Determining prognosis of colon or breast cancer by measuring TTK expression

• US 7,501,244 B2
• Filed: 09/27/2004
• Issued: 03/10/2009
• Est. Priority Date: 02/21/2001
• Status: Expired due to Fees

• Current Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Original Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Inventors: Chan, Vivien W., Reinhard, Christoph, Jefferson, Anne B.
• Primary Examiner(s): Vivlemore; Tracy
• Application Number:
  US10/951,477
• Publication Number:
  US 20050063974A1
• Time in Patent Office: 1,625 Days
• Field of Search: None
• US Class Current: 435/6.11
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C12N 9/1205 Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Y 207/01037 Protein kinase (2.7.1.37) C12Y207/11001, C12Y207/11008 - C12Y207/11013, C12Y207/11021, C12Y207/11022, C12Y207/11024, C12Y207/11025, C12Y207/1103, C12Y207/12001 take precedence
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/57415 of breast
• CPC Class Codes: G01N 33/57419 of colon
• CPC Class Codes: G01N 33/57496 involving intracellular compounds
• CPC Class Codes: G01N 33/68 involving proteins, peptides or amino acids involving lipoproteins G01N33/92
• CPC Class Codes: G01N 33/6842 Proteomic analysis of subsets of protein mixtures with reduced complexity, e.g. membrane proteins, phosphoproteins, organelle proteins

Abstract

The present invention provides methods for identification of cancerous cells by detection of expression levels of TTK, as well as diagnostic, prognostic and therapeutic methods that take advantage of the differential expression of these genes in mammalian cancer. Such methods can be useful in determining the ability of a subject to respond to a particular therapy, e.g., as the basis of rational therapy. In addition, the invention provides assays for identifying pharmaceuticals that modulate activity of these genes in cancers in which these genes are involved, as well as methods of inhibiting tumor growth by inhibiting activity of TTK.

Claims

1. A method for assessing the prognosis of a human subject having colon or breast cancer, the method comprising:

detecting a level of expression of a TTK-encoding polynucleotide in a test sample, wherein the test sample is derived from tissue of the same type, tumor, blood, plasma, or serum; and

comparing the level of expression of the TTK-encoding polynucleotide in the test sample with a level of expression of the polynucleotide in a control non-cancer sample of the same type;

wherein an increased level of expression of TTK in the test sample relative to the level of expression of the TTK-encoding polynucleotide in the control non-cancer sample is indicative of a poor prognosis for the subject.

2. The method of claim 1, wherein said detecting expression is by detection of a TTK-encoding transcript.

3. The method of claim 1, wherein the test sample is a colon sample.

4. The method of claim 1, wherein the test sample is a breast sample cell.

5. The method of claim 1 wherein the breast cancer is ductal carcinoma in situ, infiltrating ductal carcinoma, lobular carcinoma in situ, infiltrating lobular carcinoma, inflammatory breast cancer, medullary carcinoma, mucinous carcinoma, Paget'"'"'s disease of the nipple, Phyllodes tumor, or tubular carcinoma.

6. The method of claim 1 wherein the colon cancer is familial adenomatous polyposis, Gardner'"'"'s syndrome, hereditary nonpolyposis colon cancer or familial colorectal cancer.

7. The method of claim 1 wherein a poor prognosis is indicated by an increase in the expression level of the TTK-encoding polynucleotide in the test sample of at least 2 fold relative to the level of expression of the TTK-encoding polynucleotide in the normal non-cancer sample.

8. The method of claim 1 wherein a poor prognosis is indicated by an increase in the expression level of the TTK-encoding polynucleotide in the test sample of at least 2.5 fold relative to the level of expression of the TTK-encoding polynucleotide in the normal non-cancer sample.

9. The method of claim 1 wherein a poor prognosis is indicated by an increase in the expression level of the TTK-encoding polynucleotide in the test sample of at least 5 fold relative to the level of expression of the TTK-encoding polynucleotide in the normal non-cancer sample.

10. The method of claim 1 wherein TTK expression is detected by measuring TTK mRNA levels.

11. The method of claim 1 wherein TTK expression is detected by measuring TTK polypeptide levels.

12. The method of claim 1 further comprising detecting differential expression of at least one of p53, DCC, ras, FAP MAPKAPK2, MARCKS and IGF2 polynucleotide in the test sample relative to the normal non-cancer sample.

13. The method of claim 12 wherein the differential expression of p53, DCC, ras, FAP MAPKAPK2, MARCKS and IGF2 is upregulation of expression of at least one of p53, DCC, ras, FAP MAPKAPK2, MARCKS and IGF2 compared to a control.

14. The method of claim 12 wherein increased expression of TTK and differential expression of p53, DCC, ras, FAP MAPKAPK2, MARCKS and IGF2 polynucleotide in the test sample relative to the normal non-cancer sample indicates that the subject has a poor prognosis.

15. The method of claim 1 wherein expression levels of TTK polynucleotide are measured using PCR or hybridization under stringent conditions, wherein said conditions comprise incubation at 42°

C. in 50% formamide, 5×

SSC, and 0.2% SDS.

16. The method of claim 1 wherein the TTK polynucleotide comprises a nucleotide sequence at least 95% identical to a sequence of SEQ ID NO:

13.

17. The method of claim 16 wherein the nucleotide sequence at least 95% identical to a sequence of SEQ ID NO:

13 encodes a TTK polypeptide with protein kinase activity.

18. The method of claim 1 wherein the TTK polynucleotide comprises a nucleotide sequence at least 98% identical to a sequence of SEQ ID NO:

13.

19. The method of claim 1 wherein the TTK polynucleotide comprises the nucleotide sequence of SEQ ID NO:

13.

20. The method of claim 1 wherein the TTK polynucleotide comprises a nucleotide sequence encoding at least 25 contiguous amino acids of SEQ ID NO:

14.

21. The method of claim 1 wherein the TTK polynucleotide comprises a nucleotide sequence comprising between 15 to 100 contiguous nucleotides of SEQ ID NO:

13.