Androgen receptor variants and methods for making and using

• US 10,206,911 B2
• Filed: 10/25/2013
• Issued: 02/19/2019
• Est. Priority Date: 10/26/2012
• Status: Active Grant

• Current Assignee: Memorial Sloan-Kettering Cancer Center
• Original Assignee: Memorial Sloan-Kettering Cancer Center
• Inventors: Balbas, Minna D., Sawyers, Charles L., Watson, Philip
• Primary Examiner(s): Pak, Michael D
• Application Number:
  US14/438,399
• Publication Number:
  US 20150265587A1
• Time in Patent Office: 1,943 Days
• Field of Search: None
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: C07K 14/70567 Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
• CPC Class Codes: C07K 16/2857 against nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, orphan receptor
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2333/723 Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity

Abstract

The present invention encompasses the recognition that an F876L mutation of the androgen receptor (AR) gene confers resistance to the antiandrogens enzalutamide (MDV3100) and ARN-509 and is associated with incidence and/or risk of castration resistant prostate cancer (CRPC). The present invention also provides other AR polypeptide sequences associated with increased incidence and/or risk of CRPC. The present invention also provides screening methods for identification and/or characterization of novel AR polypeptide sequences associated with increased incidence and/or risk of CRPC via exposure to antiandrogens and for identification and/or characterization of agents to treat and/or reduce risk of CRPC by virtue of their effect on AR transcriptional activation.

Claims

1. In a method of treating castration resistant prostate cancer in a patient the improvement that comprises:

monitoring response of the patient to an administered course of therapy by comparing at least first and second detected presence or expression levels, determined at first and second time points, respectively, the second time point being alter the first time point, of a nucleic acid sequence that encodes a variant androgen receptor or portion thereof having an amino acid sequence containing a mutation at amino acid 876 relative to a reference androgen receptor polypeptide of SEQ ID NO;

1, wherein the mutation at amino acid 876 is F876I, F876L, or F876V, and

continuing to administer the course of therapy if the second detected presence or expression level is lower than the first detected presence or expression level, or administering a different course of therapy if the second detected presence or expression level is not lower than the first detected presence or expression level.

2. A method of treating castration resistant prostate cancer, the method comprising a step of:

administering an optimized castration resistant prostate cancer treatment to a patient undergoing a course of treatment for prostate cancer, wherein;

the patient'"'"'s response to the course of treatment has been determined by;

detecting in a first sample from the patient taken at a first time point before or during the course of treatment, a first level of a nucleic acid sequence that encodes a variant androgen receptor or portion thereof having an amino acid sequence containing a mutation at amino acid 876 relative to a reference androgen receptor polypeptide of SEQ ID NO;

1, wherein the mutation is F876I, F876L, or F876V;

detecting in a second sample from the patient taken at a second time point, later than the first time point and during the course of treatment, a second level of the nucleic acid sequence; and

comparing the first and second detected levels; and

determining that the course of treatment is the optimized castration resistant prostate cancer treatment if the second level is reduced relative to the first level or that an alternative course of treatment is the optimized castration resistant prostate cancer treatment if the second level is not reduced relative to the first level.

3. A method of treating castration resistant prostate cancer, the method comprising:

administering to a patient suffering from castration resistant prostate cancer a treatment selected by a process comprising steps of;

detecting expression level of a nucleic acid sequence that encodes a variant androgen receptor or portion thereof having an amino acid sequence containing a mutation at amino acid 876 relative to a reference androgen receptor polypeptide of SEQ ID NO;

1, wherein the mutation at amino acid 876 is F876I, F876L, or F876V in samples obtained from at least first and second time points from a patient undergoing a course or treatment for prostate cancer;

determining if the patient has a positive response to the course of treatment by comparing the detected expression level at the at least first and second time points;

selecting the treatment as appropriate in light of the determining.

4. A method of treating castration resistant prostate cancer, the method comprising a step of:

administering a castration resistant prostate cancer treatment to a patient suffering from prostate cancer that has been determined to contain or express a nucleic acid sequence that encodes a variant androgen receptor or portion thereof having an amino acid sequence containing a mutation at amino acid 876 relative to a reference androgen receptor polypeptide of SEQ ID NO;

1, wherein the mutation at amino acid 876 is F876I, F876I or F876V,

which prostate cancer treatment comprises administration of an agent that has been determined, when contacted with a population of cells expressing the variant androgen receptor or portion thereof, to decrease expression or activity of the variant androgen receptor ur portion thereof relative to that observed under comparable conditions absent the agent.