For childhood rhabdomyosarcoma (RMS), a tumor demonstrating characteristics of skeletal muscle lineage, survival has not changed significantly in over two decades. In a recent high-risk clinical trial (ARST0431) 25% of… Click to show full abstract
For childhood rhabdomyosarcoma (RMS), a tumor demonstrating characteristics of skeletal muscle lineage, survival has not changed significantly in over two decades. In a recent high-risk clinical trial (ARST0431) 25% of patients progressed during 52 weeks of chemo-radiation treatment, and 80% had tumor recurrence or progression within 24 months. Two drug modules comprise the core for treatment: VAC (vincristine, actinomycin-D, cyclophosphamide) and VI (vincristine, irinotecan). However, the molecular basis for intrinsic or acquired resistance to these combinations is poorly understood.To simulate clinical heterogeneity of RMS, we have developed 40 PDX/CDX xenograft models and using Single Mouse Testing (SMT) have characterized the sensitivity of each model to individual agents and to VAC/VI combinations. Tumor volume regression and Event-Free Survival (EFS) were used to assess chemosensitivity. To select for acquired resistance, tumor bearing mice were treated with one cycle of VAC or VI, tumor was transplanted upon regrowth when volume reached 400% of that on day 1 of treatment. The process was repeated for up to 5 cycles of therapy. Development of resistance was measured by decreased EFS and tumor progression during treatment. Parental and isogenic lines with acquired resistance were snap frozen for DNA and RNA sequencing. Sensitivity for each tumor models was assessed by EFS for treated vs untreated tumor and probability plotted against time (days) after initiating treatment. Each single agent significantly extended EFS compared to control EFS (P<0.001), consistent with known clinical activity. Of note VAC and VI combinations had greater than additive EFS (e.g. EFSVAC>>EFSvincristine + EFSactD + EFScyclophosphamide). The sensitivity of the 40 xenograft models to VAC ranged from Progressive Disease with EFS <42 days to Maintained Complete Response at 140 days. A similar range in sensitivity to VI was observed also, but the correlation between sensitivity to VAC and VI was poor (r=0.375) indicating greater sensitivity of a model to one combination than the other. Ten lines have been selected in vivo for acquired resistance to VAC and VI. Resistance was developed between cycle 2 and cycle 5 of treatment with a mean decrease in EFS of 65 +/- 15% compared to the EFS on drug cycle 1. In summary, we have characterized the sensitivity of 40 RMS xenograft models to single agents and VAC/VI combinations and have developed 20 models with acquired resistance to these combinations. Tumor tissue has been obtained from all 40 models and from 20 models with acquired drug resistance. Sequencing of these models is ongoing and preliminary results will be presented. Supported by 1 UO1 CA263981-01. Citation Format: Samson Ghilu, Peter J. Houghton, Siyuan Zheng, Raushan T. Kurmasheva. Characterization of sensitivity to single agents and combination treatments (VAC and VI) and development of acquired resistance in childhood rhabdomyosarcoma xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1680.
               
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