Prostate cancer prognostic compositions and kits

• US 9,096,907 B2
• Filed: 06/10/2013
• Issued: 08/04/2015
• Est. Priority Date: 12/24/2004
• Status: Active Grant

• Current Assignee: Stichting Katholieke Universiteit
• Original Assignee: Stichting Katholieke Universiteit
• Inventors: Hessels, Daphne, Verhaegh, Gerald, Schalken, Jack A., Witjes, J. Alfred
• Primary Examiner(s): Horlick, Kenneth R.
• Assistant Examiner(s): THOMAS, DAVID C
• Application Number:
  US13/914,303
• Publication Number:
  US 20130261171A1
• Time in Patent Office: 785 Days
• US Class Current: 1/1
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/112 Disease subtyping, staging or classification
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/16 Primer sets for multiplex assays
• CPC Class Codes: G01N 2333/96455 Kallikrein (3.4.21.34; 3.4.21.35)
• CPC Class Codes: G01N 33/57434 of prostate

Abstract

Described herein are method, compositions and kits for prognosis of prostate cancer. The methods include determining the ratio of PCA3 and of a prostate-specific marker expression in a urine sample and correlating the value of the PCA3/prostate-specific marker ratio with the aggressiveness and mortality risk of prostate cancer in the subject. The method for prognosing prostate cancer in a sample of a patient includes assessing the amount of a prostate cancer specific PCA3 mRNA and the amount of prostate-specific marker in the sample; determining a ratio value of this amount of prostate cancer specific PCA3 mRNA over the amount of prostate-specific marker; comparing the ratio value to at least one predetermined cut-off value, wherein a ratio value above the predetermined cut-off value is indicative of a higher risk of mortality of prostate cancer as compared to a ratio value below the predetermined cut-off value.

Claims

1. A method for treating prostate cancer in a patient comprising:

a) obtaining a biological sample from said patient;

b) performing a first hybridization and/or amplification assay on mRNA or cDNA derived from said sample using at least a first oligonucleotide specific for a prostate cancer associated PCA3 mRNA or cDNA;

c) determining the amount of said prostate cancer associated PCA3 mRNA or cDNA and the amount of a prostate-specific marker in said biological sample;

d) determining a first ratio value of said amount of said prostate cancer associated PCA3 mRNA or cDNA over said amount of prostate-specific marker;

e) comparing said first ratio value to at least one predetermined cut-off value;

f) identifying said patient as having a more aggressive prostate cancer when the ratio value is above said predetermined cut-off value; and

g) administering to said patient a prostate cancer treatment for a more aggressive prostate cancer.

2. The method of claim 1, further comprising determining a second ratio value of said amount of said prostate cancer associated PCA3 mRNA over said amount of prostate-specific marker at a subsequent point in time, and comparing said first ratio value to said second ratio value at said further point in time, thereby assessing the efficacy of said prostate cancer treatment over time.

3. The method of claim 1, wherein an amplification reaction is used for determining the amount of said prostate cancer associated PCA3 mRNA or cDNA.

4. The method of claim 3, wherein said amplification reaction is:

a) polymerase chain reaction (PCR);

b) nucleic acid sequence-based amplification assay (NASBA);

c) transcription mediated amplification (TMA);

d) ligase chain reaction (LCR);

or

e) strand displacement amplification (SDA).

5. The method of claim 1, wherein an amount of prostate-specific marker mRNA or cDNA is also determined.

6. The method of claim 5, wherein the amount of prostate cancer associated PCA3 mRNA or cDNA and of prostate-specific marker mRNA or cDNA is determined using a hybridization assay.

7. The method of claim 1, wherein the amount of said prostate cancer associated PCA3 mRNA or cDNA is determined by using at least one oligonucleotide that hybridizes to a PCA3 nucleic acid sequence which is:

a) a nucleic acid sequence set forth in SEQ ID NO;

1;

b) a nucleic acid sequence set forth in SEQ ID NO;

2;

or

c) a nucleic acid sequence that hybridizes under high stringency conditions to a nucleic acid sequence in a) or b).

