Abstract C001: Prospective use of the single mouse experimental design for evaluation of PLX038A against pediatric solid tumor models
Authors: Ghilu Samson , Li Qilin , Fontaine Shaun D , Santi Daniel V. , Kurmasheva Raushan T. , Zheng Siyuan , Houghton Peter J. 
Published: March 2020

Abstract
Purpose: In a previous analysis of &gt;2100 in vivo pediatric xenograft tumor/drug studies (Murphy et al. Cancer Research, 2016), we reported that results from one mouse/treatment group gave essentially similar results for 67 drugs as 10 mice (solid tumor models) or 8 mice (leukemia models). The use of fewer animals per treatment group allows for inclusion of more cancer models that more accurately represent genetic diversity within an histology or between histology’s. Further, this increase in genetic diversity allows for tumor sensitivity biomarker identification, either within a tumor type (e.g. neuroblastoma) or independent of tumor lineage. Here we have used the single mouse design to evaluate a nanoformulated camptothecin analog, PLX038A, where SN-38 (the active metabolite of irinotecan) is released at a controlled rate. Additional objectives of the study were to determine the relationship between initial tumor volume regression and Event-Free Survival (EFS), and to mine genomics data on each tumor model with a goal to identify potential biomarkers that relate to drug sensitivity. Experimental Procedures: Pediatric patient derived xenografts (PDX) were grown subcutaneously, and treatment was administered when tumors were ~300mm3(mean 297 ±34 mm3; range 260-370 mm3). Models tested included rhabdomyosarcoma (Rh10, Rh18, Rh28, Rh30, Rh30R, Rh41, Rh65), Wilms tumors (KT-5, KT-10, KT-11, KT-13); and non-CNS rhabdoid tumors (KT-12, KT-14, KT-16, RBD1, RBD2) and cell line-derived xenografts (Ewing sarcoma lines ES-1, ES-4, ES-5, ES-6, EW-8, CHLA258, TC-71, SK-NEP-1). New models include RBD1 an atypical teratoid rhabdoid tumor established from a metastatic lung lesion, NCH-EWS-1, a Ewing sarcoma from a lung lesion, and S12-6321 was established from a patient with metastatic pleiomorphic xanthoastrocytoma. All tumors were used at low passage and authenticated by STR analysis against reference profiles developed by this group. Tumor models were selected for testing without reference to genetic or molecular characteristics, or sensitivity to irinotecan in previous testing. PLX038A was administered one time at a dose of 120 umol/kg by intraperitoneal injection. For 13 models, with data for the single agent irinotecan (2.5 mg/kg daily x 5 with cycle repeated at day 21), the correlation between tumor responsiveness to PX038A and irinotecan was examined. Results: The activity of single-dose PLX038A was evaluable in 30/31 models. PLX038A induced &gt;50% volume regressions in 25 models (83%). EFS varied from 30 to &gt;120 days dependent on the xenograft model. For 13 tumor models having complete regression, EFS times varied from 38 to &gt;120 days, hence initial tumor volume regression correlated only modestly with EFS (r2= 0.453). Sensitivity to PLX038A was highly correlated with response to irinotecan (r2=0.729). Mutations in TP53BP1 were enriched in 6 sensitive tumor models compared to 4 resistant models. Conclusions: PLX038A was highly active in most xenograft models, and tumor sensitivity to PLX038A was highly correlated with sensitivity to irinotecan. Biomarkers that correlated with model sensitivity included wild type TP53, or mutant TP53 but with a mutation in TP53BP1, thus a defect in DNA damage response. These results support the value of the single mouse experimental design, and also support further development of PLX038 for pediatric clinical evaluation. Support: UO1CA199297, CA169368 and CA165995 (PJH) from NCI and CPRIT RR170055 (SZ).
Citation Format: Samson Ghilu, Qilin Li, Shaun D Fontaine, Daniel V. Santi, Raushan T. Kurmasheva, Siyuan Zheng, Peter J. Houghton. Prospective use of the single mouse experimental design for evaluation of PLX038A against pediatric solid tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C001. doi:10.1158/1535-7163.TARG-19-C001