Biomarkers for monitoring inhibition of IMPDH pathway

CLAIMS What is claimed is: 1. A nucleic acid array consisting essentially of at least 4 polynucleotides selected from the polynucleotides listed in any one or more of Tables I through VIII, wherein said polynucleotides are immobilized on a solid surface, and wherein said array further contains one or more calibration points and one or more housekeeping genes.

2. The nucleic acid array of claim 1, wherein said polynucleotides are cDNAs.

3. The nucleic acid array of claim 1, wherein said polynucleotides are oligonucleotides.

4. The nucleic acid array of claim 1, comprising at least 10 of said polynucleotides.

5. The nucleic acid array of claim 1, comprising at least 15 of said polynucleotides.

6. The nucleic acid array of claim 1, comprising at least 20 of said polynucleotides.

7. The nucleic acid array of claim 1, comprising polynucleotides hybridizing to all of the genes of Tables I through VIII.

8. The nucleic acid array of claim 1, comprising more than one polynucleotide hybridizing to the same gene.

9. A nucleic acid array consisting essentially of at least 4 distinct nucleic acid sequences selected from the group consisting of the polynucleotides listed in Table I, immobilized on the surface at discrete and known positions, wherein said nucleic acids hybridize to nucleic acids in a sample of a subject that are either up-regulated or down- regulated in response to inhibition of IMPDH.

10. A nucleic acid array consisting essentially of at least 4 distinct nucleic acid sequences selected from the group consisting of the polynucleotides listed in Table IV,

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immobilized on the surface at discrete and known positions, wherein said nucleic acids hybridize to nucleic acids in a sample of a subject that are either up-regulated or down- regulated in response to inhibition ofIMPDH.

11. The nucleic acid array of claim 10, wherein the nucleic acids on said microarray are selected from the group consisting of the genes from Table V.

12. The nucleic acid array of claim 10, wherein the nucleic acids on said microarray are selected from the group consisting of the genes from Table VI.

13. A nucleic acid array consisting essentially of at least 4 distinct nucleic acid sequences selected from the group consisting of the polynucleotides listed in Table VII, immobilized on the surface at discrete and known positions, wherein said nucleic acids hybridize to nucleic acids in a sample of a subject that are either up-regulated or down- regulated in response to inhibition of IMPDH.

14. The nucleic acid array of claim 10, wherein the surface is selected from the group consisting of a metal, silicon, a polymer plastic, paper, ceramic, quartz, gallium arsenide, metal, metalloid, cellulose, celluose acetate, nitrocellulose, and a glass.

15. The nucleic acid array of claim 14, wherein the plastic is selected from the group consisting of nylon, polycarbonate, polyethylene, polystyrene, teflon, polypropylene, poly (4-methylbutene), polymethacrylate, poly(ethylene terephthalate), rayon, polyvinylbutyrate, and polyvinylidene difluoride.

16. The nucleic acid array of claim 1, wherein said at least one control spot consists of one or more nucleic acids that are known not to be modulated with IMPDH inhibition.

17. The nucleic acid array of claim 1, wherein said array contains between 1 to 10 control spots.

18. The nucleic acid array of claim 13, wherein said surface comprises a plurality of microarrays separated from each other with a hydrophobic polymer strip.

19. The nucleic acid array of claim 13, wherein the hydrophobic polymer strip is selected from the group of polyethylene, silicone, paraffin, and Teflon@.

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20. A set of polynucleotides for use in the detection of IMPDH inhibition, wherein said polynucleotides hybridize to 4 to 314 genes selected from the group consisting of the genes set forth in any one or more of Table I, Table II, Table III, Table IV, Table V, Table VI, Table VII and Table VIII wherein the expression of each said nucleic acid is either up- or down-regulated in response to inhibition of IMPDH.

21. A set of polynucleotides for use in the prediction of efficacy of an IMPDH inhibitor in non-proliferating cells, wherein the set of polynucleotides hybridize to 4 to 38 genes selected from the group consisting of the genes set forth in Table I.

22. A set of polynucleotides for use in the prediction of efficacy of an IMPDH inhibitor in a proliferating cell, wherein the set of polynucleotides hybridize to 4 to 300 genes selected from the group consisting of the genes set forth in Table II, Table III, and Table IV.

23. The set of claim 22, wherein said proliferating cell is from a hematological cancer and said genes are selected from the group of genes set forth in Table V.

24. The set of claim 22 wherein the genes are selected from the group of genes set forth in Table VI.

25. A set of nucleic acids for use in the prediction of anti-viral efficacy of an IMPDH inhibitor, wherein the set of polynucleotides hybridize to 4 to 9 genes selected from the group consisting of the genes set forth in Table VII.

26. A set of nucleic acids for use in the prediction of efficacy of an IMPDH inhibitor as an anti-cancer agent, wherein the set of polynucleotides hybridize to the 4 genes set forth in Table VIII.

