Compound and method for treating androgen-independent prostate cancer

• US 20050153935A1
• Filed: 09/10/2004
• Published: 07/14/2005
• Est. Priority Date: 09/12/2003
• Status: Abandoned Application

• Current Assignee: Avi Biopharma, Inc.
• Original Assignee: Avi Biopharma, Inc.
• Inventors: Iversen, Patrick L., Devi, Gayathri R.
• Application Number:
  US10/938,171
• Publication Number:
  US 20050153935A1
• Time in Patent Office: Days
• US Class Current: 514/80
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring

Abstract

The present invention provides compositions and methods for treating prostate cancer. The composition comprises a morpholino antisense compound having uncharged phosphorus-containing backbone linkages and a base sequence that is complementary to a target region containing at least 12 contiguous bases in a preprocessed or processed human androgen receptor transcript. The method is designed for treating prostate cancer in a subject having a hormone-refractory (androgen-independent) prostate cancer.

Claims

1. A method of treating prostate cancer in a subject having an androgen-independent prostate cancer, as evidenced by a lack of response in PSA level to androgen-suppression therapy, said method comprising

(a) administering to the subject, an oligonucleotide analog compound characterized by:

(i) 12-40 morpholino subunits,

(ii) a substantially uncharged, phosphorus-containing backbone linking said subunits,

(iii) active uptake by human prostate cancer cells,

(iv) a base sequence that is complementary to a target region containing at least 12 contiguous bases in a preprocessed or processed human androgen receptor transcript, and which includes at least 6 contiguous bases of the sequence selected from the group consisting of;

SEQ ID NOS;

2, 7, 8, and 9-22, and

(v) capable of hybridizing with a preprocessed human androgen-receptor transcript to form a heteroduplex structure having a Tm of dissociation of at least 45°

C.,

(c) following said administering, monitoring the subject'"'"'s serum PSA level, and

(d) continuing said administering, on a periodic basis, at least until a substantial drop in the subject'"'"'s serum PSA level is observed.

2. The method of claim 1, wherein the compound administered is composed of morpholino subunits linked by uncharged, phosphorus-containing intersubunit linkages, joining a morpholino nitrogen of one subunit to a 5′

exocyclic carbon of an adjacent subunit.

3. The method of claim 2, wherein the intersubunit linkages in the compound administered are phosphorodiamidate linkages.

4. The method of claim 3, wherein the morpholino subunits in the compound administered are joined by phosphorodiamidate linkages, in accordance with the structure:

5. The method of claim 4, wherein X=NR₂, where each R is independently hydrogen or methyl in the compound administered.

6. The method of claim 1, wherein the compound administered is effective to target the start site of the processed human androgen start site and has a base sequence that is complementary to a target region containing at least 12 contiguous bases in a processed human androgen receptor transcript, and which includes at least 6 contiguous bases of the sequence selected from the group consisting of:

SEQ ID NOS;

2, 7, 8.

7. The method of claim 6, wherein the compound administered includes a base sequence selected from the group consisting of:

SEQ ID NOS;

2, 3, 4, 5, 7, and 8.

8. The method of claim 1, wherein the compound administered is effective to target a splice site of preprocessed human androgen start site and has a base sequence that is complementary to a target region containing at least 12 contiguous bases in a processed human androgen receptor transcript, and which includes at least 6 contiguous bases of the sequence selected from the group consisting of:

SEQ ID NOS;

9-22.

9. The method of claim 8, wherein the compound administered includes a base sequence selected from the group consisting of:

SEQ ID NOS;

9-22.

10. The method of claim 1, which further includes administering a chemotherapeutic agent to the subject.

11. The method of claim 1, which further includes, at a selected time after said administering, obtaining a sample of a body fluid from the subject;

and

assaying the sample for the presence of a nuclease-resistant heteroduplex comprising the oligonucleotide analog compound complexed with a complementary portion of a preprocessed human androgen receptor transcript.

12. An oligonucleotide analog compound for use in treating prostate cancer in a subject, characterized by:

(i) 12-40 morpholino subunits,

(ii) a substantially uncharged, phosphorus-containing backbone linking said subunits,

(iii) active uptake by human prostate cancer cells,

(iv) a base sequence that is complementary to a target region containing at least 12 contiguous bases in a preprocessed or processed human androgen receptor transcript, and which includes at least 6 contiguous bases of the sequence selected from the group consisting of;

SEQ ID NOS;

2, 7, 8, and 9-22, and

(v) capable of hybridizing with a preprocessed human androgen-receptor transcript to form a heteroduplex structure having a Tm of dissociation of at least 45°

C.

13. The compound of claim 12, which is composed of morpholino subunits linked by uncharged, phosphorus-containing intersubunit linkages, joining a morpholino nitrogen of one subunit to a 5′

exocyclic carbon of an adjacent subunit.

14. The compound of claim 13, wherein said intersubunit linkages are phosphorodiamidate linkages.

15. The compound of claim 14, wherein said morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure:

16. The compound of claim 15, wherein X═

NR₂, where each R is independently hydrogen or methyl.

17. The compound of claim 12, which is effective to target the start site of the processed human androgen start site and which has a base sequence that is complementary to a target region containing at least 12 contiguous bases in a processed human androgen receptor transcript, and which includes at least 6 contiguous bases of the sequence selected from the group consisting of:

SEQ ID NOS;

2, 7, 8.

18. The compound of claim 17, which includes a base sequence selected from the group consisting of:

SEQ ID NOS;

2, 3, 4, 5, 7, and 8.

19. The compound of claim 12, which is effective to target a splice site of preprocessed human androgen start site and which has a base sequence that is complementary to a target region containing at least 12 contiguous bases in a processed human androgen receptor transcript, and which includes at least 6 contiguous bases of the sequence selected from the group consisting of:

SEQ ID NOS;

9-22.

20. The compound of claim 19, which includes a base sequence selected from the group consisting of:

SEQ ID NOS;

9-22.

21. The compound of claim 12, in a composition which also includes a chemotherapeutic agent.

22. A method of confirming the presence of an effective interaction between a human androgen-receptor pre-processed transcript and an uncharged morpholino oligonucleotide analog compound, comprising

(a) administering said compound to the subject, where said compound is characterized by:

(i) 12-40 morpholino subunits, (ii) a substantially uncharged, phosphorus-containing backbone linking said subunits, (iii) active uptake by human prostate cancer cells, (iv) a base sequence that is complementary to a target region containing at least 12 contiguous bases in a preprocessed human androgen receptor transcript, and (v) capable of hybridizing with a preprocessed human androgen-receptor transcript to form a heteroduplex structure having a Tm of dissociation of at least 45°

C.,

(b) at a selected time after said administering, obtaining a sample of a body fluid from the subject; and

(c) assaying the sample for the presence of a nuclease-resistant heteroduplex comprising the oligonucleotide analog compound complexed with a complementary-sequence portion of a preprocessed human androgen-receptor transcript.