Estrogen receptor mutations and uses thereof

Patent metadata

Field	Value
Publication number	US-10093983-B2
Application number	US-201514753397-A
Country	US
Kind code	B2
Filing date	Jun 29, 2015
Priority date	Oct 14, 2011
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

Novel mutant ESR1 molecules and uses are disclosed.

First claim

We claim:

1. A method of treating a subject having a breast cancer, the method comprising:
acquiring knowledge of a presence of (a) a mutant estrogen receptor 1 (ESR1) polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide and (b) an Estrogen Receptor positive (ER+) breast cancer in said subject,
wherein the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide comprises a mutation chosen from one or more of:
(i) one or more of mutations at amino acid position 311, 341, 350, 394, 414, 433, or 503, or 538 of SEQ ID NO: 2;
(ii) a deletion of nucleotides 1046-1051 of SEQ ID NO: 1;
(iii) an insertion of a histidine as shown at amino acid position 349 of SEQ ID NO:4;
(iv) an insertion between amino acid positions 344 and 345 of SEQ ID NO: 2; or
(v) a tyrosine to cysteine substitution at amino acid position 537 (a Y537C) of SEQ ID NO: 2; and
responsive to said knowledge, administering to the subject an effective amount of an estrogen receptor modulator set forth in Table 5,
thereby treating the breast cancer in the subject.

2. The method of claim 1 , wherein the mutant ESR1 polypeptide comprises a mutation chosen from one or more of:
an aspartate to glycine substitution at amino acid position 538 (a D538G) of SEQ ID NO: 2;
a deletion of amino acids Leu-Ala-Asp (LAD) at positions 349-351 of SEQ ID NO: 2;
a threonine to methionine substitution at amino acid position 311 (a T311M) of SEQ ID NO: 2;
a serine to leucine substitution at amino acid position 341 (a S341L) of SEQ ID NO: 2;
an alanine to glutamate substitution at amino acid position 350 (a A350E) of SEQ ID NO: 2;
an arginine to histidine substitution at amino acid position 394 (a R394H) of SEQ ID NO: 2;
a glutamine substitution at amino acid position 414 of SEQ ID NO: 2;
a serine to proline substitution at amino acid position 433 (a S433P) of SEQ ID NO: 2;
an arginine to tryptophan substitution at amino acid position 503 (a R503W) of SEQ ID NO: 2; or
an insertion of a cysteine between amino acid positions 344 and 345 of SEQ ID NO:2.

3. The method of claim 1 , wherein said subject has one or more of the following:
(i) previously received a treatment with a SERM;
(ii) has failed a first or second line of treatment with a SERM;
(iii) has a late stage, metastatic progressive breast cancer;
(iv) is post-menopausal or pre-menopausal;
(v) stops a treatment with a SERM and begins a treatment with an anti-cancer agent that is not a SERM; or
(vi) is premenopausal and receives an oophorectomy.

4. The method of claim 3 , wherein the SERM is chosen from raloxifene, EM652, GW7604, keoxifene, toremifene, tamoxifen, lasofoxifene, levormeloxifene, bazedoxifene, or arzoxifene.

5. The method of claim 1 , further comprising administering to the subject an anti-cancer agent chosen from a Selective Estrogen Receptor Degrader (SERD), an aromatase inhibitor, an mTOR pathway inhibitor, or a chemotherapeutic agent.

6. The method of claim 1 , further comprising administering to the subject fulvestrant.

7. The method of claim 5 , wherein the aromatase inhibitor is chosen from aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1,4,6-androstatrien-3,17-dione (ATD), or 4-Androstene-3,6,17-trione (“6-OXO”).

8. The method of claim 5 , wherein the mTOR pathway inhibitor is chosen from rapamycin, temsirolimus, everolimus, ridaforolimus, AP23573, AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794, WYE-354, INK128, temsirolimus (CCI-779), Palomid 529 (P529), PF-04691502, or PKI-587.

9. The method of claim 1 wherein the estrogen receptor modulator is administered in combination with a different therapeutic agent or a different therapeutic modality.

10. The method of claim 9 , wherein the different therapeutic agent or different therapeutic modality is selected according to a determination of a presence of a mutation other than the mutation in the mutant ESR1 polypeptide or in the nucleic acid molecule encoding the mutant ESR1 polypeptide, and wherein the mutation other than the mutation in the mutant ESR1 polypeptide or in the nucleic acid molecule encoding the mutant ESR1 polypeptide is chosen from a HER2 mutation, a p53 mutation, a BRCA mutation, an NF1 mutation, an EGFR/myc gain, a PIK3CA mutation, a CCND1 mutation, a CDH1 mutation, or a combination thereof.

11. The method of claim 1 , wherein the acquiring knowledge step comprises determining the presence of the mutation in the mutant ESR1 polypeptide or in the nucleic acid molecule encoding the mutant ESR1 polypeptide by sequencing.

12. The method of claim 1 , wherein the subject was previously tested for the presence of a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide, wherein the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was not detected during the previous testing,
and wherein the subject was administered a SERM based on the knowledge that the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was not detected during the previous testing.

13. The method of claim 1 , wherein the subject was previously tested at intervals for the presence of a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide, and wherein the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was not detected during the previous testing,
and wherein the subject continued a treatment with a SERM based on the knowledge that the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was not detected during the previous testing.

14. The method of claim 1 , wherein the subject was previously tested or is currently being tested for the presence of the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide at six-month or one-year intervals.

15. The method of claim 1 , wherein the subject was tested at intervals for the presence of a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide, and wherein the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was detected during the testing,
and wherein the subject stopped a treatment with a SERM based on the knowledge that the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was detected during the testing.

16. The method of claim 1 , wherein the acquiring knowledge step comprises detecting the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide in a sample from the subject.

17. The method of claim 1 , further comprising:
identifying, selecting, or obtaining information or knowledge that the subject has participated in a clinical trial or has been treated for cancer;
acquiring genotype information that identifies the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide as being in the subject,
wherein the presence of the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide identifies the subject as having an increased risk for, or having, a cancer associated with the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide.

18. The method of claim 1 , wherein the mutant ESR1 polypeptide comprises a deletion of amino acids Leu-Ala-Asp (LAD) at pos

Assignees

• Found Medicine Inc

Inventors

• Cronin Maureen T
• Frampton Garrett Michael
• Lipson Doron
• Miller Vincent A
• Palmer Gary
• Ross Jeffrey S
• Stephens Philip James
• Yelensky Roman

Classifications

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/536

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• C07K16/2869

  against hormone receptors (for antibodies against neuromediator receptors C07K16/286) · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title