Methods for identifying and treating cancer patients
Methods for identifying and treating cancer patients likely to respond to topoisomerase inhibitors or likely to fail to respond to topoisomerase inhibitors are provided. The methods take advantage of the newly discovered role of BAF complexes in decatenation of DNA by topoisomerase IIa. Cancer cells are frequently at least partly defective in BAF complex activity. Such cells are targeted for therapy using certain topoisomerase IIa inhibitors according to the disclosed methods of treatment. Therapy of such cells using other topoisomerase inhibitors should be avoided.
1. A method for treating cancer in a patient having been identified as having a decreased activity of at least one BAF subunit in a tumor cell of the patient, the method comprising:
administering to the patient an effective amount of a topoisomerase inhibitor that does not cause double-stranded breaks in genomic DNA,
wherein the at least one BAF subunit is encoded by ARID1A, and
wherein the topoisomerase inhibitor that does not cause double-stranded breaks in genomic DNA is aurintricarboxylic acid, HU-331, epigallocatechin gallate, genistein, quercetin, or ICRF-193.
2. The method of claim 1 , wherein the cancer is a colorectal cancer, a clear-cell ovarian cancer, a serous ovarian cancer, a pancreatic cancer, a gastric cancer, a bladder cancer, a hepatocellular cancer, a renal cancer, a squamous cell carcinoma, a breast cancer, a medulloblastoma, a glioma, a melanoma, a lung cancer, a prostate cancer, a sarcoma, a malignant rhabdoid tumor, or a hematologic malignancy.
3. The method of claim 2 , wherein the cancer is a colorectal cancer, a clear-cell ovarian cancer, a pancreatic cancer, a gastric cancer, a bladder cancer, a hepatocellular cancer, a renal cancer, a breast cancer, a medulloblastoma, a lung cancer, a prostate cancer, a sarcoma, a malignant rhabdoid tumor, or a hematologic malignancy.
4. The method of claim 1 , wherein the patient is identified by sequencing a portion of a gene encoding the at least one BAF subunit in a tumor sample and in a non-tumor sample from the patient, and wherein a mutation in the gene encoding the at least one BAF subunit in the tumor sample compared to the non-tumor sample indicates the decreased activity of the at least one BAF subunit in the tumor sample.
5. The method of claim 1 , wherein the patient is identified by measuring transcription of a gene encoding the at least one BAF subunit in a tumor sample and in a non-tumor sample from the patient, and wherein a decreased transcription of the gene encoding the at least one BAF subunit in the tumor sample compared to the non-tumor sample indicates the decreased activity of the at least one BAF subunit in the tumor sample.
6. The method of claim 1 , wherein the patient is identified by measuring protein expression of the at least one BAF subunit in a tumor sample and in a non-tumor sample from the patient, and wherein a decreased protein expression of the at least one BAF subunit in the tumor sample compared to the non-tumor sample indicates the decreased activity of the at least one BAF subunit in the tumor sample.
7. The method of claim 1 , wherein the patient is identified by measuring post-translational modification of the at least one BAF subunit in a tumor sample and in a non-tumor sample from the patient, and wherein an altered post-translational modification of the at least one BAF subunit in the tumor sample compared to the non-tumor sample indicates the decreased activity of the at least one BAF subunit in the tumor sample.
8. The method of claim 1 , wherein the patient is identified by measuring decatenation of DNA by topoisomerase IIa in a tumor sample and in a non-tumor sample from the patient, and wherein a decreased decatenation of DNA by topoisomerase IIa in the tumor sample compared to the non-tumor sample indicates the decreased activity of the at least one BAF subunit in the tumor sample.
9. The method of claim 1 , wherein the patient is identified by determining activities of at least two BAF subunits in a tumor sample and in a non-tumor sample from the patient.
10. The method of claim 1 , wherein the patient is identified by determining activities of at least five BAF subunits in a tumor sample and in a non-tumor sample from the patient.
11. The method of claim 1 , wherein the patient is identified by sequencing a portion of a gene encoding the at least one BAF subunit, by measuring transcription of a gene encoding the at least one BAF subunit, by measuring protein expression of the at least one BAF subunit, by measuring post-translational modification of the at least one BAF subunit, or by measuring decatenation of DNA by topoisomerase IIa in a tumor sample and in a non-tumor sample from the patient.