Abstract LB-B12: Pediatric Preclinical Testing Consortium evaluation of 4’-thio-2’-deoxycytidine (TdCyd) and 5-aza-4’-thio-2’-deoxycytidine (Aza-TdCyd)
Authors: Teicher Beverly A. , Lock Richard B. , Collins Jerry M. , Gorlick Richard , Kolb E. Anders , Houghton Peter J. , Kurmasheva Raushan T. , Li Xiao-Nan , Erickson Stephen W. , Guo Yuelong , Evans Kathryn , Qi Lin , Smith Malcolm A. 
Published: August 2018

Abstract
Introduction: TdCyd and Aza-TdCyd are thionucleoside analogues that are incorporated into DNA and that reduce levels of DNMT1. TdCyd is under evaluation for adults with cancer, and clinical evaluation of aza-TdCyd is planned. Methods: TdCyd was tested at doses of 1-4 mg/kg administered by the intraperitoneal (IP) route daily x 5, repeated weekly x 4 (or repeated weekly x 2, repeated at day 21). Aza-TdCyd was tested using doses of 1-2 mg/kg administered IP daily x 5 repeated weekly x 3-4. For solid tumor experiments, events were defined as 4X increase in tumor volume from treatment day 0, for acute lymphoblastic leukemia (ALL) experiments as the proportion of human CD45+ cells in the peripheral blood exceeding 25%, and for brain tumor experiments as animals becoming moribund or developing severe neurologic deficit. The Kaplan-Meier method was used to compare time-to-event between treated and control groups. The objective response categories are progressive disease (PD, which is subdivided into progressive disease without and with growth delay, PD1 and PD2 respectively), stable disease (SD), partial response (PR), complete response (CR), and maintained complete response (MCR) [Houghton PJ, et al. Pediatr Blood Cancer 2007;49:928-40]. TdCyd and Aza-TdCyd were provided for testing by NCI. Results: Aza-TdCyd was tested against 21 xenografts: ALL (9), osteosarcoma (4), rhabdomyosarcoma (1), Ewing sarcoma (1), glioblastoma (3) and medulloblastoma (3). Tolerability for Aza-TdCyd varied by tumor panel and host mouse strain. ALL-bearing xenografts in NSG mice showed high toxicity at 2 mg/kg, with some reduction in toxicity at 1.5 mg/kg. All evaluable leukemia-bearing animals treated with Aza-TdCyd achieved MCR. For the three xenograft lines with more than 75% evaluable animals, EFS was extended 6- to 14-fold compared to control, with leukemia recurrence delayed &gt; 5 weeks from treatment cessation. For non-CNS solid tumor xenografts, there were no objective responses, but an osteosarcoma and a rhabdomyosarcoma xenograft showed pronounced slowing of tumor growth with &gt; 2-fold prolongation in EFS compared to control. Prolongation in median time to event compared to controls for the glioblastoma and medulloblastoma xenografts tested was small, ranging from 0.83- to 1.58-fold. TdCyd was evaluated against 22 xenograft lines, most overlapping with those tested against Aza-TdCyd. TdCyd was well tolerated when dosed at 1-2 mg/kg. None of the xenografts studied showed objective responses to TdCyd, and the greatest prolongation of EFS compared to control was only 2.3-fold among the ALL xenografts and only 1.5-fold among the solid tumor/CNS xenografts. Conclusions: Aza-TdCyd showed impressive remission-inducing activity for ALL xenografts at 1.5-2.0 mg/kg, but high toxicity was also observed. No solid tumor xenografts showed consistent tumor regression to Aza-TdCyd, but an osteosarcoma and a rhabdomyosarcoma xenograft showed pronounced control of tumor growth. TdCyd showed little activity across solid tumor and ALL xenografts at the dose/schedules evaluated. Future plans include additional testing of sarcoma and renal tumor models and Aza-TdCyd dose-response determination for select ALL xenograft lines. (Supported by NCI Grants: CA199222; CA199221; CA199297; CA199288; CA199000)
Citation Format: Beverly A. Teicher, Richard B. Lock, Jerry M. Collins, Richard Gorlick, E. Anders Kolb, Peter J. Houghton, Raushan T. Kurmasheva, Xiao-Nan Li, Stephen W. Erickson, Yuelong Guo, Kathryn Evans, Lin Qi, Malcolm A. Smith. Pediatric Preclinical Testing Consortium evaluation of 4’-thio-2’-deoxycytidine (TdCyd) and 5-aza-4’-thio-2’-deoxycytidine (Aza-TdCyd) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B12.