METHODS OF TREATING CANCER
Provided herein are methods of treating a subject, such as a subject that has cancer, that include administering a therapeutically effective amount of a STING antagonist or a cGAS inhibitor or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, e.g., as compared to a reference level, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level.
1 . A method of treating a subject in need thereof, the method comprising:
(a) identifying a subject having a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level; and
(b) administering a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject.
2 . A method of treating a subject in need thereof, the method comprising administering a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level.
3 . A method of selecting a treatment for a subject in need thereof, the method comprising:
(a) identifying a subject having a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level; and
(b) selecting for the identified subject a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.
4 . A method of selecting a treatment for a subject in need thereof, the method comprising selecting a treatment comprising a therapeutically effective amount of a STING antagonist or cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level.
5 . A method of selecting a subject for treatment, the method comprising:
(a) identifying a subject having a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level; and
(b) selecting the identified subject for treatment with a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.
6 . A method of selecting a subject for participation in a clinical trial, the method comprising:
(a) identifying a subject having a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level; and
(b) selecting the identified subject for participation in a clinical trial that comprises administration of a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.
7 . A method of selecting a subject for participation in a clinical trial, the method comprising selecting a subject identified as having a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level, for participation in a clinical trial that comprises administration of a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.
8 . A method of predicting a subject's responsiveness to a STING antagonist or cGAS inhibitor, the method comprising:
(a) determining that a subject has a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level; and
(b) identifying that the subject determined to have (i) one or both of (i) decreased TREX1 expression and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level, in step (a) has an increased likelihood of being responsive to treatment with a STING antagonist or a cGAS inhibitor.
9 . A method of predicting a subject's responsiveness to a STING antagonist or cGAS inhibitor, the method comprising identifying a subject determined to have a cancer cell having (i) one or both of (i) decreased TREX1 level and/or activity, and (ii) increased cGAS/STING signaling pathway activity, and/or (ii) an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level, as having an increased likelihood of being responsive to treatment with a STING antagonist or a cGAS inhibitor.
10 . The method of any one of claims 1 - 9 , wherein the subject is identified having a cancer cell having both (i) decreased TREX1 level and/or activity and (ii) increased cGAS/STING signaling pathway activity; and
optionally wherein the subject is identified as having an elevated level of cGAMP in a serum or tumor sample of the subject as compared to a reference level.
11 . The method of any one of claims 1 - 10 , wherein the increased cGAS/STING signaling pathway activity and/or the elevated level of cGAMP is a result of a decreased level and/or activity of BRCA1 in the cancer cell.
12 . The method of any one of claims 1 - 11 , wherein the increased cGAS/STING signaling pathway activity is a result of a decreased level and/or activity of BRCA2 gene; or a decreased level and/or activity of SAMHD1 in the cancer cell; or a decreased level and/or activity of DNASE2 in the cancer cell; or a decreased level and/or activity of PARP1 in the cancer cell; or a decreased level and/or activity of RPA1 in the cancer cell; or a decreased level and/or activity of RAD51 in the cancer cell; or an increased level and/or activity of MUS81 in the cancer cell; or an increased level and/or activity of IFI16 in the cancer cell; or an increased level and/or activity of cGAS in the cancer cell; or an increased level and/or activity of DDX41 in the cancer cell; or an increased level and/or activity of EXO1 in the cancer cell; an increased level and/or activity of DNA2 in the cancer cell; or an increased level and/or activity of RBBP8 (CtIP) in the cancer cell; or an increased level and/or activity of MRE11 in the cancer cell.
13 . The method of any one of claims 1 - 11 , wherein the increased cGAS/STING signaling pathway activity and/or the elevated level of cGAMP is a result of a decreased level and/or activity of BLM in the cancer cell.
14 . The method of any one of claims 1 - 11 , wherein the increased cGAS/STING signaling pathway activity is a result of a gain-of-function mutation of STING, with the proviso that the method does not comprise administering a treatment comprising a therapeutically effective amount of a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject.
15 . The method of claim 3 or 4 , further comprising administering the selected treatment to the subject.
16 . The method of claim 8 or 9 , further comprising administering a therapeutically effective amount of a STING antagonist or a cGAS inhibitor to a subject identified as having an increased likelihood of being responsive to treatment with a STING antagonist or a cGAS inhibitor.
17 . The method of any one of claims 1 - 16 , wherein the subject has been diagnosed or identified as having a cancer, such as a cancer is selected from the group consisting of: renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.
18 . The method of any one of claims 1 - 17 , wherein the STING antagonist is a compound of any one of Formulas I-X, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.
19 . The method of any one of claims 1 - 17 , wherein the STING antagonist or the cGAS inhibitor is a compound selected from the group consisting of the compounds in Tables 1-10, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.