Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma

作     者：Samson Ghilu Christopher L.Morton Angelina V.Vaseva Siyuan Zheng Raushan T.Kurmasheva Peter J.Houghton 

作者机构：Department of Molecular MedicineGreehey Children’s Cancer Research InstituteUT HealthSan AntonioTX 78229USA Department of SurgerySt.Jude Children’s Research HospitalMemphisTN 38105USA Department of Epidemiology and BiostatisticsGreehey Children’s Cancer Research InstituteUT HealthSan AntonioTX 78229USA 

出 版 物：《Cancer Drug Resistance》 (癌症耐药（英文）)

年 卷 期：2022年第5卷第1期

页      面：80-89页

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by CA23099 NO1-CM42216 UO1CA199297 RO1CA169368 PO1CA165995 and CPRIT RP160716 

主　　题：Rhabdomyosarcoma patient-derived xenografts combination therapy intrinsic drug resistance acquired drug resistance 

摘      要：Aim:Despite aggressive multiagent protocols,patients with metastatic rhabdomyosarcoma(RMS)have poor *** a recent high-risk trial(ARST0431),25% of patients failed within the first year,while on therapy and 80% had tumor progression within 24 ***,the mechanisms for tumor resistance are essentially *** we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ***:A Single Mouse Testing(SMT)protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine,actinomycin D,cyclophosphamide(VAC)*** response was determined by caliper measurement,and tumor regression and event-free survival(EFS)were used as endpoints for *** tumors at regrowth were transplanted into recipient mice,and the treatment was repeated until tumors progressed during the treatment period(i.e.,became resistant).At transplant,tumor tissue was stored for biochemical and omics ***:The sensitivity to VAC of 34 RMS models was *** varied from 3 weeks to20 *** models were classified as having intrinsic resistance,intermediate sensitivity,or high sensitivity to VAC *** to VAC was developed in multiple models after 2-5 cycles of therapy;however,there were examples where sensitivity remained unchanged after 3 cycles of ***:The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS *** such,it provides a platform for assessing in vivo drug resistance mechanisms at a“populationlevel,simulating conditions in vivo that lead to clinical *** VAC-resistant models represent“high-risktumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.