used to generate subcutaneous xenografts, and stably luciferase-transfected SW1222 cells were used to establish a model of hepatic metastases in immunocompromised mice. Imaging and biodistribution studies were conducted to confirm the selective tumor localization of 131I-huA5B7. Efficacy was evaluated on the basis of tumor growth delay and survival, along with markers of DNA damage response, cell cycle, proliferation, and apoptosis. Results: Selective tumor targeting was achieved with 131I-huA5B7 alone or in combination with cetuximab without observable toxicity. Compared with monotherapy, combining cetuximab with radioimmunotherapy significantly and synergistically reduced tumor growth and prolonged survival of mice in 2 of the subcutaneous and in the metastatic tumor model. Evidence of DNA damage, G2/M arrest, significantly decreased proliferation, and increased apoptosis were observed with radioimmunotherapy and the combination therapy. However, a significant decrease in DNA-protein kinase expression with the combination regimen suggests that the addition of cetuximab suppressed DNA repair. Conclusion: Our results demonstrate enhanced therapeutic efficacy with the combination of cetuximab and radioimmunotherapy in CRC, which could potentially translate into successful clinical outcomes. This strategy could improve the treatment of residual disease postoperatively and ultimately prevent or delay recurrence. Furthermore, other carcinoembryonic antigen–expressing malignancies could also benefit from this approach. ER -