BIOMARKERS USEFUL FOR DIAGNOSING PROSTATE CANCER, AND METHODS THEREOF

• US 20090127454A1
• Filed: 03/23/2007
• Published: 05/21/2009
• Est. Priority Date: 03/24/2006
• Status: Active Grant

• Current Assignee: Med-Life Discoveries LP
• Original Assignee: Phenomenome Discoveries Inc.
• Inventors: Bingham, Erin, Ritchie, Shawn
• Granted Patent: US 8,409,794 B2
• Time in Patent Office: Days
• US Class Current: 250/282
• CPC Class Codes: C07F 9/091 with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: G01N 2333/745 Assays involving non-enzymic blood coagulation factors
• CPC Class Codes: G01N 2405/04 Phospholipids, i.e. phosphoglycerides
• CPC Class Codes: G01N 30/7233 interfaced to liquid or supercritical fluid chromatograph interfaces in general for introducing or extracting samples to be analysed with specially adapted mass spectrometer, see H01J49/04
• CPC Class Codes: G01N 33/49 Blood chemical methods for determining blood cell populations G01N33/5094; chemical analysis of blood groups or blood types G01N33/80
• CPC Class Codes: G01N 33/57434 of prostate
• CPC Class Codes: G01N 33/6848 Methods of protein analysis involving mass spectrometry

Abstract

The present invention describes a method for predicting a health-state indicative of the presence of prostate cancer. The method measures the intensities of specific small biochemicals, called metabolites, in a blood sample from a patient with an undetermined health-state, and compares these intensities to the intensities observed in a population of healthy individuals and/or to the intensities previously observed in a population of confirmed prostate cancer-positive individuals. The method enables a practitioner to determine the probability that a screened patient is positive for prostate cancer.

Claims

1-36. -36. (canceled)

37. A method for diagnosing prostate cancer or the risk of prostate cancer in a patient, the method comprising the steps of:

a) analyzing a sample from said patient to obtain quantifying data for one or more than one metabolite marker;

b) comparing the quantifying data for said one or more than one metabolite marker to corresponding data obtained from one or more than one reference sample, wherein said comparison can be used to diagnose prostate cancer or the risk of prostate cancer, wherein the one or more than one metabolite marker is selected from the metabolites listed in Table 1, or any combination thereof.

38. The method of claim 37, wherein step a) comprises analyzing the sample by liquid chromatography mass spectrometry (LC-MS).

39. The method of claim 37, wherein the method is a high-throughput method and step a) comprises analyzing the sample by direct injection or liquid chromatography and linear ion trap tandem mass spectrometry.

40. The method of claim 37, wherein said one or more than one reference sample is a plurality of samples obtained from control individuals;

one or more than one baseline sample obtained from the patient at an earlier date;

or a combination thereof.

41. The method of claim 37, wherein said one or more than one metabolite marker is selected from the group consisting of lysophospholipids, including lysophosphatidylcholines, lysophosphatidylethanolamines, lysophosphatidyldimethylethanolamines, lysophosphatidylserines, lysosphingosylphosphoryl-cholines, lysophosphatidylglycerols, lysophosphatidylinositols, platelet activating factors (PAFs), and combinations thereof.

42. The method of claim 37, wherein said one or more than one metabolite marker comprises metabolites with accurate masses measured in Daltons of, or substantially equivalent to, a) 495.3328, b) 517.3148, c) 519.3328, d) 521.3480, e) 523.3640, f) 541.3148, g) 545.3460, h) 481.3171, i) 531.3123, j) 541.3422, k) 555.3101, l) 565.3394, m) 567.3546, and n) 569.3687;

and wherein the metabolites are decreased in patients with prostate cancer.

43. The method of claim 42, wherein metabolites a) to g) are lysophosphatidylcholine-related compounds and metabolites h) to n) are N,N-dimethyl-lysophosphoethanolamine-related compounds.

44. The method of claim 42, wherein the one or more than one metabolite is further characterized by an MS/MS spectrum as shown in

a) FIG. 7, and/or as described in Table 3;

b) FIG. 8, and/or as described in Table 4;

c) FIG. 9, and/or as described in Table 5;

d) FIG. 10, and/or as described in Table 6;

e) FIG. 11, and/or as described in Table 7;

f) FIG. 12, and/or as described in Table 8;

g) FIG. 13, and/or as described in Table 9;

h) FIG. 14, and/or as described in Table 12;

i) FIG. 15, and/or as described in Table 13;

j) FIG. 16, and/or as described in Table 14;

k) FIG. 17, and/or as described in Table 15;

l) FIG. 18, and/or as described in Table 16;

m) FIG. 19, and/or as described in Table 17; and

n) FIG. 20, and/or as described in Table 18, respectively.

