Identification of polynucleotides and polypeptide for predicting activity of compounds that interact with protein tyrosine kinases and/or protein tyrosine kinase pathways

20070166704

10/348119

January 17, 2003

The present invention describes polynucleotides and polypeptides that have been discovered to correlate to the relative intrinsic sensitivity or resistance of cells, e.g., colon cell lines, to treatment with compounds that interact with and inhibit src tyrosine kinases. These polynucleotides and polypeptides have been shown, through a weighted voting cross validation program, to have utility in predicting the intrinsic resistance and sensitivity of colon cell lines to these compounds. Such polynucleotides and polypeptides whose expression levels correlate highly with drug sensitivity or resistance comprise predictor or marker sets of polynucleotides and polypeptides that are useful in methods of predicting drug response and as prognostic or diagnostic indicators in disease management, particularly in those disease areas in which signaling through src tyrosine kinase of the src tyrosine kinase pathway is involved with the disease process.

Huang, Fei (Princeton, NJ, US); Fairchild, Craig R. (Yardley, PA, US); Lee, Francis Y. (Yardley, PA, US); Shaw, Peter (Yardley, PA, US)

1. A predictor set comprising a plurality of polynucleotides whose expression pattern is predictive of the response of cells to treatment with a compound that modulates protein tyrosine kinase activity or members of the protein tyrosine kinase pathway.

2. The predictor set according to claim 1 wherein the polynucleotides are selected from the group consisting of: a.) the polynucleotides provided in Table 3; b.) the sensitive predictor polynucleotides provided in Table 3; c.) the resistant predictor polynucleotides provided in Table 3; d.) the polynucleotides provided in Table 4; e.) the sensitive predictor polynucleotides provided in Table 4; f.) the resistant predictor polynucleotides provided in Table 4; g.) the polynucleotides provided in Table 5; h.) the sensitive predictor polynucleotides provided in Table 5; i.) the resistant predictor polynucleotides provided in Table 5; j.) the polynucleotides provided in Table 6; k.) the sensitive predictor polynucleotides provided in Table 6; and l.) the resistant predictor polynucleotides provided in Table 6;

3. The predictor set according to claim 2 wherein the plurality of polynucleotides comprise the number of polynucleotides selected from the group consisting of: a.) at least about 5 polynucleotides; b.) at least about 10 polynucleotides; c.) at least about 15 polynucleotides; d.) at least about 20 polynucleotides; e.) at least about 25 polynucleotides; and f.) at least about 30 polynucleotides.

4. The predictor set according to claims 3 wherein the plurality of polynucleotides comprise a member of the group consisting of: a.) the polynucleotides provided in Table 10; b.) the sensitive predictor polynucleotides provided in Table 10; c.) the resistant predictor polynucleotides provided in Table 10; d.) the polynucleotides provided in Table 11; e.) the sensitive predictor polynucleotides provided in Table 11; f.) the resistant predictor polynucleotides provided in Table 11; g.) the polynucleotides provided in Table 12; h.) the sensitive predictor polynucleotides provided in Table 12; and i.) the resistant predictor polynucleotides provided in Table 12.

5. The predictor set according to claim 4 wherein the protein tyrosine kinases are selected from the group consisting of: Src, Fgr, Fyn, Yes, Blk, Hck, Lck and Lyn, Bcr-abl, Jak, PDGFR, c-kit and Ephr.

6. The predictor set according to claim 5 wherein the compound is selected from the group consisting of: a.) antisense reagents directed to said polynucleotides; b.) antibodies directed against polypeptides encoded by said polynucleotides; and c.) small molecule compounds.

7. The predictor set according to claim 5 wherein the compound is selected from the group consisting of: a.) BMS-A; b.) BMS-B; c.) BMS-C; and d.) BMS-D.

8. The predictor set according to claim 1 wherein said cells are colon cancer cells.

9. A predictor set comprising a plurality of polypeptides whose expression pattern is predictive of the response of cells to treatment with compounds that modulate protein tyrosine kinase activity or members of the protein tyrosine kinase pathway.

10. The predictor set according to claim 9 wherein the polypeptides are selected from the group consisting of: a.) the polypeptides provided in Table 3; b.) the sensitive predictor polypeptides provided in Table 3; c.) the resistant predictor polypeptides provided in Table 3; d.) the polypeptides provided in Table 4; e.) the sensitive predictor polypeptides provided in Table 4; f.) the resistant predictor polypeptides provided in Table 4; g.) the polypeptides provided in Table 5; h.) the sensitive predictor polypeptides provided in Table 5; i.) the resistant predictor polypeptides provided in Table 5; j.) the polypeptides provided in Table 6; k.) the sensitive predictor polypeptides provided in Table 6; and l.) the resistant predictor polypeptides provided in Table 6.

11. The predictor set according to claim 10 wherein the plurality of polypeptides comprise the number of polypeptides selected from the group consisting of: a.) at least about 5 polypeptides; b.) at least about 10 polypeptides; c.) at least about 15 polypeptides; d.) at least about 20 polypeptides; e.) at least about 25 polypeptides; and f.) at least about 30 polypeptides.

