AHR INHIBITORS AND USES THEREOF

1 . A method of treating cancer, comprising selecting a patient who is AHR nuclear positive, and administering to the patient a therapeutically effective amount of an AHR inhibitor.

2 . The method of claim 1 , wherein the cancer is selected from bladder cancer, melanoma, ovarian cancer, and HNSCC.

3 . The method of claim 1 or 2 , wherein selecting a patient who is AHR nuclear positive comprises IHC staining a tumor biopsy core of a patient.

4 . The method of claim 3 , wherein selecting a patient who is AHR nuclear positive comprises selecting a patient having about 5% or more cells in a tumor biopsy core which are AHR nuclear staining positive.

5 . The method of claim 4 , wherein selecting a patient who is AHR nuclear positive comprises selecting a patient having about 20% or more cells in a tumor biopsy core which are AHR nuclear staining positive.

6 . The method of claim 5 , wherein selecting a patient who is AHR nuclear positive comprises selecting a patient having about 50% or more cells in a tumor biopsy core which are AHR nuclear staining positive.

7 . The method of any one of claims 4 - 6 , wherein the tumor biopsy core is a tumor region of the tumor biopsy core.

8 . The method of any one of claims 4 - 6 , wherein the tumor biopsy core is a tumor microenvironment (or stroma) region of the tumor biopsy core.

9 . The method of any one of claims 4 - 6 , wherein staining positive refers to all staining intensity (including 1+, 2+, and 3+ intensities) by CTA scoring.

10 . The method of any one of claims 4 - 6 , wherein staining positive refers to pooled 2+ and 3+ staining intensity by CTA scoring.

11 . The method of claim 1 or 2 , wherein the AHR inhibitor is Compound A:

or a pharmaceutically acceptable salt thereof.

12 . A method of treating bladder cancer in a patient, comprising:

IHC staining a tumor tissue of a patient;

selecting a patient having about 5%, 20%, or 50%, or more cells in a tumor region of a tumor biopsy core which are AHR nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring; and

administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

13 . A method of treating HNSCC in a patient, comprising:

IHC staining a tumor tissue of a patient;

selecting a patient having about 5%, 20%, or 50%, or more cells in a tumor region of a tumor biopsy core which are AHR nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring; and

administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

14 . A method of treating ovarian cancer in a patient, comprising:

IHC staining a tumor tissue of a patient;

selecting a patient having about 5%, 20%, or 50%, or more cells in a tumor region of a tumor biopsy core which are AHR nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring; and

administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

15 . A method of treating melanoma in a patient, comprising:

IHC staining a tumor tissue of a patient;

selecting a patient having about 5%, 20%, or 50%, or more cells in a tumor region of a tumor biopsy core which are AHR nuclear staining positive at all staining intensity (including 1+, 2+, and 3+ intensities) or at pooled 2+ and 3+ staining intensity by CTA scoring; and

administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

16 . A method for identifying or selecting a cancer patient who is AHR nuclear positive, comprising IHC staining a tumor tissue of a patient, and selecting a patient who is AHR nuclear staining positive.

17 . The method of claim 16 , wherein selecting a patient who is AHR nuclear staining positive comprises selecting a patient having about 5% or more cells in a tumor biopsy core which are staining positive.

18 . The method of claim 16 , wherein selecting a patient who is AHR nuclear staining positive comprises selecting a patient having about 20% or more cells in a tumor biopsy core which are staining positive.

19 . The method of claim 16 , wherein selecting a patient who is AHR nuclear staining positive comprises selecting a patient having about 50% or more cells in a tumor biopsy core which are staining positive.

20 . The method of any one of claims 17 - 19 , wherein the tumor biopsy core is a tumor region of the tumor biopsy core.

21 . The method of any one of claims 17 - 19 , wherein the tumor biopsy core is a tumor microenvironment (or stroma) region of the tumor biopsy core.

22 . The method of any one of claims 17 - 19 , wherein staining positive refers to all staining intensity (including 1+, 2+, and 3+ intensities) by CTA scoring.

23 . The method of any one of claims 17 - 19 , wherein staining positive refers to pooled 2+ and 3+ staining intensity by CTA scoring.

24 . The method of claim 16 , wherein the tumor tissue is a bladder tumor tissue, a melanoma tissue, an ovarian tumor tissue, or an HNSCC tumor tissue.

25 . A method for IHC staining a tumor tissue of a patient, comprising staining a tumor tissue section using AHR monoclonal antibody FF3399.

26 . The method of claim 25 , further comprising measuring staining intensity in a tumor biopsy core.

27 . A method of treating cancer comprising selecting a patient who has an AHR gene amplification and administering to the patient a therapeutically effective amount of an AHR antagonist.

28 . The method of claim 27 , wherein the selecting a patient who has an AHR gene amplification comprises using Next Generation Sequencing (NGS), RNAscope, or fluorescent in situ hybridization (FISH) to identify the AHR gene amplification.

29 . The method of claims 27 or 28 , wherein the AHR gene amplification is determined by assaying cells from a tumor sample.

30 . The method of any one of claims 27 - 29 , wherein about 10% of the cells from the tumor sample have at least about three copies of AHR.

31 . The method of any one of claims 27 - 30 , wherein the cancer is selected from bladder cancer, melanoma, ovarian cancer, and HNSCC.

32 . The method of any one of claims 27 - 31 , wherein the AHR antagonist is:

or a pharmaceutically acceptable salt thereof; or

(ii) a metabolite of Compound A, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

33 . A method of treating cancer in a patient who has an AHR gene amplification comprising administering to the patient a therapeutically effective amount of an AHR antagonist.

34 . The method of claim 33 , wherein about 10% of the cells from a tumor sample from the patient have at least about three copies of AHR.

35 . The method of claims 33 or 34 , wherein the cancer is selected from bladder cancer, melanoma, ovarian cancer, and HNSCC.

36 . The method of any one of claims 33 - 35 , wherein the AHR antagonist is:

or a pharmaceutically acceptable salt thereof; or

(ii) a metabolite of Compound A, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

37 . A method of treating cancer in a patient who is AHR nuclear positive comprising administering to the patient a therapeutically effective amount of an AHR antagonist.

38 . The method of claim 37 , wherein the patient who is AHR nuclear positive has about 5% or more cells in a tumor sample which are AHR nuclear staining positive.

39 . The method of claim 38 , wherein the tumor sample is a tumor biopsy core of the patient.

40 . The method of any one of claims 37 - 39 , wherein the cancer is selected from bladder cancer, melanoma, ovarian cancer, and HNSCC.

41 . The method of any one of claims 37 - 40 , wherein the AHR antagonist is:

or a pharmaceutically acceptable salt thereof; or

(ii) a metabolite of Compound A, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.