[R01] Preclinical mouse models of liposarcoma for immuno-oncology applications
Ente: National Cancer Institute
Scadenza: 2031-07-31
Importo max: 609.997 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Liposarcoma (LPS) is type of soft tissue sarcoma (STS) which arises in adipose tissues. The most common
subtypes are well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma, which are both
characterized by alterations in p53 function due to either genomic amplification of MDM2, which encodes a
negative regulator of p53 (over 90% of cases), or TP53 mutation (7% of cases). While surgical resection is the
most effective treatment option, patients have high rates of recurrence and distant metastasis. Patients with
metastatic disease have a poor overall survival of only 12-15 months due to the low response rates to systemic
chemotherapy. While immunotherapy has shown tremendous efficacy in several types of solid tumors, research
focusing on the immune biology of sarcoma has been limited given the rarity of the disease with limited availability
of human samples and lack of immunocompetent mouse models. To address this need, we have developed an
innovative, immunocompetent, genetically-engineered mouse model of LPS. This model is driven by adipocyte-
specific Cre recombinase, facilitating targeted deletion of Pten and Trp53. These mice, designated ACPP,
reliably develop tumors that mimic human liposarcoma based on histology, transcriptome analysis, and biological
behavior. Preliminary findings also indicate that this model replicates the heterogeneity of human DDLPS tumors
in that about 20% have high tumor infiltrating lymphocytes. We also generated syngeneic cell lines from three
independent DDLPS ACPP tumors which produce tumors with 100% penetrance as orthotopic allografts in
C57BL/6 mice. In preliminary studies, we show tumor inhibition and intratumoral T cell changes within the tumor
microenvironment in one of the cell line allografts following using anti-PD1 immunotherapy, which we do not see
with the other two cell lines. These preliminary findings support our ability to develop a panel of DDLPS cell lines
with biological heterogeneity as seen in patients. In this proposal, we aim to credential our newly-developed LPS
mouse models as faithful mimics of human disease by performing cross-species characterization of ACPP LPS
tumors and derivative cell lines and testing their utility as preclinical models by (1) validating ACPP mice as
representative models of human LPS through detailed molecular and cellular comparisons (2) establishing and
characterizing a series of syngeneic DDLPS cell lines from ACPP tumors and (3) assessing therapeutic response
to immune checkpoint inhibitors and chemotherapy in ACPP mice and DDLPS cell line allografts in proof-of-
concept translational studies. The successful completion of this project would highly impact the sarcoma
community by providing essential tools for conducting precise mechanism-driven preclinical translational studies,
in the pursuit of ultimately bringing novel and effective immunotherapeutics to improve the survival of sarcoma
patients.
Istituzione: UNIVERSITY OF MICHIGAN AT ANN ARBOR
PI: Christina Vadala Angeles
Progetto: 1R01CA308965-01A1
Settori: National Cancer Institute
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