12. The predictor set according to claims 11 wherein the plurality of polypeptides comprise a member of the group consisting of: a.) polypeptides provided in Table 10; b.) the sensitive predictor polypeptides provided in Table 10; c.) the resistant predictor polypeptides provided in Table 10; d.) the polypeptides provided in Table 11; e.) the sensitive predictor polypeptides provided in Table 11; f.) the resistant predictor polypeptides provided in Table 11; g.) the polypeptides provided in Table 12; h.) the sensitive predictor polypeptides provided in Table 12; and i.) the resistant predictor polypeptides provided in Table 12.

13. The predictor set according to claim 12 wherein the protein tyrosine kinases are selected from the group consisting of: Src, Fgr, Fyn, Yes, Blk, Hck, Lck and Lyn, Bcr-abl, Jak, PDGFR, c-kit and Ephr.

14. The predictor set according to claim 13 wherein the compound is selected from the group consisting of: a.) antisense reagents directed to polynucleotides encoding said polypeptides; b.) antibodies directed against said polypeptides; and c.) small molecule compounds.

15. The predictor set according to claim 13 wherein the compound is selected from the group consisting of: a.) BMS-A; b.) BMS-B; c.) BMS-C; and d.) BMS-D.

16. The predictor set according to claim 9 wherein said cells are colon cancer cells.

17. A method for predicting whether a compound is capable of modulating the activity of cells, comprising the steps of: a.) obtaining a sample of cells; b.) determining whether said cells express a plurality of markers; and c.) correlating the expression of said markers to the compounds ability to modulate the activity of said cells.

18. The method according to claim 17 wherein the plurality of markers are polynucleotides.

19. The method according to claim 18 wherein the polynucleotides are selected from the group consisting of: a.) the polynucleotides of claim 1; b.) the polynucleotides of claim 2; c.) the polynucleotides of claim 3; and d.) the polynucleotides of claim 4.

20. The method according to claim 19 wherein the compounds are a member of the group consisting of: a.) the compounds according to claim 5; b.) the compounds according to claim 6; and c.) the compounds according to claim 7.

21. The method according to claim 18 wherein the cells are colon cancer cells.

22. The method according to claim 17 wherein the plurality of markers are polypeptides.

23. The method according to claim 22 wherein the polypeptides are selected from the group consisting of: a.) the polypeptides of claim 9; b.) the polypeptides of claim 10; c.) the polypeptides of claim 11; and d.) the polypeptides of claim 12.

24. The method according to claim 23 wherein the compounds are a member of the group consisting of: d.) the compounds according to claim 13; e.) the compounds according to claim 14; and f.) the compounds according to claim 15.

25. The method according to claim 19 wherein the cells are colon cancer cells.

26. A plurality of cell lines for identifying polynucleotides and polypeptides whose expression levels correlate with compound sensitivity or resistance of cells associated with a disease state.

27. The plurality of cell lines according to claim 26 wherein said cell lines are colon cancer cell lines.

28. The plurality of cell lines according to claim 27 wherein said cell lines comprise one or more cell lines provided in Table 1.

29. A method of identifying polynucleotides and polypeptides that predict compound sensitivity or resistance of cells associated with a disease state, comprising the steps of: a.) subjecting the plurality of cell lines according to claim 28 to one or more compounds; b.) analyzing the expression pattern of a microarray of polynucleotides or polypeptides; and c.) selecting polynucleotides or polypeptides that predict the sensitivity or resistance of cells associated with a disease state by using said expression pattern of said microarray.

30. The method according. to claim 23 wherein the compounds are a member of the group consisting of: a.) the compounds according to claim 5; b.) the compounds according to claim 6; c.) the compounds according to claim 7; d.) the compounds according to claim 13; e.) the compounds according to claim 14; and f.) the compounds according to claim 15

31. The method according to claim 29 wherein said disease is colon cancer.

32. A method for predicting whether an individual requiring treatment for a disease state, will successfully respond or will not respond to said treatment comprising the steps of: a.) obtaining a sample of cells from said individual; b.) determining whether said cells express a plurality of markers; and c.) correlating the expression of said markers to the individuals ability to respond to said treatment.

33. The method according to claim 32 wherein the plurality of markers are polynucleotides.

34. The method according to claim 33 wherein the polynucleotides are selected from the group consisting of: a.) the polynucleotides of claim 1; b.) the polynucleotides of claim 2; c.) the polynucleotides of claim 3; and d.) the polynucleotides of claim 4.

35. The method according to claim 34 wherein the compounds are a member of the group consisting of: a.) the compounds according to claim 5; b.) the compounds according to claim 6; and c.) the compounds according to claim 7.

36. The method according to claim 33 wherein the disease state is colon cancer.

37. The method according to claim 34 wherein the plurality of markers are polypeptides.

38. The method according to claim 37 wherein the polypeptides are selected from the group consisting of: a.) the polypeptides of claim 9; b.) the polypeptides of claim 10; c.) the polypeptides of claim 11; and d.) the polypeptides of claim 12.

39. The method according to claim 38 wherein the compounds are a member of the group consisting of: a.) the compounds according to claim 5; b.) the compounds according to claim 6; and c.) the compounds according to claim 7.

40. The method according to claim 37 wherein the disease state is colon cancer.

435006/000

12; 07

edspap.20070166704