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Publication Number
US-12692548-B2
Publication Date
2026-07-28
Expiration Date
Abstract
Provided herein are methods related to detecting rearrangements in the B-cell lymphoma 6 (BCL6) corepressor (BCOR) or BCL6 corepressor-like protein I (BCORL1) gene, as well as methods of treatment, uses, and kits related thereto. As demonstrated herein, detection of BCOR rearrangements can be used to identify individuals that may benefit from treatment with a targeted therapeutic, such as a CDK inhibitor, an MDM2 inhibitor, a tyrosine kinase inhibitor, a MEK inhibitor, an mTOR inhibitor, or a Hh inhibitor. In some embodiments, the BCOR rearrangement is a fusion gene between BCOR and L3MBTL2, EP300, NUTM2G, MAP7D2, RALGPS1 RGAG1, CREBBP, ING3, NUGGC, or KMT 2D.
Core Innovation
The disclosed methods treat or delay progression of uterine sarcoma by detecting, acquiring knowledge of, or responding to knowledge of a specified BCOR rearrangement in an individual's sample. Following rearrangement identification, an effective amount of a targeted therapeutic comprising a CDK, MDM2, tyrosine kinase, MEK, mTOR, PIK3CA or AKT, or Hh inhibitor is administered. The specified rearrangement comprises an internal BCOR gene rearrangement characterized by a chromosome X inversion or a fusion with designated partner genes.
The underlying genomic analysis identifies novel BCOR fusion partners and frequent alterations activating the cyclin D–CDK4 pathway, such as CDK4 amplification, CCND2 amplification, or CDKN2A loss. Additionally, BCORL1-altered uterine sarcomas display similar morphology and recurrent alterations in the CDK4 pathway, NF1, and the mTOR pathway. Because standard fusion panels may miss BCORL1 mutations or internal BCOR rearrangements, sequencing workflows, detection systems, and kits are described to guide targeted therapeutic selection.
Claims Coverage
The claim coverage includes three independent claims directed to treating or delaying progression of uterine sarcoma based on a specified BCOR rearrangement, comprising three inventive features.
Treatment responsive to knowledge of a BCOR rearrangement
Administering an effective amount of a targeted therapeutic comprising a CDK, MDM2, tyrosine kinase, MEK, mTOR, PIK3CA or AKT, or Hh inhibitor to treat or delay progression of uterine sarcoma responsive to knowledge of a specified BCOR rearrangement in an individual's sample, wherein the rearrangement is a fusion with L3MBTL2, EP300, NUTM2G, MAP7D2, RALGPS1, RGAG1, ING3, NUGGC, or KMT2D, or an internal BCOR gene rearrangement characterized by a chromosome X inversion.
Acquiring knowledge of a BCOR rearrangement before treatment
Acquiring knowledge of a specified BCOR gene rearrangement in an individual's sample and, responsive to that knowledge, administering an effective amount of a targeted therapeutic comprising a CDK, MDM2, tyrosine kinase, MEK, mTOR, PIK3CA or AKT, or Hh inhibitor to treat or delay progression of uterine sarcoma, wherein the rearrangement is a fusion with L3MBTL2, EP300, NUTM2G, MAP7D2, RALGPS1, RGAG1, ING3, NUGGC, or KMT2D, or an internal rearrangement characterized by a chromosome X inversion.
Detecting a BCOR rearrangement before treatment
Detecting a specified BCOR gene rearrangement in an individual's sample and administering an effective amount of a targeted therapeutic comprising a CDK, MDM2, tyrosine kinase, MEK, mTOR, PIK3CA or AKT, or Hh inhibitor to treat or delay progression of uterine sarcoma, wherein the rearrangement is a fusion with L3MBTL2, EP300, NUTM2G, MAP7D2, RALGPS1, RGAG1, ING3, NUGGC, or KMT2D, or an internal rearrangement characterized by a chromosome X inversion.
The independent claims cover three treatment methods distinguished by responding to existing knowledge of a specified BCOR rearrangement, acquiring that knowledge, or detecting the rearrangement, followed by targeted inhibitor administration.
Stated Advantages
The genomic findings support biomarker-informed targeted treatment by identifying BCOR and BCORL1 alterations alongside frequent CDK4-pathway alterations in uterine sarcomas.
The methods treat or delay progression of uterine sarcoma.
Documented Applications
Treatment or delaying progression of uterine sarcoma, including endometrial stromal sarcoma, associated with or responsive to a specified BCOR rearrangement using a targeted therapeutic comprising a CDK, MDM2, tyrosine kinase, MEK, mTOR, PIK3CA or AKT, or Hh inhibitor.
Diagnostic detection and assessment of BCOR rearrangements or BCORL1 alterations using sequencing-based workflows, detection systems, or kits, recommended when FISH or fusion-panel testing is negative.
Administration of MEK or mTOR inhibitors in refractory BCORL1-mutated tumors.
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