45. The method of claim 44, wherein the one or more than one metabolite is further characterized by molecular formula a) C₂₄H₅₀NO₇P, b) C₂₆H₄₈NO₇P, c) C₂₆H₅₀NO₇P, d) C₂₆H₅₂NO₇P, e) C₂₆H₅₄NO₇P, f) C₂₈H₄₈NO₇P, g) C₂₈H₅₂NO₇P, h) C₂₃H₄₈NO₇P, i) C₃₀H₄₆NO₅P, j) C₂₅H₅₂NO₉P, k) C₂₅H₅₀NO₁₀P, l) C₂₇H₅₂NO₉P, m) C₂₇H₅₄NO₉P, and n) C₂₇H₅₆NO₉P, respectively.

46. The method of claim 45, wherein the one or more than one metabolite is further characterized by the structure

47. A method for diagnosing prostate cancer or the risk of prostate cancer in a patient, the method comprising the steps of:

a) analyzing a sample from said patient to obtain quantifying data for one or more than one metabolite marker;

b) obtaining a ratio for each of the one or more than one metabolite marker to an internal control metabolite;

c) comparing each ratio of said one or more than one metabolite marker to the internal control metabolite to corresponding data obtained from one or more than one reference sample, wherein said comparison can be used to diagnose prostate cancer or the risk of prostate cancer,

wherein the one or more than one metabolite marker is selected from metabolites listed in Table 1, or any combination thereof.

48. The method of claim 47, wherein step a) comprises analyzing the sample by liquid chromatography mass spectrometry (LC-MS).

49. The method of claim 47, wherein the method is a high-throughput method and step a) comprises analyzing the sample by direct injection or liquid chromatography and linear ion trap tandem mass spectrometry.

50. The method of claim 47, wherein said one or more than one reference sample is a plurality of samples obtained from control individuals;

one or more than one baseline sample obtained from the patient at an earlier date;

or a combination thereof.

51. The method of claim 47, wherein said one or more than one metabolite marker is selected from the group consisting of lysophospholipids, including lysophosphatidylcholines, lysophosphatidylethanolamines, lysophosphatidyldimethylethanolamines, lysophosphatidylserines, lysosphingosylphosphorylcholines, lysophosphatidylglycerols, lysophosphatidylinositols, platelet activating factors (PAFs), and combinations thereof.

52. The method of claim 47, wherein said one or more than one metabolite marker comprises metabolites with accurate masses measured in Daltons of, or substantially equivalent to, a) 495.3328, b) 517.3148, c) 519.3328, d) 521.3480, e) 523.3640, f) 541.3148, g) 545.3460, h) 481.3171, i) 531.3123, j) 541.3422, k) 555.3101, l) 565.3394, m) 567.3546, and n) 569.3687;

and wherein the ratio of metabolite to the internal control metabolite is decreased in patients with prostate cancer.

53. The method of claim 52, wherein metabolites a) to g) are lysophosphatidylcholine-related compounds and metabolites h) to n) are N,N-dimethyl phosphoethanolamine-related compounds.

54. The method of claim 52, wherein the one or more than one metabolite is further characterized by an MS/MS spectrum as shown in

a) FIG. 7, and/or as described in Table 3;

b) FIG. 8, and/or as described in Table 4;

c) FIG. 9, and/or as described in Table 5;

d) FIG. 10, and/or as described in Table 6;

e) FIG. 11, and/or as described in Table 7;

f) FIG. 12, and/or as described in Table 8;

g) FIG. 13, and/or as described in Table 9;

h) FIG. 14, and/or as described in Table 12;

i) FIG. 15, and/or as described in Table 13;

j) FIG. 16, and/or as described in Table 14;

k) FIG. 17, and/or as described in Table 15;

l) FIG. 18, and/or as described in Table 16;

m) FIG. 19, and/or as described in Table 17; and

n) FIG. 20, and/or as described in Table 18, respectively.

55. The method of claim 54, wherein the one or more than one metabolite is further characterized by molecular formula a) C₂₄H₅₀NO₇P, b) C₂₆H₄₈NO₇P, c) C₂₆H₅₀NO₇P, d) C₂₆H₅₂NO₇P, e) C₂₆H₅₄NO₇P, f) C₂₈H₄₈NO₇P, g) C₂₈H₅₂NO₇P, h) C₂₃H₄₈NO₇P, i) C₃₀H₄₆NO₅P, j) C₂₅H₅₂NO₉P, k) C₂₅H₅₀NO₁₀P, l) C₂₇H₅₂NO₉P, m) C₂₇H₅₄NO₉P, and n) C₂₇H₅₆NO₉P, respectively.

56. The method of claim 55, wherein the one or more than one metabolite is further characterized by the structure

57. A method for evaluating the efficacy of a therapy for treating prostate cancer in a patient, comprising:

a) analyzing a sample from said patient to obtain quantifying data for one or more than one metabolite marker;

b) comparing said quantifying data to corresponding data obtained from one or more than one reference sample, wherein said comparison can be used to determine whether the therapy is improving the health state of the patient,

wherein the one or more than one metabolite marker is selected from metabolites listed in Table 1, or any combination thereof.

