BCOR rearrangements and uses thereof
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.
1 . A method of treating or delaying progression of cancer, comprising, responsive to knowledge of a rearrangement in a BCOR gene in a sample from an individual, administering to the individual an effective amount of a treatment that comprises a targeted therapeutic comprising a CDK inhibitor, an MDM2 inhibitor, a tyrosine kinase inhibitor, a MEK inhibitor, an mTOR inhibitor, PIK3CA or AKT inhibitor, or a Hh inhibitor; wherein the BCOR rearrangement: (a) results in a fusion gene between BCOR and L3MBTL2, EP300, NUTM2G, MAP7D2, RALGPS1, RGAG1, ING3, NUGGC, or KMT2D; or (b) is an internal BCOR gene rearrangement characterized by a chromosome X inversion; wherein the cancer is uterine sarcoma.
2 . A method of treating or delaying progression of cancer, comprising:
(a) acquiring knowledge of a rearrangement in a BCOR gene in a sample from an individual; wherein the BCOR rearrangement: (a) results in a fusion gene between BCOR and L3MBTL2, EP300, NUTM2G, MAP7D2, RALGPS1, RGAG1, ING3, NUGGC, or KMT2D; or (b) is an internal BCOR gene rearrangement characterized by a chromosome X inversion; and
(b) responsive to said knowledge, administering to the individual an effective amount of a treatment that comprises a targeted therapeutic comprising a CDK inhibitor, an MDM2 inhibitor, a tyrosine kinase inhibitor, a MEK inhibitor, an mTOR inhibitor, PIK3CA or AKT inhibitor, or a Hh inhibitor;
wherein the cancer is uterine sarcoma.
3 . A method of treating or delaying progression of cancer, comprising:
(a) detecting a rearrangement in a BCOR gene in a sample from an individual; wherein the BCOR rearrangement: (a) results in a fusion gene between BCOR and L3MBTL2, EP300, NUTM2G, MAP7D2, RALGPS1, RGAG1, ING3, NUGGC, or KMT2D; or (b) is an internal BCOR gene rearrangement characterized by a chromosome X inversion; and
(b) administering to the individual an effective amount of a treatment that comprises a targeted therapeutic comprising a CDK inhibitor, an MDM2 inhibitor, a tyrosine kinase inhibitor, a MEK inhibitor, an mTOR inhibitor, PIK3CA or AKT inhibitor, or a Hh inhibitor;
wherein the cancer is uterine sarcoma.
4 . The method of claim 3 , wherein the cancer is endometrial stromal sarcoma (ESS).
5 . The method of claim 3 , wherein a sample obtained from the cancer is:
(a) characterized by 19 or fewer mutations per megabase (Mb); and/or
(b) microsatellite stable.
6 . The method of claim 3 , wherein the cancer is resistant or refractory to treatment with conventional chemotherapy.
7 . The method of claim 3 , further comprising selectively enriching for one or more nucleic acids comprising a rearrangement in a BCOR gene to produce an enriched sample.
8 . The method of claim 3 , wherein the treatment further comprises a second therapeutic agent that comprises a chemotherapeutic agent, immune checkpoint inhibitor (ICI), cancer immunotherapy, cell-based therapy, or nucleic acid-based therapy.
9 . The method of claim 3 , wherein the sample from the individual comprises fluid, cells, or tissue.
10 . The method of claim 9 , wherein the sample from the individual comprises a tumor biopsy, a circulating tumor cell, or a nucleic acid sample that comprises mRNA, genomic DNA, circulating tumor DNA, cell-free DNA, or cell-free RNA.