SIGNATURE AND DETERMINANTS ASSOCIATED WITH METASTASIS AND METHODS OF USE THEREOF

• US 20110182881A1
• Filed: 06/26/2009
• Published: 07/28/2011
• Est. Priority Date: 06/26/2008
• Status: Abandoned Application

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Scott, Kenneth L., Ghosh, Papia, Chin, Lynda
• Application Number:
  US13/001,203
• Publication Number:
  US 20110182881A1
• Time in Patent Office: Days
• US Class Current: 424/130.1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/6809 Methods for determination or identification of nucleic acids involving differential detection
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2545/113 with an external standard/control, i.e. control reaction is separated from the test/target reaction
• CPC Class Codes: C12Q 2600/112 Disease subtyping, staging or classification
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: G01N 2800/56 Staging of a disease; Further complications associated with the disease
• CPC Class Codes: G01N 2800/60 Complex ways of combining multiple protein biomarkers for diagnosis
• CPC Class Codes: G01N 33/57484 involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Abstract

The present invention provides methods of detecting cancer using biomarkers.

Claims

1. A method with a predetermined level of predictability for assessing a risk of development of a metastatic tumor in a subject comprising:

a. measuring the level of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-25, 41, 61, 62, 63, 66, 74, 96, 99, 103, 126, 135, 137, 138, 177, 190, 210, 212, 217, 218, 227, 239, 261, and 271 in a sample from the subject, and

b. measuring a clinically significant alteration in the level of the two or more DETERMINANTS in the sample, wherein the alteration indicates an increased risk of developing a metastatic tumor in the subject.

2. The method of claim 1, further comprising measuring an effective amount of one or more DETERMINANTS selected from the group consisting of

DETERMINANTS 26-40, 42-60, 64, 65, 67-73, 75-95, 97, 98, 100-102, 104-125, 127-134, 136, 139-176, 178-189, 191-209, 211, 213-216, 219-226, 228-238, 240-260, 262-270, 272-360.

3. The method of claim 1 or 2, further comprising measuring at least one standard parameters associated with said tumor.

4. The method of claim 1, wherein the level of a DETERMINANT is measured electrophoretically or immunochemically.

5. The method of claim 4, wherein the immunochemical detection is by radioimmunoassay, immunofluorescence assay or by an enzyme-linked immunosorbent assay.

6. The method of claim 1, wherein the subject has a primary tumor, a recurrent tumor, or a metastatic tumor.

7. The method of claim 1, wherein the sample is a tumor biopsy.

8. The method of claim 1, wherein said biopsy is a core biopsy, an excisional tissue biopsy or an incisional tissue biopsy.

9. The method of claim 1, wherein the level of expression of five or more DETERMINANTS is measured.

14. The method of claim 2, wherein the second sample is taken from the subject after being treated for the tumor.

10. A method with a predetermined level of predictability for assessing for assessing a risk of development of a metastatic tumor in a subject comprising:

a. measuring the level of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-25, 41, 61, 62, 63, 66, 74, 96, 99, 103, 126, 135, 137, 138, 177, 190, 210, 212, 217, 218, 227, 239, 261, and 271 in a sample from the subject, and

b. comparing the level of the two or more DETERMINANTS to a reference value.

11. The method of claim 10, wherein the reference value is an index value.

12. A method with a predetermined level of predictability for assessing the progression of a tumor in a subject comprising:

a. detecting the level of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-25, 41, 61, 62, 63, 66, 74, 96, 99, 103, 126, 135, 137, 138, 177, 190, 210, 212, 217, 218, 227, 239, 261, and 271 in a first sample from the subject at a first period of time;

b. detecting the level of two or more DETERMINANTS in a second sample from the subject at a second period of time;

c. comparing the level of the two or more DETERMINANTS detected in step (a) to the amount detected in step (b), or to a reference value.

13. The method of claim 12, wherein the first sample is taken from the subject prior to being treated for the tumor.

15. A method with a predetermined level of predictability for monitoring the effectiveness of treatment for a metastatic tumor:

a. detecting the level of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-25, 41, 61, 62, 63, 66, 74, 96, 99, 103, 126, 135, 137, 138, 177, 190, 210, 212, 217, 218, 227, 239, 261, and 271 in a first sample from the subject at a first period of time;

b. detecting the level of two or more DETERMINANTS in a second sample from the subject at a second period of time;

c. comparing the level of the two or more DETERMINANTS detected in step (a) to the amount detected in step (b), or to a reference value, wherein the effectiveness of treatment is monitored by a change in the level of two or more DETERMINANTS from the subject.

16. The method of claim 15, wherein the subject has previously been treated for the metastatic tumor.

17. The method of claim 15, wherein the first sample is taken from the subject prior to being treated for the metastatic tumor.

18. The method of claim 15, wherein the second sample is taken from the subject after being treated for the metastatic tumor.

