Abstract 1231: Improving survival in pancreatic cancer using Doxorubicin in combination with L-DOS47

Abstract

BACKGROUND: The tumor microenvironment is acidic, which inhibits the activity of weakly basic drugs such as doxorubicin. In order to test whether neutralization of tumor acidity can improve survival in pancreatic cancer-bearing mice treated with doxorubicin, we tested doxorubicin in combination with L-DOS47. L-DOS47 is a novel therapy comprised of urease conjugated to an antibody against CEACAM6, which raises the pH in the tumor microenvironment by converting endogenous urea to NH3 and CO2. Our findings demonstrate that raising tumor pH with L-DOS47 can improve responses to chemotherapy. As L-DOS47 is currently in clinical testing for NSCLC, current study is clinically relevant. METHODS: Panc02 pancreatic cancer cell line (obtained from Emmanual Zervos, East Carolina University, Greenville, NC) was infected to express CEACAM6. 1 x 106 CEACAM6 Panc02 Clone were injected subcutaneously in the right flank of C57BL/6 mice. Four days later, tumor sizes were measured with calipers and mice were forcibly randomized into 3 groups (10 mice/ group). The 3 groups were treated with Doxorubicin only; L-DOS47 4 hours before Doxorubicin; and L-DOS47 24 hours before Doxorubicin. The rationale for different timings were that MRS measurements of tumor pH indicate that tumor alkalization has been observed both 4 and 24 hours following injection of L-DOS47. Treatments were begun immediately after randomization. Doxorubicin (2.5 mg/kg) was injected every 3-4 days and L-DOS47 (90 μg/kg) was injected either 4 or 24 hour prior to Doxorubicin i.v. RESULTS: All mice were humanely euthanized when tumors either reached 2000 mm3 (endpoint) or had serious ulcerations. For the tumors hadn’t reached to the endpoint due to serious ulcerations, times to reach the endpoint were estimated using a mathematical model that describes exponential tumor growth. Kaplan Meier survival curves were generated for each treatment group. According to Log-rank Mantel-Cox, Log-rank for trend, Gehan-Breslow-Wilcoxon test observed mice group survival was significantly different from each other (p<0.008 for all 3 tests). The probability of survival of mice group treated with L-DOS47 either 4 or 24 hours before doxorubicin was significantly better than doxorubicin only group. CONCLUSION: In this study we have observed that neutralizing tumor pH can improve the effect of chemotherapy in vivo. This is consistent with prior observations where neutralization with bicarbonate improved the response to chemotherapy via reversal of an ion-trapping effect [1]. The current work is significant, however, as L-DOS47 can be used clinically, whereas bicarbonate cannot. References: [1] Raghunand, N., Mahoney, B.P., and Gillies, R.J.: ‘Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents’, Biochem Pharmacol, 2003, 66, (7), pp. 1219-1229. Citation Format: Sultan Damgaci, Heman Chao, Marni D. Uger, Arig Ibrahim-Hashim, Eunjung Kim, Pedro Pedro M. Enriquez-Navas, Dominique Abrahams, Alexander R. Anderson, Albert Guvenis, Robert J. Gillies. Improving survival in pancreatic cancer using Doxorubicin in combination with L-DOS47 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1231.