Abstract 4129: An isolation strategy for biomarkers that predict cancer relapse after 5-FU based adjuvant chemotherapy

Abstract

Abstract [Background] Adjuvant chemotherapy based on 5-FU has been a mainstay of postoperative treatment for the majority of cancers arising in the gastrointestinal tract. Although adjuvant chemotherapy has shown a favorable success rate, there are still considerable numbers of patients who experience cancer relapse following this therapy. Therefore, being able to predict chemosensitivity with data backed by solid molecular evidence would allow us to select biologically reasonable drugs, as well as to avoid adverse effects in those patients who may fail to benefit from chemotherapy. [Materials and Methods] Several candidate markers have been isolated based on the drug-protein association from a “chemosensitivity and protein expression matrix” obtained by a “conventional chemosensitivity assay for 12 drugs” and a “quantitative lysate array for 50 proteins” using a panel of 12 cancer cell lines. The panel of candidate proteins was examined by immunohistochemistry and tissue microarrays of 79 gastrointestinal cancer cases treated with 5-FU based adjuvant chemotherapy after curative operation. A functional assay by siRNA gene knockdown was also performed to confirm whether the protein expression actually affects the chemosensitivity. [Results] The 79 gastrointestinal cancer patients who underwent a curative operation followed by 5-FU based adjuvant chemotherapy were investigated by clinicopathological study and immunohistochemistry. Among the candidate proteins measured in these 79 patients, expression of nuclear NFκB showed a significant association with cancer relapse (median observation period, 2.8 years; p<0.0001, Fisher's exact test). A Kaplan-Meier estimation confirmed that the time to relapse (TTR) was significantly shorter for patients who were positive for nuclear NFκB expression-positive than for negative cases (p<0.0001, Log-Rank test). In a subset analysis, in terms of cancer lesions, the nuclear expression of NFκB showed stronger discriminatory power in predicting the relapse of gastric cancer than of colon cancer. A functional validation study using gene knockdown of NFκB by siRNA revealed increased chemosensitivity for 5-FU in the gastric cancer cell line, MKN45 (p<0.05, t-test). [Discussion] Candidate biomarkers were isolated using a quantitative “chemosensitivity and protein expression matrix,” which has been used for small molecule screening in anti-cancer drug discovery. In the present study, we adopted the technologies using clinically “approved” drugs to predict chemosensitivity in terms of cancer relapse. Our results indicate that nuclear expression of NFκB may be a good marker for consideration of alternative adjuvant chemotherapeutic regimens for post-operative gastrointestinal cancer patients immediately after the operation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4129. doi:10.1158/1538-7445.AM2011-4129