Novel estrogen receptor mutations and uses thereof

Patent metadata

Field	Value
Publication number	US-2016201135-A1
Application number	US-201514820217-A
Country	US
Kind code	A1
Filing date	Aug 6, 2015
Priority date	Oct 14, 2011
Publication date	Jul 14, 2016
Grant date	—

Abstract

Novel mutant ESR1 molecules and uses are disclosed.

First claim

1 . A method of treating a subject having a breast cancer, comprising:
acquiring knowledge of a presence of a mutant estrogen receptor 1 (ESR1) and an Estrogen Receptor positive (ER+) status, in said subject, wherein the mutant ESR1 comprises a mutation in the ligand binding domain of ESR1; and responsive to said knowledge, administering to the subject an effective amount of an anti-cancer agent other than a Selective Estrogen Receptor Modulator (SERM), thereby treating the breast cancer in the subject.

2 . The method of claim 1 , wherein the mutant ESR1 comprises a mutation chosen from one or more of:
a missense mutation at position 537, 538, 311, 341, 350, 394, 414, 433, or 503 of the amino acid sequence of SEQ ID NO:2 ( FIGS. 2A-2B ), a deletion of nucleotides 1046-1051 of SEQ ID NO:3, or an insertion between positions 344 and 345 of SEQ ID NO:2.

3 . The method of claim 1 , wherein the mutant ESR1 comprises a mutation chosen from one or more of:
a tyrosine to asparagine substitution at position 537 (a Y537N) of SEQ ID NO: 2; a tyrosine to cysteine substitution at position 537 (a Y537C) of SEQ ID NO: 2; an aspartate to glycine substitution at position 538 (a D538G) of SEQ ID NO: 2; a deletion of amino acids LAD at positions 349-351 of SEQ ID NO:4, an insertion of H position 349 of SEQ ID NO:3; a threonine to methionine substitution at position 311 (a T311M) of SEQ ID NO: 2; a serine to leucine substitution at position 341 (a S341L) of SEQ ID NO: 2; an alanine to glutamate substitution at position 350 (a A350E) of SEQ ID NO: 2; an arginine to histidine substitution at position 394 (a R394H) of SEQ ID NO: 2; a glutamine substitution at position 414 of SEQ ID NO: 2; an insertion to a stop codon (a Q414*) of SEQ ID NO: 2; a serine to proline substitution at position 433 (a S433P) of SEQ ID NO: 2; an arginine to tryptophan substitution at position 503 (a R503W) of SEQ ID NO: 2, or an insertion of a cysteine between amino acids G344 and L345 of SEQ ID NO:2.

4 . The method of claim 1 , wherein said subject previously received treatment with a SERM.

5 . The method of claim 1 , wherein said subject has failed a first or second line of treatment with a SERM.

6 . The method of claim 1 , wherein said subject has a late stage, metastatic progressive breast cancer.

7 . The method of claim 1 , wherein said the subject is post-menopausal or pre-menopausal.

8 . The method of claim 1 , wherein the subject stops treatment with the SERM and begins treatment with an anti-cancer agent that is not a SERM.

9 . The method of claim 1 , wherein the SERM is chosen from raloxifene, EM652, GW7604, keoxifene, toremifene, tamoxifen, lasofoxifene, levormeloxifene, bazedoxifene, or arzoxifene.

10 . The method of claim 1 , wherein the anti-cancer agent is a SERD (Selective Estrogen Receptor Degrader), an aromatase inhibitor, an mTOR pathway inhibitor, or a chemotherapeutic agent.

11 . The method of claim 1 , wherein the subject is postmenopausal, and wherein the subject receives a SERD, an aromatase inhibitor, an mTOR pathway inhibitor, or a chemotherapeutic agent.

12 . The method of claim 1 , wherein the anti-cancer agent is fulvestrant.

13 . The method of claim 11 , wherein the aromatase inhibitor is 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.

14 . The method of claim 11 , 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, Palomid 529, PF-04691502, or PKI-587.

15 . The method of claim 1 , wherein the anti-cancer agent is administered in combination with a different therapeutic agent or a different therapeutic modality.

16 . The method of claim 15 , wherein the different therapeutic agent or modality is selected based on a mutation chosen from one or more of HER2 mutation, a HER2 amplification, a p53 mutation, a BRCA mutation, an NF1 mutation, an EGFR/myc gain, a PIK3CA mutation, a CCND1 mutation or a CDH1 mutation.

17 . The method of claim 1 , wherein the acquiring knowledge step comprises determining the presence of the ESR1 mutation by sequencing.

18 . The method of claim 1 , wherein the subject was tested at intervals for the presence of a mutant ESR1, and wherein a mutation in the ligand binding domain of ESR1 was not detected and the subject continued treatment with a SERM based on the knowledge that a mutation in the ligand binding domain of ESR1 was not detected.

19 . The method of claim 1 , wherein the subject was tested for the presence of the mutant ESR1 at 6 month or one year intervals.

20 . The method of claim 1 , wherein the subject was tested at intervals for the presence of a mutant ESR1, and wherein a mutation in the ligand binding domain of ESR1 was detected and the subject stopped treatment with the SERM based on the knowledge that a mutation in the ligand binding domain of ESR1 was detected.

21 . A method of treating a subject having a metastatic ER+ breast cancer, comprising:
acquiring knowledge of the presence of a constitutively activating estrogen receptor 1 (ESR1) mutation in said subject; and administering to the subject an effective amount of an alternative therapy chosen from a SERD, an aromatase inhibitor, an anti-estrogen, a non-steroidal ERα antagonist, a tamoxifen analogue, or a combination thereof,
thereby treating the breast cancer in the subject.

22 . The method of claim 21 , wherein the ESR1 mutation comprises a mutation chosen from a mutation at amino acid 537 or 538, or a combination thereof, of SEQ ID NO: 2.

23 . The method of claim 21 , wherein said subject has been previously treated with tamoxifen.

24 . The method of claim 23 , wherein said subject is ER+ and has a late stage, metastatic progressive breast cancer.

25 . The method of claim 24 , wherein the agent is a SERD.

26 . The method of claim 24 , wherein the anti-estrogen is fulvestrant.

27 . The method of claim 24 , wherein the aromatase inhibitor is 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.

28 . The method of claim 24 , wherein the agent is a non-steroidal ER.alpha. antagonist or a tamoxifen analogue.

29 . A method of treating a subject having a breast cancer, comprising:
acquiring knowledge of a presence of a mutant estrogen receptor 1 (ESR1) and an Estrogen Receptor positive (ER+) status, in said subject, wherein the mutant ESR1 comprises a mutation in the ligand binding domain of ESR1; and responsive to said knowledge, administering to the subject an effective amount of a SERD.

30 . The method of claim 15 , wherein the different therapeutic agent or a different therapeutic modality is an mTOR pathway inhibitor.

Assignees

• Teva Pharma

Inventors

• Cronin Maureen T
• Frampton Garrett Michael
• Lipson Doron
• Miller Vincent A
• Palmer Gary
• Ross Jeffrey S
• Stephens Philip James
• Yelensky Roman
• Soussan-Gutman Lior
• Dvir Addie
• Wolf Ido

Classifications

• A61K31/565

  not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title