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.