Fusion genes associated with progressive prostate cancer

Patent metadata

Field	Value
Publication number	US-2016376666-A1
Application number	US-201615199056-A
Country	US
Kind code	A1
Filing date	Jun 30, 2016
Priority date	Dec 30, 2013
Publication date	Dec 29, 2016
Grant date	—

Abstract

The present invention relates to methods and compositions for determining whether a subject having prostate cancer is at greater risk of developing progressive disease, and methods of treating the subjects. It is based, at least in part, on the discovery that approximately 90% of men carrying at least one of the following fusion genes: TRMT11-GRIK2, SLC45A2-AMACR, MTOR-TP53BP1, LRRC59-FLJ60017, TMEM135-CCDC67 and CCNH-C5orf30 experienced prostate cancer recurrence, metastases and/or prostate cancer-specific death after radical prostatectomy (each examples of “progressive prostate cancer”), while these outcomes occurred in only 36% of men not carrying any of these fusion genes. It is also based, at least in part, on the discovery that no patient studied survived five years without recurrence if their primary prostate cancer contained a TRMT11-GRIK2 or MTOR-TP53BP1 fusion gene. It is also based, at least in part, on the discovery that the protein encoded by the MAN2A1-FER fusion gene exhibits kinase activity.

First claim

What is claimed is:

1 . A method of treating a subject, comprising (i) determining whether a subject is at increased risk of manifesting progressive prostate cancer comprising determining whether a prostate cancer cell of the subject contains a fusion gene selected from the group consisting of TRMT11-GRIK2, SLC45A2-AMACR, MTOR-TP53BP1, LRRC59-FLJ60017, TMEM135-CCDC67, KDM4B-AC011523.2, MAN2A1-FER, PTEN-NOLC1, CCNH-C5orf30, ZMPSTE24-ZMYM4, CLTC-ETV1, ACPP-SEC13, DOCK7-OLR1, PCMTD1-SNTG1 and a combination thereof; and (ii) where the cell contains a fusion gene so that the subject is at increased risk, performing one or more of cryotherapy, radiation therapy, chemotherapy, hormone therapy, high-intensity focused ultrasound, frequent monitoring, frequent prostate-specific antigen (PSA) checks and radical prostatectomy.

2 . The method of claim 1 , wherein the fusion gene is selected from the group consisting of TRMT11-GRIK2, SLC45A2-AMACR, PTEN-NOLC1, MTOR-TP53BP1 and a combination thereof.

3 . The method of claim 1 , wherein the subject is determined to be at increased risk of rapid relapse.

4 . The method of claim 1 , wherein the subject is determined to be at increased risk of relapse.

5 . A method of treating a subject, comprising (i) determining whether a subject is at increased risk of manifesting progressive prostate cancer comprising determining whether a prostate cancer cell of the subject contains a fusion gene selected from the group consisting of TRMT11-GRIK2, SLC45A2-AMACR, MTOR-TP53BP1, LRRC59-FLJ60017, TMEM135-CCDC67, KDM4B-AC011523.2, MAN2A1-FER, PTEN-NOLC1, CCNH-C5orf30, ZMPSTE24-ZMYM4, CLTC-ETV1 ACPP-SEC13, DOCK7-OLR1, PCMTD1-SNTG1 and a combination thereof; and (ii) where the cell contains a fusion gene so that the subject is at increased risk, (a) administering a therapeutically effective amount of an inhibitor specific for the fusion gene contained within the cell, (b) administering a therapeutically effective amount of an agent that inhibits the product of the fusion gene contained within the cell, (c) administering a therapeutically effective amount of an siRNA targeting the fusion gene contained within the cell, (d) administering a therapeutically effective amount of an anti-cancer agent or (e) performing a targeted genome editing procedure on one or more prostate cancer cells within the subject.

6 . The method of claim 5 , wherein the fusion gene is selected from the group consisting of TRMT11-GRIK2, SLC45A2-AMACR, PTEN-NOLC1, MTOR-TP53BP1 and a combination thereof.

7 . The method of claim 5 , wherein the subject is determined to be at increased risk of rapid relapse.

8 . The method of claim 5 , wherein the subject is determined to be at increased risk of relapse.

9 . The method of claim 5 , wherein the fusion gene is MAN2A1-FER and a therapeutically effective amount of a FER inhibitor is administered.

10 . The method of claim 9 , wherein the subject is determined to be at increased risk of rapid relapse.

11 . The method of claim 9 , wherein the subject is determined to be at increased risk of relapse.

12 . The method of claim 5 , wherein the fusion gene is SLC45A2-AMACR and a therapeutically effective amount of a racemase inhibitor is administered.

13 . A kit comprising one or more pairs of primers for PCR analysis of one or more fusion genes selected from the group consisting of TRMT11-GRIK2, SLC45A2-AMACR, MTOR-TP53BP1, LRRC59-FLJ60017, TMEM135-CCDC67, PTEN-NOLC1, CCNH-C5orf30, TRMT11-GRIK2, SLC45A2-AMACR, KDM4B-AC011523.2, MAN2A1-FER, MTOR-TP53BP, ZMPSTE24-ZMYM4, CLTC-ETV1, ACPP-SEC13, DOCK7-OLR1, PCMTD1-SNTG11 and a combination thereof.

14 . A kit comprising one or more pairs of probes for FISH analysis of one or more fusion genes selected from the group consisting of TRMT11-GRIK2, SLC45A2-AMACR, MTOR-TP53BP1, LRRC59-FLJ60017, TMEM135-CCDC67, PTEN-NOLC1, CCNH-C5orf30, TRMT11-GRIK2, SLC45A2-AMACR, KDM4B-AC011523.2, MAN2A1-FER, MTOR-TP53BP1, ZMPSTE24-ZMYM4, CLTC-ETV1, ACPP-SEC13, DOCK7-OLR1, PCMTD1-SNTG1 and a combination thereof.

Assignees

• Univ Of Pittsburgh - Of The Commonwealth System Of Higher Education

Inventors

• Luo Jianhua
• Yu Yangping
• Nelson Joel B
• Michalopoulos George Konstantine
• Tseng Chien-Cheng
• Ding Ying

Classifications

• C12Q2600/158

  Expression markers · CPC title

• C12Q2600/16

  Primer sets for multiplex assays · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12Q2600/118

  Prognosis of disease development · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title