Preclinical Modeling of Leiomyosarcoma Identifies Susceptibility to Transcriptional CDK Inhibitors through Antagonism of E2F-Driven Oncogenic Gene Expression
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Published on: June 13, 2018
Matthew L Hemming1, Patrick Bhola1, Michael A Loycano2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Purpose:
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.
Experimental Design:
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.
Results:
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.
Conclusions:
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.
Insights
Patient-derived xenograft (PDX) models accurately represent leiomyosarcoma (LMS) tumors, offering a new way to test therapies. These models show LMS is vulnerable to cyclin-dependent kinase (CDK) inhibitors, suggesting a new treatment strategy.
Area of Science:
- Oncology
- Translational Research
- Cancer Biology
Background:
- Leiomyosarcoma (LMS) is a challenging cancer with limited treatment options.
- Existing cell lines lack fidelity, hindering research into LMS biology and therapy development.
- Novel preclinical models are crucial for advancing understanding and treatment of advanced LMS.
Purpose of the Study:
- To characterize patient-derived xenograft (PDX) models for leiomyosarcoma (LMS).
- To assess the fidelity of LMS PDX models to their original patient tumors.
- To evaluate potential targeted therapies using these established PDX models.
Main Methods:
- Implanted 49 LMS surgical samples into immunocompromised mice.
- Characterized engrafted tumors using histology, next-generation sequencing, and RNA sequencing.
- Selected candidate therapies based on pathway activation or BH3 profiling.
Main Results:
- LMS PDX models maintained histologic and genomic fidelity to parental tumors across passages.
- Transcriptional analysis showed LMS PDX clustered with patient samples, differing mainly in microenvironment signatures.
- Identified susceptibility of LMS PDX to transcriptional cyclin-dependent kinase (CDK) inhibition, disrupting E2F-driven programs and inhibiting tumor growth.
Conclusions:
- LMS PDX models are valuable tools for preclinical research and discovering novel therapeutic vulnerabilities.
- Transcriptional CDK inhibitors show promise as a therapeutic strategy for LMS.
- These findings support clinical trials of CDK inhibitors for patients with leiomyosarcoma.
