Replication stress pathway agent compositions and methods for treating cancer
Provided herein are methods of treating cancer in a subject, wherein the cancer is extrachromosomal DNA-positive (ecDNA-positive) or therapeutically resistant, the method comprising administering to the subject a therapeutically effective amount of a replication stress (RS) pathway agent alone or in combination with a targeted therapeutic.
1. A method of treating an ecDNA-associated cancer in a subject comprising:
administering to the subject a therapeutically effective amount of (i) a replication stress pathway agent (RSPA), wherein the RSPA is a CHK1 inhibitor, and (ii) a cancer-targeted therapeutic agent,
wherein cells of the ecDNA-associated cancer have an ecDNA signature, wherein the cells of the ecDNA-associated cancer comprise an amplification of a first gene or portion thereof and the amplification is present on ecDNA, and
wherein the cancer-targeted therapeutic agent is directed against a protein encoded by the first gene,
thereby decreasing growth or number of the cells of the ecDNA-associated cancer in the subject.
2. The method of claim 1 , wherein the first gene comprises an oncogene, a drug-resistance gene, a therapeutic target gene, or a checkpoint inhibitor gene.
3. The method of claim 1 , wherein the subject has not been previously treated with the cancer-targeted therapeutic agent.
4. The method of claim 1 , wherein the cells of the ecDNA-associated cancer are resistant or non-responsive to a previous therapeutic agent.
5. The method of claim 1 , wherein the method prevents an increase of ecDNA in the cells of the ecDNA-associated cancer.
6. The method of claim 1 , wherein a level of oncogene amplification and/or a level of copy number variation (CNV) in the circulating cells of the ecDNA-associated cancer is reduced after treatment as compared to the level of oncogene amplification and/or CNV in the circulating cells of the ecDNA-associated cancer prior to treatment.
7. The method of claim 1 , wherein the ecDNA signature is selected from the group consisting of a gene amplification; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation signature (TIS); a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof.
8. The method of claim 1 , wherein cells of the ecDNA-associated cancer are identified as having an ecDNA signature by imaging ecDNA in cells, detecting ecDNA using an oncogene binding agent, DNA sequencing, or any combination thereof.
9. The method of claim 1 , wherein the cancer-targeted therapeutic agent is administered prior to the RSPA.
10. The method of claim 9 , wherein the cells of the ecDNA-associated cancer develop the ecDNA signature after administration of the cancer-targeted therapeutic agent, and prior to administration of the RSPA.
11. The method of claim 1 , wherein the cancer-targeted therapeutic agent is administered concurrently with the RSPA.
12. The method of claim 11 , wherein the cells of the ecDNA-associated cancer have developed the ecDNA signature prior to administration of the RSPA and the cancer-targeted therapeutic agent.
13. The method of claim 1 , wherein ecDNA is identified in circulating tumor DNA of the subject.
14. The method of claim 1 , wherein the of the ecDNA-associated cancer comprises a solid tumor.