Abstract 5470: Blocking wound-induced tumor repopulation between chemotherapy cycles as a novel approach to abrogate chemoresistance

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Acquired chemoresistance remains a major clinical issue in the management of advanced solid cancers. Initial response to cytotoxic chemotherapy is common, but certain patients progressively become unresponsive after multiple chemotherapy cycles. While causes of drug resistance are multiple and complex, here we approach this problem from a new angle: we studied whether repopulation of residual surviving cancer cells between chemotherapy cycles contributes to progressive chemoresistance. Currently the identity of repopulating cancer cells following chemotherapy is unknown, and the underlying molecular mechanisms that initiate tumor repopulation remain poorly understood. In the present study we use bladder cancer as a model and report that quiescent cancer stem cells (CSCs) are unexpectedly recruited to proliferate and repopulate residual tumors in response to chemotherapy-induced damage. This phenomenon is similar to how normal resident tissue stem cells mobilize to wound sites for tissue repair. We further investigate whether blockade of this wound-induced CSC repopulation can provide an innovative approach to abrogate chemoresistance. Previously we showed that cytokeratin 14 (CK14) marks the most primitive bladder cancer cells and abundance of CK14+ cancer cells in patients correlates with poor survival. Here, we followed the standard clinical chemotherapy regimen with gap periods to allow recovery of normal tissues between treatment cycles. While one cycle of gemcitabine and cisplatin effectively reduced tumor growth in vivo, a generalized expansion of CK14+ CSCs occurred in residual tumors during these gap periods between cycles. Further analysis revealed the induction of a “wound-response” gene signature in residual tumors and active recruitment of quiescent CSCs into proliferation in response to chemotherapy-induced damage. We demonstrated that prostaglandin E2 (PGE2) released by neighboring dying cancer cells could induce CSC expansion in a paracrine manner. This undesirable CSC expansion could be abrogated by a PGE2 neutralizing antibody and Celecoxib, an FDA approved COX2 inhibitor that blocks PGE2 signaling. In vivo administration of Celecoxib blocked the induction of “wound-response” gene signature and significantly attenuated progressive development of chemoresistance in xenograft tumors, including primary xenografts derived from a patient who failed chemotherapy.These results revealed a new mechanism by which CSCs contribute to therapeutic resistance via repopulating residual tumors between chemotherapy cycles. Repopulation was initiated by dying cells that induced wound response and recruitment of CSCs to repair chemotherapy-induced damages. Therapeutic intervention with Celecoxib effectively blocked this process and improved chemotherapeutic response in bladder tumors, supporting further validation in other solid cancers. Citation Format: Antonina V. Kurtova, Jing Xiao, Qianxing Mo, Senthil Pazhanisamy, Ross Krasnow, Seth P. Lerner, Fengju Chen, Terrence Roh, Erica Lay, Philip L. Ho, Keith S. Chan. Blocking wound-induced tumor repopulation between chemotherapy cycles as a novel approach to abrogate chemoresistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5470. doi:10.1158/1538-7445.AM2015-5470