Study Overview
Researchers set out to identify tumor suppressors involved in the development of undifferentiated pleomorphic sarcoma (UPS), a common adult soft tissue sarcoma that has historically lacked clear, recurrent driver mutations to target for therapy.
Key Findings
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Discovery of a Tumor Suppressor: Using a customized in vivo CRISPR/Cas9 screen in mice, the team identified BRCA1-associated protein 1 (BAP1) as a powerful tumor suppressor in soft tissue sarcomas.
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Immune System Impact: Sarcomas lacking the Bap1 gene were found to create a highly immunosuppressive tumor microenvironment, helping the cancer evade the immune system.
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A Crucial Biomarker: In human cases of UPS, the researchers observed that BAP1 protein levels are typically reduced, while the expression of polo-like kinase 1 (PLK1) is elevated.
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Tumor Vulnerability: Functional tests revealed that these Bap1-deficient sarcomas rely heavily on PLK1 to grow and survive.
Therapeutic Implications
The study highlights a promising new treatment path for this specific subset of sarcomas:
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Targeting PLK1: Treating the tumors with volasertib, a drug that inhibits PLK1, significantly suppressed tumor growth in mouse models.
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Combination Therapy: The most effective approach was combining the PLK1 inhibitor with anti-PD-1 therapy (an immune checkpoint inhibitor). This combination provided better tumor control and improved survival rates compared to using either treatment on its own.
Link to Journal
