Cancer treatment targeting non-coding RNA overexpression

• US 8,957,042 B2
• Filed: 03/07/2013
• Issued: 02/17/2015
• Est. Priority Date: 03/07/2012
• Status: Expired due to Fees

• Current Assignee: Texas A&M University System
• Original Assignee: Texas A&M University System
• Inventors: Safe, Stephen, Kim, KyoungHyun
• Primary Examiner(s): Bowman, Amy
• Application Number:
  US13/789,546
• Publication Number:
  US 20130267575A1
• Time in Patent Office: 712 Days
• Field of Search: None
• US Class Current: 514/44
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/616 by carboxylic acids, e.g. acetylsalicylic acid
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 33/36 Arsenic; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12Q 1/6876 Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes

Abstract

Provided herein are methods directed to modulating the pro-oncogenic effects of noncoding RNAs (ncRNAs) through their interactions with specificity protein transcription factors (SpTFs). In one aspect, the disclosure provides a method of inhibiting growth of a cell, such as a transformed or cancer cell, characterized by overexpression of at least one specificity protein (Sp)-regulated ncRNA and expression of at least one Sp transcription factor (SpTF), the method comprising contacting the cell with an effective amount of an SpTF agent. In some embodiments, the ncRNA is a long noncoding RNA (lncRNA). In some embodiments, the ncRNA is a microRNA (miR). Also provided are methods of treating a cell proliferative disease, predicting the response of a subject to SpTF agent-based treatment, and monitoring the efficacy of a SpTF agent-based treatment in a subject.

Claims

1. A method of inhibiting growth of a cancer cell characterized by overexpression of at least one specificity protein (Sp)-regulated non-coding RNA (ncRNA), compromising reducing the expression or activity of the at least one specificity protein (Sp)-regulated non-coding RNA (ncRNA) by contacting the cell with an effective amount of a specificity protein transcription factor (SpTF) agent that downregulates or represses activity of Sp1, Sp3, or Sp4 wherein the cell is derived from a solid tumor.

2. The method of claim 1, wherein the cancer cell is selected from the group consisting of a breast cancer cell, a pancreatic cancer cell, a liver cancer cell, a lung cancer cell, a prostate cancer cell, a follicular lymphoma cancer cell, and a bladder cancer cell.

3. The method of claim 1, wherein the overexpression of the at least one Sp-regulated ncRNA in the cancer cell can be determined by comparing the expression level in the cancer cell to a reference standard.

4. The method of claim 1, wherein comparing the expression level in the cancer cell to a reference standard comprises comparing the expression level of the at least one Sp-regulated ncRNA to the expression level of the at least one Sp-regulated ncRNA in a noncancerous cell derived from the same tissue.

5. The method of claim 1, wherein the at least one Sp-regulated ncRNA is a long non-coding RNA (lncRNA).

6. The method of claim 5, wherein the IncRNA is selected from the group consisting of HOTAIR, HOTAIRM, HOTTIP, MALAT-1, linc-HEIH, HULC, and AY12907.

7. The method of claim 1, wherein the at least one SpTF is Sp1, Sp3, Sp4 or other Sp/KLF transcription factor.

8. The method of claim 1, wherein the SpTF agent comprises:

(i) a phytochemical or derivative that induces reactive oxygen species (ROS) or phosphatase activity;

(ii) a naturally-occurring or synthetic triterpenoid;

(iii) a non-steroidal anti-inflammatory drug (NSAID);

(iv) an antisense microRNA oligonucleotide;

(v) an agent that causes overexpression of ZBTB10, ZBTB4, or related transcriptional repressor, or that induces proteasome/caspase-dependent degradation of Sp transcription factors;

(vi) a thiazolidinedione;

(vii) a nitro-aspirin;

(viii) an isothiocyanate;

(ix) aspirin;

(x) arsenic trioxide;

(xi) metformin;

(xii) silibinin;

or

(xiii) a cannabinoid.

9. The method of claim 8, wherein the triterpenoid is methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate or methyl 2-cyano-3,11-dioxo-18β

-olean-1,12-dien-30-oate.

10. The method of claim 1, further comprising contacting the cell with one or more small interfering RNA (siRNA) molecules that hybridize with the mRNA encoding an SpTF under physiological or cell-culture conditions.

11. The method of claim 1, wherein the cell is in vivo in a subject.

12. The method of claim 1, wherein the cell is in vitro.

13. The method of claim 12, wherein the cell is derived from or comprised in a sample obtained from a subject haying a cell proliferative disease or suspected of having a cell proliferative disease.

14. A method of inhibiting growth of a cancer cell characterized by overexpression of at least one specificity protein (Sp)-regulated non-coding RNA (ncRNA), comprising reducing the expression or activity of the at least one specificity protein (Sp)-regulated non-coding RNA (ncRNA) by contacting the cell with an effective amount of a specificity protein transcription factor (SpTF) agent that downregulates or represses activity of Sp1, Sp3, or Sp4, wherein the cell is a pancreatic cancer cell, a breast cancer cell, a cervical cancer cell, a prostate cancer cell, bladder cancer cell, or a rhabdomyosarcoma cell.