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), 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 KRAS gene or portion thereof and the amplification is present on ecDNA, and
wherein the cancer-targeted therapeutic agent is directed against a KRAS protein encoded by the KRAS gene,
thereby decreasing growth or number of cells of the ecDNA-associated cancer in the subject.
2. The method of claim 1 , wherein the KRAS protein comprises a mutant form of KRAS.
3. The method of claim 2 , wherein the KRAS protein comprises a point mutation, an insertion, a deletion, a fusion, or a combination thereof.
4. The method of claim 2 , wherein the mutant form of KRAS is KRASG12C.
5. The method of claim 1 , wherein the RSPA is selected from the group consisting of a RNR inhibitor, an ATR inhibitor, a CHK1 inhibitor, a WEE1 inhibitor, and a PARG inhibitor.
6. The method of claim 5 , wherein the RNR inhibitor is selected from the group consisting of 5-chloro-2-(n-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) propyl) sulfamoyl)benzamide, cladribine, clofarabine, COH29 (N-[4-(3,4-dihydroxyphenyl)-5-phenyl-1,3-thiazol-2-yl]-3,4-dihydroxybenzamide), fludarabine, gemcitabine, hydroxyurea, motexafin gadolinium, tezacitabine, and triapine.
7. The method of claim 5 , wherein the CHK1 inhibitor is selected from the group consisting of AZD-7762, BEBT-260, GDC-0575, LY-2880070, PF-477736, prexasertib, rabusertib (LY-2603618), RG-7602, SCH-900776, SRA737, and XCCS-605B.
8. The method of claim 5 , wherein the WEE1 inhibitor is selected from the group consisting of AZD1775 (MK1775), Bos-I, bosutinib, DC-859/A, Debio 0123, IMP7068, NUV-569, PD0166285, PD0407824, SC-0191, SDR-7995, SDR-7778, and ZN-c3.
9. The method of claim 5 , wherein the ATR inhibitor is selected from the group consisting of ART-0380, ATRN-119, ATRN-212, AZ-20, AZZ-6738, BAY-1895344, berzosertib (M-6620, VX-970; VE-822), BKT-300, IMP-9064, M-1774, M-4344 (VX-803), M-6620, nLs-BG-129, NU-6027, RP-3500, and SC-0245.
10. The method of claim 1 , wherein the subject has not been previously treated with the cancer-targeted therapeutic agent.
11. The method of claim 1 , wherein the subject has been previously treated with the cancer-targeted therapeutic agent.
12. The method of claim 1 , wherein the cells of the ecDNA-associated cancer are resistant or non-responsive to a previous therapeutic agent.
13. The method of claim 1 , wherein the method prevents an increase of ecDNA in the cells of the ecDNA-associated cancer.
14. The method of claim 1 , wherein the method reduces a level of ecDNA or reduces gene expression from the ecDNA in the cells of the ecDNA-associated cancer.
15. 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 or in circulating tumor DNA 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.
16. 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.
17. 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), 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 a focal amplification of a KRAS gene or portion thereof and
wherein the cancer-targeted therapeutic agent is directed against a KRAS protein encoded by the KRAS gene,
thereby decreasing growth or number of cells of the ecDNA-associated cancer in the subject.
18. The method of claim 17 , 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.
19. 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), and (ii) a cancer-targeted therapeutic agent,
wherein the cells of the ecDNA-associated cancer comprise an amplification of a KRAS gene or portion thereof and the amplification is present on ecDNA, and
wherein the cancer-targeted therapeutic agent is directed against a KRAS protein encoded by the KRAS gene,
thereby decreasing growth or number of cells of the ecDNA-associated cancer in the subject.
20. The method of claim 19 , wherein the cells of the ecDNA-associated cancer are resistant or non-responsive to a previous therapeutic agent.