19. A method with a predetermined level of predictability for selecting a treatment regimen for a subject diagnosed a tumor comprising:

a. detecting the level of an effective amount of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-25, 41, 61, 62, 63, 66, 74, 96, 99, 103, 126, 135, 137, 138, 177, 190, 210, 212, 217, 218, 227, 239, 261, and 271 in a first sample from the subject at a first period of time;

b. optionally detecting the level of an effective amount of two or more DETERMINANTS in a second sample from the subject at a second period of time;

c. comparing the level of the two or more DETERMINANTS detected in step (a) to a reference value, or optionally, to the amount detected in step (b).

20. The method of claim 19, wherein the subject has previously been treated for the tumor.

21. The method of claim 19, wherein the first sample is taken from the subject prior to being treated for the tumor.

22. The method of claim 19, wherein the second sample is taken from the subject after being treated for the tumor.

24. A kit comprising a plurality of DETERMINANT detection reagents that detect the corresponding DETERMINANTS selected from the group consisting of DETERMINANTS 1-25, 41, 61, 62, 63, 66, 74, 96, 99, 103, 126, 135, 137, 138, 177, 190, 210, 212, 217, 218, 227, 239, 261, and 271, sufficient to generate the profile of claim 20.

25. The kit of claim 24, wherein the detection reagent comprises one or more antibodies or fragments thereof.

26. The kit of claim 24, wherein the detection reagent comprises one or more oligonucleotides.

27. The kit of claim 24, wherein the detection reagent comprises one or more aptamers.

30. The panel of claim 26, wherein the physiological or biochemical pathway comprises cell migration, angiogenesis, extracellular matrix degradation or anoikis.

23. A metastatic tumor reference expression profile, comprising a pattern of marker levels of an effective amount of two or more markers selected from the group consisting of DETERMINANTS 1-25, 41, 61, 62, 63, 66, 74, 96, 99, 103, 126, 135, 137, 138, 177, 190, 210, 212, 217, 218, 227, 239, 261, and 271

28. A machine readable media containing one or more metastatic tumor reference expression profiles according to claim 23, and optionally, additional test results and subject information.

29. A DETERMINANT panel comprising one or more DETERMINANTS that are indicative of a physiological or biochemical pathway associated metastasis.

31. A DETERMINANT panel comprising one or more DETERMINANTS that are indicative of the progression of a tumor.

32. A method of identifying a biomarker that is prognostic for a disease comprising:

a) identifying one or more genes that are differentially expressed in said disease compared to a control to produce a gene target list; and

b) identifying one or more genes on said target list that is associated with a functional aspect of the progression of said disease.

thereby identifying a biomarker that is prognostic for said disease.

33. The method of claim 32, further comprising the step of identifying one or more genes on said gene target list that comprise an evolutionarily conserved change to produce a second gene target list.

34. The method of claim 32, wherein said disease is cancer.

35. The method of claim 34, wherein said cancer is metastatic cancer.

36. The method of claim 32, wherein said functional aspect is cell migration, angiogenesis, extracellular matrix degradation or anoikis.

37. A method of identifying a compound that modulates the activity or expression of a DETERMINANT comprising

(a) providing a cell expressing the DETERMINANT;

(b) contacting the cell with a composition comprising a candidate compound; and

(c) determining whether the substance alters the expression or activity of the DETERMINANT;

whereby, if the alteration observed in the presence of the compound is not observed when the cell is contacted with a composition devoid of the compound, the compound identified modulates the activity or expression of a DETERMINANT.

38. The method of claim 37 wherein said cell is contacted in vivo, ex vivo or in vitro.

39. A method of treating a cancer in a subject comprising administering to said subject a compound that modulates the activity or expression of a DETERMINANT.

40. A method of treating a cancer in a subject comprising administering to said subject an agent that modulates the activity or expression of a compound that is modulated by a DETERMINANT.

41. The method of claim 40, wherein said compound is TGFβ

or CXCR4

42. The method of claim 41, wherein said agent is a TGFβ

inhibitor or a CXCR4 inhibitor.

43. A method of treating a patient with a tumor, comprising:

identifying a patient with a tumor, wherein two or more of DETERMINANTS 1-360 are altered in a clinically significant manner as measured in a sample from the tumor, and

treating the patient with a therapeutic regimen that prevents or reduces tumor metastasis.

44. A method of selecting a tumor patient in need of adjuvant treatment, comprising:

assessing the risk of metastasis in the patient by measuring two or more of DETERMINANTS 1-360, wherein clinically significant alteration of said two or more DETERMINANTS in a tumor sample from the patient indicates that the patient is in need of adjuvant treatment.

45. A method of informing a treatment decision for a tumor patient, comprising:

obtaining information on two or more of DETERMINANTS 1-360 in a tumor sample from the patient, and

selecting a treatment regimen that prevents or reduces tumor metastasis in the patient if said two or more DETERMINANTS are altered in a clinically significant manner.