A novel uterine leiomyosarcoma mouse model for therapeutic development

Title: A novel uterine leiomyosarcoma mouse model for therapeutic development PROJECT SUMMARY: Uterine leiomyosarcoma is an extremely rare but clinically aggressive uterine cancer arising from the smooth muscle of the uterus. Each year, it is estimated to occur in 6 out of every 1,000,000 women in the United States. The average age at diagnosis is 51 and women with uterine leiomyosarcomas have a poor prognosis. Current therapies for uterine leiomyosarcoma are not very effective and the primary treatment of uterine leiomyosarcoma are surgery. Due to the intrinsic rarity of this disease, prospective randomized clinical trials examining the outcome in individuals with uterine leiomyosarcoma is limited. Moreover, a poor understanding of the pathogenesis of this disease is also a major knowledge gap to develop effective treatment strategies. Thus, preclinical uterine leiomyosarcoma models that recapitulate the human disease is desperately needed to support clinical trial readiness. Homozygous p53 mutations and homozygous Pten deletion have been observed in approximately 61% and 19% human uterine leiomyosarcomas respectively, genetic mouse models with p53 homozygous mutations and homozygous deletion of Pten will be genetically relevant to the human disease. However, to generate homozygous p53 mutations with previously developed conditional Trp53 mutant allele (such as LSL p53-R172H) in mice is not feasible. It is because, mice with homozygous LSL p53-R172H allele are p53 null and will die of mainly lymphomas at 4-6 month of age. However, the Trp53wm-R172H and Trp53wm- R245W alleles, recently developed at our Institute, express functional wild-type p53 even in mice with homozygous genotype. Thus, these novel alleles allow homologous mutant p53 expression and Pten deletion to be generated upon Amhr2-Cre-mediated recombination. Our preliminary data showed that mouse with homozygous p53 mutation and homozygous deletion of Pten developed metastatic uterine leiomyosarcoma around 24 weeks of age. RNAseq and Gene Set Enrichment Analysis (GSEA) indicated that the gene expression of uterine leiomyosarcoma from these mice is like that of human uterine leiomyosarcoma. Thus, we propose to further understand the mechanism underlying the initiation and progression of uterine leiomyosarcoma using these mouse models, which will lead to more rational drug development and testing. Since p53 mutation and Pten deletion are also very common in other cancers, what we will learn from these mouse models will potentially benefit the study of other cancer with heterozygous or homozygous p53 mutations for therapeutic development.