The role of p53 in combination radioimmunotherapy with 64Cu- DOTA-cetuximab and cisplatin in a mouse model of colorectal cancer

Yunjun Guo, Jesse J. Parry, Richard Laforest, Buck E. Rogers, Carolyn J. Anderson

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Radioimmunotherapy has been successfully used in the treatment of lymphoma but thus far has not demonstrated significant efficacy in humans beyond disease stabilization in solid tumors. Radioimmunotherapy with 64Cu was highly effective in a hamster model of colorectal cancer, but targeted radiotherapies with this radionuclide have since not shown as much success. It is widely known that mutations in key proteins play a role in the success or failure of cancer therapies. For example, the KRAS mutation is predictive of poor response to anti-epidermal growth factor receptor therapies in colorectal cancer, whereas p53 is frequently mutated in tumors, causing resistance to multiple therapeutic regimens. Methods: We previously showed that nuclear localization of 64Cu-labeled DOTA-cetuximab was enhanced in p53 wild-type tumor cells. Here, we examine the role of p53 in the response to radioimmunotherapy with 64Cu-DOTA-cetuximab in KRAS-mutated HCT116 tumor-bearing mice, with and without cisplatin, which upregulates wild-type p53. Results: Experiments with HCT116 cells that are p53 +/+ (p53 wild-type) and -/- (p53 null) grown in cell culture demonstrated that preincubation with cisplatin increased expression of p53 and subsequently enhanced localization of 64Cu from 64Cuacetate and 64Cu-DOTA-cetuximab to the tumor cell nuclei. Radioimmunotherapy studies in p53-positive HCT116 tumor-bearing mice, receiving either radioimmunotherapy alone or in combination with cisplatin, showed significantly longer survival in mice receiving unlabeled cetuximab or cisplatin alone or in combination (all, P < 0.01). In contrast, the p53-negative tumor-bearing mice treated with radioimmunotherapy alone or combined with cisplatin showed no survival advantage, compared with control groups (all, P > 0.05). Conclusion: Together, these data suggest that 64Cu specifically delivered to epidermal growth factor receptor-positive tumors by cetuximab can suppress tumor growth despite the KRAS status and present opportunities for personalized clinical treatment strategies in colorectal cancer. COPYRIGHT

Original languageEnglish
Pages (from-to)1621-1629
Number of pages9
JournalJournal of Nuclear Medicine
Volume54
Issue number9
DOIs
StatePublished - Sep 1 2013

Keywords

  • Colorectal cancer
  • KRAS mutation
  • Radioimmunotherapy

Fingerprint

Dive into the research topics of 'The role of p53 in combination radioimmunotherapy with 64Cu- DOTA-cetuximab and cisplatin in a mouse model of colorectal cancer'. Together they form a unique fingerprint.

Cite this