27. A method for predicting whether a candidate IMPDH inhibitory agent will produce a therapeutic effect in a subject comprising: contacting a biological sample with said inhibitory agent and determining the expression level of four or more prognostic genes selected from the group consisting of the genes set forth in one or more of Gene Table I, Gene Table II, Gene Table III, Gene Table IV, Gene Table V, Gene Table VI, Gene Table VII and Gene Table VIII in said biological sample, wherein a modulation of the expression

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level of four or more of genes similar to the modulation resulting from a known IMPDH inhibitor is indicative that said agent is a therapeutically effective IMPDH inhibitory agent.

28. The method of claim 27, wherein said effect is a clinical response.

29. The method of claim 27, wherein said subject is a mammal.

30. The method of claim 27, wherein said subject is a human patient.

31. The method of claim 27, wherein said biological sample is a sample from a cancer patient, and wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, and lung cancer.

32. The method of claim 27, wherein the alteration of expression in response to said IMPDH inhibitory agent is similar to the alteration in expression seen in response to administration of VX-944.

33. The method of claim 27, wherein said biological sample is a tissue sample comprising cancer cells.

34. The method of claim 27, wherein said tissue is fixed, paraffin- 'embedded, fresh, or frozen.

35. The method of claim 34, where the tissue is from a biopsy.

36. The method of claim 27, wherein the biological sample is obtained by fine needle aspiration, bronchial lavage, or transbronchial biopsy.

37. The method of claim 27, wherein the expression level of said prognostic RNA transcript or transcripts is determined by PCR.

38. The method of claim 27, wherein the expression level of said expression product or products is determined by immunohistochemistry.

39. The method of claim 27, wherein the expression level of said expression product or products is determined by in situ hybridization.

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40. The method of claim 27, wherein the assay for the measurement of said prognostic RNA transcripts or their expression products is provided in the form of a kit or kits.

41. A method of preparing a prognostic profile for a subject's response to an IMPDH inhibitor comprising the steps of: (a) exposing ex vivo cells of said subject to an IMPDH inhibitor; (b) subjecting RNA extracted from the cells of step (a) to gene expression profiling; (c) determining the expression level of at least four genes selected from the group consisting of the genes set forth in one or more of Table I, Table II, Table III, Table IV, Table V, Table VI, Table VII and Table VIII in said cells; and (d) comparing the expression levels obtained in step (c) to expression levels obtained in the absence of said IMPDH inhibitor, wherein a modulation of the expression 'level of said four or more of genes in response to said IMPDH inhibitor indicates that said subject is likely to be responsive to said inhibitor.

42. A method of preparing a prognostic profile for a subject's response to an IMPDH inhibitor comprising the steps of: (a) administering to said subject to an IMPDH inhibitor; (b) subjecting RNA extracted from the cells of said subject to gene expression profiling; (c) determining the expression level of at least four genes selected from the group consisting of the genes set forth in one or more of Table I, Table II, Table III, Table IV, Table V, Table VI, Table VII and Table VIII in said cells of said subject;STDC0434 and (d) comparing the expression levels obtained in step c to expression levels obtained in the absence of said administration of said IMPDH inhibitor, wherein a modulation of the expression level of said four or more of genes in response to said IMPDH inhibitor administration indicates that said IMPDH inhibitor will likely predict the subject's response to said IMPDH inhibitor administration.

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43. The method of claim 42, wherein said response is therapeutic response, toxicity, dose range, or patient stratification.

44. The method of claim 41 or 42 wherein said cells are cancer cells obtained from said subject.

45. The method of claim 44, wherein said cancer cells are selected from the group consisting of breast cancer, ovarian cancer, hematological cancer, gastric cancer, colorectal cancer, pancreatic cancer, and lung cancer.

46. The method of claim 44, wherein said cancer cells are in a fixed, paraffin-embedded biopsy sample of said cancer.

47. The method of claim 44, wherein said cancer cells are from a fresh biopsy sample of said cancer.

48. The method of claim 44, wherein said cancer cells are cultured ex vivo.

49. The method of claim claim 41 or 42 wherein said expression profile is compiled into a report that includes recommendation for a treatment for said subject with an IMPDH inhibitor.

50. The method of claim 41 or 42 wherein if altered expression of one or more of the genes selected from the genes set forth in Tables I, II, III, IV, V, VI, VII, and VIII, or the corresponding expression product is determined, said report includes a prediction that said subject is a suitable candidate for IMPDH inhibition-based therapy.

51. The method of claim 42, further comprising the step of treating said patient with an IMPDH inhibitory agent.

52. The method of claim 42, wherein the IMPDH inhibitory agent is identified according to the method of claim 27.

53. The method of claim 42, wherein said biological sample is a blood sample, a tissue biopsy, or a tumor cell isolated from a tumor biopsy.

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54. A kit comprising the nucleic acid array of any of claims 1-19 or a set of polynucleotides of any of claims 20-26, a container, and instructions for use.

55. The kit of claim 54, further comprising nucleic acids of a reference subject.