58. The method of claim 57, wherein step a) comprises analyzing the sample by liquid chromatography mass spectrometry (LC-MS).

59. The method of claim 57, wherein the method is a high-throughput method and step a) comprises analyzing the sample by direct injection or liquid chromatography and linear ion trap tandem mass spectrometry.

60. The method of claim 57, wherein said one or more than one reference sample is a plurality of samples obtained from control individuals;

one or more than one pre-therapy baseline sample obtained from the patient;

or a combination thereof.

61. The method of claim 57, wherein said one or more than one metabolite marker comprises metabolites with accurate masses measured in Daltons of, or substantially equivalent to, a) 495.3328, b) 517.3148, c) 519.3328, d) 521.3480, e) 523.3640, f) 541.3148, g) 545.3460, h) 481.3171, i) 531.3123, j) 541.3422, k) 555.3101, l) 565.3394, m) 567.3546, and n) 569.3687;

and wherein the metabolites are decreased in patients with prostate cancer.

62. The method of claim 61, wherein the one or more than one metabolite is further characterized by an MS/MS spectrum as shown in

a) FIG. 7, and/or as described in Table 3;

b) FIG. 8, and/or as described in Table 4;

c) FIG. 9, and/or as described in Table 5;

d) FIG. 10, and/or as described in Table 6;

e) FIG. 11, and/or as described in Table 7;

f) FIG. 12, and/or as described in Table 8;

g) FIG. 13, and/or as described in Table 9;

h) FIG. 14, and/or as described in Table 12;

i) FIG. 15, and/or as described in Table 13;

j) FIG. 16, and/or as described in Table 14;

k) FIG. 17, and/or as described in Table 15;

l) FIG. 18, and/or as described in Table 16;

m) FIG. 19, and/or as described in Table 17; and

n) FIG. 20, and/or as described in Table 18, respectively.

63. The method of claim 62, wherein the one or more than one metabolite is further characterized by molecular formula a) C₂₄H₅₀NO₇P, b) C₂₆H₄₈NO₇P, c) C₂₆H₅₀NO₇P, d) C₂₆H₅₂NO₇P, e) C₂₆H₅₄NO₇P, f) C₂₈H₄₈NO₇P, g) C₂₈H₅₂NO₇P, h) C₂₃H₄₈NO₇P, i) C₃₀H₄₆NO₅P, j) C₂₅H₅₂NO₉P, k) C₂₅H₅₀NO₁₀P, l) C₂₇H₅₂NO₉P, m) C₂₇H₅₄NO₉P, and n) C₂₇H₅₆NO₉P, respectively.

64. The method of claim 63, wherein the one or more than one metabolite is further characterized by the structure

65. A method for evaluating the efficacy of a therapy for treating prostate cancer in a patient, comprising:

a) analyzing a sample from said patient to obtain quantifying data for one or more than one metabolite marker;

b) obtaining a ratio for each of the one or more than one metabolite marker to an internal control metabolite;

c) comparing each ratio of said one or more than one metabolite marker to the internal control metabolite to corresponding data obtained from one or more than one reference sample, wherein said comparison can be used to determine whether the therapy is improving the health state of the patient,

wherein the one or more than one metabolite marker is selected from metabolites listed in Table 1, or any combination thereof.

66. The method of claim 65, wherein step a) comprises analyzing the sample by liquid chromatography mass spectrometry (LC-MS).

67. The method of claim 65, wherein the method is a high-throughput method and step a) comprises analyzing the sample by direct injection or liquid chromatography and linear ion trap tandem mass spectrometry.

68. The method of claim 65, wherein said one or more than one reference sample is a plurality of samples obtained from control individuals;

one or more than one pre-therapy baseline sample obtained from the patient;

or a combination thereof.

69. The method of claim 65, wherein said one or more than one metabolite marker comprises metabolites with accurate masses measured in Daltons of, or substantially equivalent to, a) 495.3328, b) 517.3148, c) 519.3328, d) 521.3480, e) 523.3640, f) 541.3148, g) 545.3460, h) 481.3171, i) 531.3123, j) 541.3422, k) 555.3101, l) 565.3394, m) 567.3546, and n) 569.3687;

and wherein the ratio of metabolite to the internal control metabolite is decreased in patients with prostate cancer.