8. The method of claim 1, wherein the amount of prostate-specific marker protein contained in said biological sample is determined.

9. The method of claim 8, wherein an antibody is used to determine said amount of prostate-specific marker protein.

10. The method of claim 1, wherein said prostate-specific marker is:

PSA, HK2/KLK2, PSMA, transglutaminase 4, acid phosphatase, PCGEM1, NKX3.1, prostate stem cell antigen (PSCA), prostate tumor inducing gene-1 (PTI-1), PDEF, TMPRSS2 or Prostase.

11. The method of claim 1, wherein said cut-off value is selected from 132×

10<sup>−

3</sup> and 200×

10<sup>−

3</sup>.

12. The method of claim 10, wherein said prostate-specific marker is PSA, and wherein said biological sample from said subject comprises at least 3 ng/ml of serum PSA protein.

13. The method of claim 1, wherein said biological sample is:

urine, prostate tissue resection, prostate tissue biopsy, ejaculate or bladder washing.

14. The method of claim 1, wherein said biological sample is a urine sample collected not following a digital rectal examination.

15. The method of claim 1, wherein said biological sample is a urine sample obtained after a digital rectal examination.

19. The method of claim 1, wherein said prostate cancer associated PCA3 mRNA or cDNA lacks intron 3 between exons 3 and 4a.

16. A method for treating prostate cancer in a patient, comprising:

a) obtaining a first biological sample from said patient before or during therapy and a second biological sample after said therapy;

b) performing a first hybridization and/or amplification assay on mRNA or cDNA derived from said first biological sample using at least a first oligonucleotide specific for a prostate cancer associated PCA3 mRNA or cDNA;

c) determining the amount of said prostate cancer associated PCA3 mRNA or cDNA and the amount of a prostate-specific marker in said first biological sample obtained before or during said therapy;

d) determining a ratio value of said amount of said prostate cancer associated PCA3 RNA or cDNA over said amount of said prostate-specific marker;

e) repeating b), c) and d) using said second biological sample obtained after said therapy; and

f) comparing the ratio value of said second biological sample obtained after therapy with the ratio value of said first biological sample obtained before or during therapy;

g) indentifying said patient as having prostate cancer progression when the ratio value of said second biological sample obtained after therapy is above the ratio value of said first sample obtained before or during therapy; and

h) administering to said patient a prostate cancer treatment for a more aggressive prostate cancer.

20. The method of claim 16, wherein said prostate cancer associated PCA3 mRNA or cDNA lacks intron 3 between exons 3 and 4a.

17. A method for treating prostate cancer in a prostate cancer patient comprising:

a) obtaining a first biological sample from said patient, wherein said first biological sample is taken from said patient before or during prostate cancer treatment;

b) performing an in vitro nucleic acid amplification assay on mRNA or cDNA derived from said first biological sample using a first primer pair which is specific to a prostate cancer associated PCA3 mRNA or cDNA and a second primer pair which is specific for a prostate-specific marker mRNA or cDNA;

c) quantifying said PCA3 mRNA or cDNA and said prostate-specific marker mRNA or DNA in said first biological sample;

d) calculating a first normalized ratio of PCA3 over said prostate-specific marker;

e) repeating b) and c) using a second biological sample, wherein said second biological sample is obtained at a further point in time during therapy using the same or different primer pairs;

f) calculating a second normalized ratio of PCA3 over said prostate-specific marker; and

g) comparing said first and second normalized ratios;

h) identifying said patient as having;

aa) a more aggressive prostate cancer, bb) prostate cancer progression, cc) a prostate cancer of a higher grade;

or dd) a prostate cancer of a higher stage, when the ratio value of said second biological sample obtained at a further point in time is above the ratio value of said first biological sample obtained before or during therapy; and

i) administering to said patient a prostate cancer treatment for a more aggressive prostate cancer.

18. The method of claim 17, wherein said normalized ratios are calculated using PCA3 over PSA.

21. The method of claim 17, wherein said prostate cancer associated PCA3 mRNA or cDNA lacks intron 3 between exons 3 and 4a.