Abstract 2963: A novel uterine leiomyosarcoma mouse model

Abstract

Abstract 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 is 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, a preclinical uterine leiomyosarcoma models that recapitulate the human disease is desperately needed to support clinical trial readiness. Since both p53 mutations and Pten homozygous deletion have been observed in 61% and 64% human uterine leiomyosarcomas respectively [3], we are generating genetic mouse models with Amhr2-Cre Ptenfl/fl p53R245Wfl/fl (homozygous p53 mutation), Amhr2-Cre Ptenfl/fl p53R245Wfl/+ (heterozgyous p53 mutation) and Amhr2-Cre Ptenfl/fl (control) genotypes. Our unpublished preliminary data showed that mouse with homozygous p53 mutation and homozygous deletion of Pten developed metastatic uterine leiomyosarcoma at 24 weeks of age with 100% penetrance. However, mouse with heterozygous p53 mutation and homozygous deletion of Pten did not develop uterine leiomyosarcoma at the age of 24 weeks. From the public available human uterine leiomyosarcoma RNAseq data, 80% of those tumors with p53 mutations had homozygous mutations. Previous mouse model with homozygous deletion of p53 gene and/or BRCA1 with Amhr2-Cre only had uterine leiomyosarcoma developed in approximately 50% of mice around 13 months without metastasis. RNAseq and RPPA functional data of the uterine leiomyosarcomas from our novel mouse models are being generated for comparison with known genomic profiles of human uterine leiomyosarcomas. The RNAseq and RPPA functional proteomic data from comparing uterine tissues from homozygous and heterozygous p53 mutated mice provide insight in the understanding the development of uterine leiomyosarcoma and for future clinical trials. Citation Format: Chun Wai Ng, Kwong-Kwok Wong. A novel uterine leiomyosarcoma mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2963.