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Uterine Leiomyosarcoma Sequences Point to Potentially Targetable Somatic Mutations

NEW YORK – Researchers in the US, South Korea, Spain, and Italy have uncovered recurrent somatic alterations that appear to drive the development of uterine leiomyosarcomas (uLMS), including mutations that appeared apt to respond to targeted treatments in patient-derived models of the aggressive uterine smooth muscle tumors.

"Our integrated analysis results define mutated genes and pathways involved in uLMS carcinogenesis," the study's authors wrote in a paper published in Proceedings of the National Academy of Sciences on Monday, "and provide a strong preclinical rationale for clinical trials targeting specific driver mutations/pathways in patients with advanced, metastatic, or recurrent uLMS."

For their analysis, the researchers assessed whole-genome, exome, and/or RNA sequences — generated at Yale University or for a Cancer Genome Atlas (TCGA) adult soft tissue sarcoma study — on dozens of uLMS tumor samples from 83 individuals with uLMS from the US and Italy, including two patient-derived xenograft (PDX) lines. The sequence data highlighted recurrent somatic mutations in TP53, MED12, PTEN, and other genes, along with some 29 copy number losses, at least eight copy number gains, and fusion events involving 92 genes.

The team's findings suggested that more than three-quarters of the 21 fully genome-sequenced tumors had undergone dramatic genome rearrangements such as chromothripsis or chromoplexy.

When the investigators took a closer look at the mutation signatures and recurrently altered pathways present in the tumors, meanwhile, they determined that one-quarter of the 48 fresh-frozen uLMS samples they considered contained apparent homologous-recombination repair deficiencies (HRD) and 1 percent showed microsatellite instability.

Along with recurrent alterations in genes from the PI3K/mTOR and C-MYC/BET pathways, such results hinted that a subset of uLMS cases might be susceptible to PARP inhibitor treatments used to target HRD, the PIK3CA inhibitor copanlisib (Bayer's Aliqopa), or to a BET-inhibiting compound known as GS-626510 — a possibility the team explored using the sequenced uLMS PDX lines grown in mouse models treated with copanlisib, GS-626510, or the PARP inhibitor olaparib (Lynparza from AstraZeneca) or with the drug delivery vehicle alone.

"Using two fully sequenced patient-derived-xenografts (PDXs) harboring deranged C-MYC/BET and PTEN/PIK3CA pathways and/or an HRD signature, we found olaparib (PARPi), GS-626510 (BETi), and copanlisib (PIK3CAi) monotherapy to significantly inhibit in vivo uterine leiomyosarcomas growth," co-senior author Alessandro Santin, a team leader with the Yale Cancer Center-Smilow Cancer Hospital gynecological cancer program and an obstetrics, gynecology, and reproductive sciences researcher at the Yale, said in a statement.

Santin and his colleagues noted that "[s]ince advanced/recurrent and/or metastatic uLMS remain incurable, our comprehensive genetic results, combined with our preclinical validation data using PDXs, strongly suggest that HRD, ERBB2/PI3K/AKT/mTOR, and C-MYC/BET deranged pathways may be clinically susceptible to targeted inhibitors in a large subset of uLMS."