Biomarker indicating response to poziotinib therapy for cancer

Patent metadata

Field	Value
Publication number	US-2020370102-A1
Application number	US-201816763714-A
Country	US
Kind code	A1
Filing date	Nov 14, 2018
Priority date	Nov 14, 2017
Publication date	Nov 26, 2020
Grant date	—

Abstract

Provided are biomarkers that are sensitive or resistant to poziotinib therapy for cancer and methods of using the biomarkers.

First claim

1 . A pharmaceutical composition for the treatment of cancer of a subject, the pharmaceutical composition comprising poziotinib, wherein the subject has cancer cells that have
at least one selected from copy number amplification of the ERBB2 gene, one or more mutations in an ERBB2 gene region including the ERBB2 gene and a sequence within 10 kb upstream of the ERBB2 gene, an ERBB3 wild-type gene, a BARD1 wild-type gene, a SETBP1 wild-type gene, a PIK3CA wild-type gene, one or more mutations in the NOTCH3 gene, one or more mutations in the SH2B3 gene, copy number amplification of the CDK12 gene, copy number deletion of the BRCA1 gene, copy number deletion of the STAT3 gene, and no copy number variation of the FGFR3 gene.

2 . The pharmaceutical composition of claim 1 , wherein the cancer comprises breast cancer, ovarian cancer, head and neck cancer, lung cancer, gastric cancer, colon cancer, kidney cancer, blood cancer, or pancreatic cancer.

3 . The pharmaceutical composition of claim 1 , wherein the subject has a HER2-positive metastatic breast cancer.

4 . The pharmaceutical composition of claim 1 , wherein the subject has undergone HER2-targeted cancer treatment, not treatment with poziotinib.

5 . The pharmaceutical composition of claim 1 , wherein the cancer cells have one or more mutations in an extracellular domain-encoding region of the ERBB2 gene or within 10 kb upstream of the ERBB2 gene.

6 . The pharmaceutical composition of claim 1 , wherein the cancer cells have a log 2 (ratio) value of the ERBB2 gene which is 1 or more, 2 or more, or 4 or more, wherein the ratio is obtained by dividing a copy number of the ERRB2 gene in the cancer cells by a copy number of the ERRB2 gene in normal cells.

7 . The pharmaceutical composition of claim 1 , wherein the cancer cells are sensitive to poziotinib.

8 . The pharmaceutical composition of claim 1 , wherein a mutation in the ERBB2 gene region includes a nucleotide mutation that causes substitution of at least one amino acid selected from Q568E, P601R, I628M, P885S, R143Q, R434Q, and E874K in the amino acid sequence of ERBB2 of SEQ ID NO: 1, and at least one substitution mutation selected from substitution of G at position 1898 with C in a nucleotide sequence encoding ERBB2 of SEQ ID NO: 2, substitution of A at position 100 with Gin a nucleotide sequence of SEQ ID NO: 3, and substitution of C at position 100 with Tin a nucleotide sequence of SEQ ID NO: 4.

9 . The pharmaceutical composition of claim 8 , wherein the nucleotide mutation that causes substitution of at least one amino acid selected from Q568E, P601R, I628M, P885S, R143Q, R434Q, and E874K comprises at least one substitution selected from substitution of C at position 1702 with G, substitution of C at position 1802 with G, substitution of C at position 1884 with G, substitution of C at position 2653 with T, substitution of G at position 428 with A, substitution of G at position 1301 with A, and substitution of G at position 2620 with A, in the nucleotide sequence of SEQ ID NO: 2.

10 . Use of poziotinib in the preparation of medicaments for the treatment of a subject having cancer, wherein the subject has cancer cells that have
at least one selected from copy number amplification of the ERBB2 gene, one or more mutations in an ERBB2 gene region including the ERBB2 gene and a sequence within 10 kb upstream of the ERBB2 gene, the ERBB3 wild-type gene, the BARD1 wild-type gene, the SETBP1 wild-type gene, the PIK3CA wild-type gene, one or more mutations in the NOTCH3 gene, one or more mutations in the SH2B3 gene, copy number amplification of the CDK12 gene, copy number deletion of the BRCA1 gene, copy number deletion of the STAT3 gene, and no copy number variation of the FGFR3 gene.

