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 WEE1 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 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.