70. The method of claim 69, wherein the one or more than one metabolite is further characterized by an MS/MS spectrum as shown in

a) FIG. 7, and/or as described in Table 3;

b) FIG. 8, and/or as described in Table 4;

c) FIG. 9, and/or as described in Table 5;

d) FIG. 10, and/or as described in Table 6;

e) FIG. 11, and/or as described in Table 7;

f) FIG. 12, and/or as described in Table 8;

g) FIG. 13, and/or as described in Table 9;

h) FIG. 14, and/or as described in Table 12;

i) FIG. 15, and/or as described in Table 13;

j) FIG. 16, and/or as described in Table 14;

k) FIG. 17, and/or as described in Table 15;

l) FIG. 18, and/or as described in Table 16;

m) FIG. 19, and/or as described in Table 17; and

n) FIG. 20, and/or as described in Table 18, respectively.

71. The method of claim 70, wherein the one or more than one metabolite is further characterized by molecular formula a) C₂₄H₅₀NO₇P, b) C₂₆H₄₈NO₇P, c) C₂₆H₅₀NO₇P, d) C₂₆H₅₂NO₇P, e) C₂₆H₅₄NO₇P, f) C₂₈H₄₈NO₇P, g) C₂₈H₅₂NO₇P, h) C₂₃H₄₈NO₇P, i) C₃₀H₄₆NO₅P, j) C₂₅H₅₂NO₉P, k) C₂₅H₅₀NO₁₀P, l) C₂₇H₅₂NO₉P, m) C₂₇H₅₄NO₉P, and n) C₂₇H₅₆NO₉P, respectively.

72. The method of claim 71, wherein the one or more than one metabolite is further characterized by the structure

73. A method for diagnosing prostate cancer or the risk of prostate cancer a patient comprising the steps of:

screening a sample from said patient for the presence or absence of one or more metabolic markers selected from the group consisting of metabolites listed in Table 1 or fragments or derivatives thereof, wherein a difference in intensity of one or more of said metabolic markers indicates the presence of prostate cancer or the risk of prostate cancer.

74. The method of claim 73, wherein the method comprises analyzing the sample by liquid chromatography mass spectrometry (LC-MS).

75. The method of claim 73, wherein the method is a high throughput method and comprises analyzing the sample by direct injection or liquid chromatography and linear ion trap tandem mass spectrometry.

76. The method of claim 73, wherein said one or more than one metabolite marker is selected from the group consisting of lysophospholipids, including lysophosphatidylcholines, lysophosphatidylethanolamines, lysophosphatidyldimethylethanolamines, lysophosphatidylserines, lysosphingosylphosphoryl-cholines, lysophosphatidylglycerols, lysophosphatidylinositols, platelet activating factors (PAFs), and combinations thereof.

77. The method of claim 73, wherein said one or more than one metabolite marker comprises metabolites with accurate masses measured in Daltons of, or substantially equivalent to, a) 495.3328, b) 517.3148, c) 519.3328, d) 521.3480, e) 523.3640, f) 541.3148, g) 545.3460, h) 481.3171, i) 531.3123, j) 541.3422, k) 555.3101, l) 565.3394, m) 567.3546, and n) 569.3687;

and wherein the metabolites are decreased in patients with prostate cancer.

78. The method of claim 77, wherein metabolites a) to g) are lysophosphatidylcholine-related compounds and metabolites h) to n) are N,N-dimethyl-lysophosphoethanolamine-related compounds.

79. The method of claim 77, wherein the one or more than one metabolite is further characterized by an MS/MS spectrum as shown in

a) FIG. 7, and/or as described in Table 3;

b) FIG. 8, and/or as described in Table 4;

c) FIG. 9, and/or as described in Table 5;

d) FIG. 10, and/or as described in Table 6;

e) FIG. 11, and/or as described in Table 7;

f) FIG. 12, and/or as described in Table 8;

g) FIG. 13, and/or as described in Table 9;

h) FIG. 14, and/or as described in Table 12;

i) FIG. 15, and/or as described in Table 13;

j) FIG. 16, and/or as described in Table 14;

k) FIG. 17, and/or as described in Table 15;

l) FIG. 18, and/or as described in Table 16;

m) FIG. 19, and/or as described in Table 17; and

n) FIG. 20, and/or as described in Table 18, respectively.

80. The method of claim 79, wherein the one or more than one metabolite is further characterized by molecular formula a) C₂₄H₅₀NO₇P, b) C₂₆H₄₉NO₇P, c) C₂₆H₅₀NO₇P, d) C₂₆H₅₂NO₇P, e) C₂₆H₅₄NO₇P, f) C₂₈H₄₈NO₇P, g) C₂₈H₅₂NO₇P, h) C₂₃H₄₈NO₇P, i) C₃₀H₄₆NO₅P, j) C₂₅H₅₂NO₉P, k) C₂₅H₅₀NO₁₀P, l) C₂₇H₅₂NO₉P, m) C₂₇H₅₄NO₉P, and n) C₂₇H₅₆NO₉P, respectively.

81. The method of claim 80, wherein the one or more than one metabolite is further characterized by the structure