Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2022 Jun 1;28(11):2397-2408. doi: 10.1158/1078-0432.CCR-21-3523.
Leiomyosarcoma (LMS) is a neoplasm characterized by smooth muscle differentiation, complex copy-number alterations, tumor suppressor loss, and the absence of recurrent driver mutations. Clinical management for advanced disease relies on the use of empiric cytotoxic chemotherapy with limited activity, and novel targeted therapies supported by preclinical research on LMS biology are urgently needed. A lack of fidelity of established LMS cell lines to their mesenchymal neoplasm of origin has limited translational understanding of this disease, and few other preclinical models have been established. Here, we characterize patient-derived xenograft (PDX) models of LMS, assessing fidelity to their tumors of origin and performing preclinical evaluation of candidate therapies.
We implanted 49 LMS surgical samples into immunocompromised mice. Engrafting tumors were characterized by histology, targeted next-generation sequencing, RNA sequencing, and ultra-low passage whole-genome sequencing. Candidate therapies were selected based on prior evidence of pathway activation or high-throughput dynamic BH3 profiling.
We show that LMS PDX maintain the histologic appearance, copy-number alterations, and transcriptional program of their parental tumors across multiple xenograft passages. Transcriptionally, LMS PDX cocluster with paired LMS patient-derived samples and differ primarily in host-related immunologic and microenvironment signatures. We identify susceptibility of LMS PDX to transcriptional cyclin-dependent kinase (CDK) inhibition, which disrupts an E2F-driven oncogenic transcriptional program and inhibits tumor growth.
Our results establish LMS PDX as valuable preclinical models and identify strategies to discover novel vulnerabilities in this disease. These data support the clinical assessment of transcriptional CDK inhibitors as a therapeutic strategy for patients with LMS.
平滑肌肉瘤（LMS）是一种以平滑肌分化为特征的肿瘤，具有复杂的拷贝数改变、肿瘤抑制因子丢失，以及缺乏反复出现的驱动突变。对于晚期疾病的临床管理依赖于经验性细胞毒性化疗，其活性有限，迫切需要基于 LMS 生物学的临床前研究的新型靶向治疗。由于已建立的 LMS 细胞系对其间叶性肿瘤起源的忠实性有限，因此对这种疾病的转化理解有限，而且很少建立其他临床前模型。在这里，我们对 LMS 的患者来源异种移植（PDX）模型进行了特征描述，评估了它们与其肿瘤起源的忠实性，并对候选治疗方法进行了临床前评估。
我们将 49 个 LMS 手术样本植入免疫缺陷小鼠中。移植瘤通过组织学、靶向下一代测序、RNA 测序和超低代全基因组测序进行表征。候选治疗方法的选择基于先前对途径激活或高通量动态 BH3 分析的证据。
我们表明，LMS PDX 在多个异种移植传代中保持其亲本肿瘤的组织学外观、拷贝数改变和转录程序。在转录水平上，LMS PDX 与配对的 LMS 患者来源样本共聚类，主要差异在于宿主相关的免疫和微环境特征。我们发现 LMS PDX 对转录周期蛋白依赖性激酶（CDK）抑制敏感，这种抑制破坏了 E2F 驱动的致癌转录程序并抑制肿瘤生长。
我们的结果确立了 LMS PDX 作为有价值的临床前模型，并确定了发现这种疾病新弱点的策略。这些数据支持将转录 CDK 抑制剂作为 LMS 患者的治疗策略进行临床评估。
