Related Experiment Video
Updated: May 19, 2026
Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor
Published on: August 25, 2023
Comparative gene expression profiling of benign and malignant lesions reveals candidate therapeutic compounds for
Badreddin Edris1, Jonathan A Fletcher, Robert B West
1Department of Pathology, Stanford University Medical Center, Stanford, CA 93205, USA.
Abstract:
Leiomyosarcoma (LMS) is a malignant, soft-tissue tumor for which few effective therapies exist. Previously, we showed that there are three molecular subtypes of LMS. Here, we analyzed genes differentially expressed in each of the three LMS subtypes as compared to benign leiomyomas and then used the Connectivity Map (cmap) to calculate enrichment scores for the 1309 cmap drugs in order to identify candidate molecules with the potential to induce a benign, leiomyoma-like phenotype in LMS cells. 11 drugs were selected and tested for their ability to inhibit the growth of three human LMS cell lines. We identified two drugs with in vitro efficacy against LMS, one of which had a strongly negative enrichment score (Cantharidin) and the other of which had a strongly positive enrichment score (MG-132). Given MG-132's strong inhibitory effect on LMS cell viability, we hypothesized that LMS cells may be sensitive to treatment with other proteasome inhibitors and demonstrated that bortezomib, a clinically-approved proteasome inhibitor not included in the original cmap screen, potently inhibited the viability of the LMS cell lines. These findings suggest that systematically linking LMS subtype-specific expression signatures with drug-associated expression profiles represents a promising approach for the identification of new drugs for LMS.
Insights
This study identifies potential new therapies for leiomyosarcoma (LMS) by analyzing gene expression profiles. Researchers found that proteasome inhibitors like bortezomib show significant efficacy against LMS cells in vitro.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Leiomyosarcoma (LMS) is a rare soft-tissue cancer with limited treatment options.
- Previous research identified three distinct molecular subtypes of LMS.
- Understanding the molecular differences between LMS and benign leiomyomas is crucial for therapeutic development.
Purpose of the Study:
- To identify novel therapeutic agents for LMS by targeting subtype-specific gene expression profiles.
- To discover drugs that can revert LMS cells towards a benign leiomyoma-like phenotype.
- To evaluate the in vitro efficacy of candidate drugs against human LMS cell lines.
Main Methods:
- Differential gene expression analysis between LMS subtypes and benign leiomyomas.
- Utilized the Connectivity Map (cmap) database to screen 1309 drugs for potential efficacy.
- In vitro testing of selected drugs on three human LMS cell lines.
Main Results:
- Two drugs, Cantharidin and MG-132, demonstrated in vitro efficacy against LMS cell lines.
- MG-132, a proteasome inhibitor, showed a strong inhibitory effect on LMS cell viability.
- Bortezomib, another proteasome inhibitor, also potently inhibited LMS cell viability, suggesting a broader sensitivity to this drug class.
Conclusions:
- Linking LMS subtype-specific gene expression signatures with drug profiles is a promising strategy for novel drug discovery.
- Proteasome inhibitors represent a potential therapeutic avenue for LMS treatment.
- Further investigation into bortezomib and related compounds for LMS is warranted.
