Distinguishing pca3 messenger rna species in benign and malignant prostate tissues

Abstract

This invention concerns the discovery of two distinct PCA3 mRNA sequences. One of these sequences corresponds to a short PCA3 mRNA molecule whereas the other PCA3 RNA molecule is longer as it comprises an additional sequence between exon 3 and exon 4a. The short RNA is associated with prostate cancer whereas the long RNA sequence is associated with a non-malignant state of the prostate. Based on the differential expression levels of these two PCA3 RNA sequences, protocols for the diagnosis of prostate disease are provided. The invention also relates to therapeutic approaches to prostate cancer.

What is claimed is: 
     
         1 . A method for treating a subject having or suspected of having prostate cancer, said method comprising:
 (a) assessing whether PCA3 RNA from said subject's prostate cells, or cDNAs derived therefrom, comprise or lack an additional sequence between PCA3 exon 3 and PCA3 exon 4a, said additional sequence corresponding essentially to nucleotides 27 to 254 of SEQ ID NO: 1,   (b) classifying said subject, based on the assessment in (a), as having:
 (i) a non-malignant prostatic state, when said PCA3 RNA that lacks said additional sequence is present at a lower level than said PCA3 RNA that comprises said additional sequence; or 
 (ii) a malignant prostatic state, when said PCA3 RNA that lacks said additional sequence is present at a higher level than said PCA3 RNA that comprises said additional sequence; and 
   (c) selecting and/or adapting said subject's treatment based on the classification in (b).   
     
     
         2 . The method of  claim 1 , wherein said assessing in (a) comprises performing a hybridization and/or amplification reaction on PCA3 RNAs from said subject's prostate cells, or from cDNAs derived therefrom, to determine whether said PCA3 RNAs or cDNAs comprise or lack said additional sequence between PCA3 exon 3 and PCA3 exon 4a. 
     
     
         3 . The method of  claim 2 , wherein said amplification reaction comprises a reaction which is: a nucleic acid sequence-based amplification reaction (NASBA), a polymerase chain reaction (PCR), a transcription-based amplification reaction, a strand displacement amplification (SDA), a ligase chain reaction (LCR), or a Qβ replicase reaction. 
     
     
         4 . The method of  claim 2 , wherein said hybridization and/or amplification reaction employs at least one oligonucleotide which hybridizes specifically to:
 (a) PCA3 exon 3;   (b) PCA3 exon 4a;   (c) the PCA3 exon 3-exon 4a junction;   (d) the PCA3 exon 3-intron 3 junction; or   (e) the PCA3 intron 3-exon 4a junction.   
     
     
         5 . The method of  claim 4 , wherein said oligonucleotide hybridizes specifically to a PCA3 exon 3-exon 4a junction as defined by nucleotide positions 26 and 27 of SEQ ID NO: 2. 
     
     
         6 . The method of  claim 5 , wherein said oligonucleotide hybridizes under high stringency conditions to at least 10, at least 15, or at least 18 consecutive nucleotides across nucleotides 26 and 27 of SEQ ID NO: 2. 
     
     
         7 . The method of  claim 6 , wherein said high stringency conditions comprise a hybridization at 65° C. in 5×SSC, 5×Denhardt's solution, 1% SDS, and 100 μg/mL denatured carrier DNA. 
     
     
         8 . The method of  claim 1 , further comprising recommending that said subject undergo a prostate biopsy if said subject is classified as having a malignant prostatic state. 
     
     
         9 . The method of  claim 2 , further comprising recommending that said subject undergo a prostate biopsy if said subject is classified as having a malignant prostatic state. 
     
     
         10 . The method of  claim 1 , further comprising recommending that said subject not undergo a prostate biopsy, when said subject is classified as having a non-malignant prostatic state. 
     
     
         11 . The method of  claim 2 , further comprising recommending that said subject not undergo a prostate biopsy, when said subject is classified as having a non-malignant prostatic state. 
     
     
         12 . The method of  claim 1 , wherein if said subject is classified as having a malignant prostatic state then said selecting and/or adapting said subject's treatment in (c) comprises a recommendation of:
 (i) initiating an anti-prostate cancer treatment;   (ii) continuing an ongoing anti-prostate cancer treatment; or   (iii) initiating a more aggressive anti-prostate cancer treatment.   
     
     
         13 . The method of  claim 2 , wherein if said subject is classified as having a malignant prostatic state then said selecting and/or adapting said subject's treatment in (c) comprises a recommendation of:
 (i) initiating an anti-prostate cancer treatment;   (ii) continuing an ongoing anti-prostate cancer treatment; or   (iii) initiating a more aggressive anti-prostate cancer treatment.   
     
     
         14 . The method of  claim 12 , wherein said more aggressive anti-prostate cancer treatment comprises surgical prostatectomy. 
     
     
         15 . The method of  claim 13 , wherein said more aggressive anti-prostate cancer treatment comprises surgical prostatectomy. 
     
     
         16 . The method of  claim 1 , wherein if said subject is classified as having a non-malignant prostatic state then said selecting and/or adapting said subject's treatment in (c) comprises a recommendation of stopping or discontinuing of an anti-prostate cancer treatment. 
     
     
         17 . The method of  claim 2 , wherein if said subject is classified as having a non-malignant prostatic state then said selecting and/or adapting said subject's treatment in (c) comprises a recommendation of stopping or discontinuing of an anti-prostate cancer treatment. 
     
     
         18 . The method of  claim 8 , wherein if said subject remains classified as having a malignant prostatic state following said prostate biopsy, then said selecting and/or adapting said subject's treatment in (c) comprises a recommendation of:
 (i) initiating an anti-prostate cancer treatment;   (ii) continuing an ongoing anti-prostate cancer treatment; or   (iii) initiating a more aggressive anti-prostate cancer treatment.   
     
     
         19 . The method of  claim 9 , wherein if said subject remains classified as having a malignant prostatic state following said prostate biopsy, then said selecting and/or adapting said subject's treatment in (c) comprises a recommendation of:
 (i) initiating an anti-prostate cancer treatment;   (ii) continuing an ongoing anti-prostate cancer treatment; or   (iii) initiating a more aggressive anti-prostate cancer treatment.