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Alveolar soft part sarcoma (ASPS) is a rare pediatric malignancy which has characteristically poor clinical outcomes due to a propensity to metastasize along with a complete lack of chemotherapeutic options. One additional difficulty of this rare tumor is an absence of established in vivo models. Here, we describe the establishment of a patient derived xenograft model (PDX), and corresponding cell line, from the lung metastases of a 14-year-old female diagnosed with ASPS. Using this model, we performed a drug screen, from which the proteasome inhibitor carfilzomib inhibited tumor cell viability and growth in vitro and in vivo. To further elucidate factors implicated in tumor progression and chemotherapy resistance, we characterized the microenvironment and secretome of the ASPS PDX. In keeping with recent literature showing large numbers of tumor associated macrophage (TAMs) in ASPS, we found that 96% of the myeloid cells present in the PDX were TAMS, with 35% taking on a pro-tumor phenotype. Further, factors secreted by the tumor microenvironment largely support immune cell recruitment and pro-tumor phenotypes. Interestingly, in vivo assessment demonstrates that Iba1+ macrophage populations decrease by 60% with carfilzomib treatment. This prompted investigation into the potential impact of TAMs on ASPS growth and progression, and if they are implicated in the therapeutic response to carfilzomib. Based on preliminary findings that carfilzomib targets the pro-tumor phenotypic states of bone marrow derived macrophage in vitro, we hypothesize that carfilzomib alters the recruitment and phenotype of TAMs, decreasing tumor cell viability in vitro, and thus tumor burden in vivo. Citation Format: Alexis M. Philippot, Ngoc Ha Dang, Shyam V. Menon, Jennifer Bourdage, Xueqing Lun, Bo Young Ahn, Stephen M. Robbins, Donna L. Senger. Defining the microenvironment of alveolar soft part sarcoma & it’s role in therapeutic outcomes [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A006. |
