Abstract 1222: Caspase mediated prodrugs RGDEVD-DOX with EMC-DEVD-S-DOX in combination with anti PD-1 antibody for triple negative breast cancer
Authors: Kim Ha Rin , Chung Seung Woo , Cho Youngseok , Byun Youngro 
Published: August 2019

Here we suggest a new effective strategy to overcome tumor heterogeneity for eradicating metastatic triple negative breast cancer (TNBC). As a first strategy, we applied a combination therapy of caspase-3 mediated “targeting” (RGDEVD-DOX) and “maintaining” (EMC-DEVD-S-DOX) prodrugs, given in a sequential manner. RGDEVD-DOX is designed to target integrin αvβ3 and induce apoptosis specifically in tumor cells. EMC-DEVD-S-DOX binds to circulating albumin after administration to show enhanced half-life and accumulates at tumor site. In the apoptotic tumor tissue, caspase-3 releases free doxorubicin from the prodrug and this induces indiscriminate killing of surrounding tumor cells regardless of the integrin αvβ3 expression, resulting in continuous activation of prodrug. As another strategy, RGDEVD-DOX, by specifically targeting tumor cells, shows minimal systemic immunosuppression unlike conventional doxorubicin therapy and we expect that its immunomodulatory effects can synergize the therapeutic benefit of αPD-1 antibody. In order to determine the efficacy of RGDEVD-DOX and EMC-DEVD-S-DOX combination, we performed in vivo efficacy test using two TNBC xenograft models. In case of MDA-MB-231 and 4T1 xenograft models, combination therapy showed 80% (p=0.0006) and 75% (p&lt;0.0001) of tumor growth inhibition respectively compared the control group. In order to evaluate the anti-metastatic effect of combination therapy, we prepared TNBC metastasis model. We found that the combination therapy significantly attenuated metastatic incidence compared to monotherapy groups. This result implies that RGDEVD-DOX targets metastatic tumor and EMC-DEVD-S-DOX maintains the anti-metastatic effects in a consecutive fashion. To identify a synergistic effect of RGDEVD-DOX combining immunotherapy, we carried out combination therapy of αPD-1 and RGDEVD-DOX in TNBC mouse model. We assessed the tumor inhibition and evaluated anti-metastatic effect in lung by measuring bioluminescence intensity of 4T1-Luciferase cells. We found that the combination therapy exerted not only inhibitory effect of primary tumor but also anti-metastatic effect. In conclusion, we verified that combination therapy of RGDEVD-DOX with EMC-DEVD-S-DOX or αPD-1 showed synergistic effect in TNBC mouse model. We demonstrate that the sequential combination therapy successively reduces the incidence of metastasis and prolongs survival in TNBC model. Collectively, we propose that RGDEVD-DOX is a promising caspase-3 mediated prodrug in respect of overcoming tumor heterogeneity and stimulating a tumor-specific immune response, which can synergize the efficacy of immunotherapy.

Citation Format: Ha Rin Kim, Seung Woo Chung, Youngseok Cho, Youngro Byun. Caspase mediated prodrugs RGDEVD-DOX with EMC-DEVD-S-DOX in combination with anti PD-1 antibody for triple negative breast cancer [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 1222.