11 . A method of treating cancer in a subject, the method comprising administering a therapeutically effective amount of poziotinib to the subject having cancer, wherein the subject has cancer cells that have
at least one selected from copy number amplification of the ERBB2 gene, one or more mutations in an ERBB2 gene region including the ERBB2 gene and a sequence within 10 kb upstream of the ERBB2 gene, the ERBB3 wild-type gene, the BARD1 wild-type gene, the SETBP1 wild-type gene, the PIK3CA wild-type gene, one or more mutations in the NOTCH3 gene, one or more mutations in the SH2B3 gene, copy number amplification of the CDK12 gene, copy number deletion of the BRCA1 gene, copy number deletion of the STAT3 gene, and no copy number variation of the FGFR3 gene.

12 . The method of claim 11 , wherein the cancer comprises breast cancer, ovarian cancer, head and neck cancer, lung cancer, gastric cancer, colon cancer, kidney cancer, blood cancer, or pancreatic cancer.

13 . The method of claim 11 , wherein the subject has a HER2-positive metastatic breast cancer.

14 . The method of claim 11 , wherein the subject has undergone HER2-targeted cancer treatment, not treatment with poziotinib.

15 . The method of claim 11 , wherein the cancer cells have one or more mutations in an extracellular domain-encoding region of the ERBB2 gene or the sequence within 10 kb upstream of the ERBB2 gene.

16 . The method of claim 11 , wherein the cancer cells have an average number of replication units of the ERBB2 gene of 2 or more.

17 . The method of claim 11 , wherein a mutation in the ERBB2 gene region comprises a nucleotide mutation that causes substitution of at least one amino acid selected from Q568E, P601R, I628M, P885S, R143Q, R434Q, and E874K in the amino acid sequence of ERBB2 of SEQ ID NO: 1, and at least one substitution mutation selected from substitution of G at position 1898 with C in a nucleotide sequence encoding ERBB2 of SEQ ID NO: 2, substitution of A at position 100 with Gin a nucleotide sequence of SEQ ID NO: 3, and substitution of C at position 100 with T in a nucleotide sequence of SEQ ID NO: 4.

18 . The method of claim 17 , wherein the nucleotide mutation that causes substitution of at least one amino acid selected from Q568E, P601R, I628M, P885S, R143Q, R434Q, and E874K comprises at least one substitution selected from substitution of C at position 1702 with G, substitution of C at position 1802 with G, substitution of C at position 1884 with G, substitution of C at position 2653 with T, substitution of G at position 428 with A, substitution of G at position 1301 with A, and substitution of G at position 2620 with A, in the nucleotide sequence of SEQ ID NO: 2.

19 . A method of treating poziotinib-sensitive cancer in a subject, the method comprising: detecting that a cancer cell-containing sample obtained from the subject has
at least one selected from copy number amplification of the ERBB2 gene, one or more mutations in an ERBB2 gene region including the ERBB2 gene and a sequence within 10 kb upstream of the ERBB2 gene, the ERBB3 wild-type gene, the BARD1 wild-type gene, the SETBP1 wild-type gene, the PIK3CA wild-type gene, one or more mutations in the NOTCH3 gene, one or more mutations in the SH2B3 gene, copy number amplification of the CDK12 gene, copy number deletion of the BRCA1 gene, copy number deletion of the STAT3 gene, and no copy number variation of the FGFR3 gene, wherein having at least one selected from copy number amplification of the ERBB2 gene, one or more mutations in the ERBB2 gene region including the ERBB2 gene and a sequence within 10 kb upstream of the ERBB2 gene, the ERBB3 wild-type gene, the BARD1 wild-type gene, the SETBP1 wild-type gene, the PIK3CA wild-type gene, one or more mutations in the NOTCH3 gene, one or more mutations in the

Assignees

• Hanmi Pharm Ind Co Ltd
• Nat Cancer Ct
• Samsung Life Public Welfare Foundation

Inventors

• Park Yeon Hee
• Park Kyung Hee
• Lee Eun Jin
• Park Woong Yang
• Kim Min Chae
• Park Young Whan
• Kim Jung Yong

Classifications

• C12Q1/6886 Primary

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

• C12Q2600/106

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

• C12Q2600/158

  Expression markers · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title