Anti-tumor therapy

Patent metadata

Field	Value
Publication number	US-2016333355-A1
Application number	US-201415109945-A
Country	US
Kind code	A1
Filing date	Oct 24, 2014
Priority date	Jan 15, 2014
Publication date	Nov 17, 2016
Grant date	—

Abstract

Compositions, kits and methods for treating cancer in a subject in need thereof are disclosed involving one or more genes the suppression of which renders the cancer chemosensitive and/or radiosensitive.

First claim

We claim:

1 . A method of treating cancer in a subject in need thereof, comprising: regulating endogenous IFNbeta (IFNβ) production in the subject by at least one of:
a) suppressing a therapeutically effective amount of at least one of a product or an expression of an Interferon-Stimulated Gene (ISG) in the subject;
b) maintaining a therapeutically effective amount of activation of Type I Interferon in the subject;
c) inducing a therapeutically effective amount of activation of Type I Interferon in the subject; and
d) maintaining radio/chemoprotection of normal non-disease state tissue in the subject by suppressing in a therapeutically effective amount at least one of:
i) a primary RNA or DNA sensor;
ii) a major adaptor protein of a RNA/DNA-dependent pathway of IFN production; and
iii) up-regulation or activation or gene transfer of two apical repressors of a RNA/DNA-dependent pathway of IFN production; and

administering to the subject a therapeutic amount of ionizing radiation.

2 . The method of claim 1 , wherein the method comprises suppressing the product or the expression of the Interferon-Stimulated Gene (ISG).

3 . The method of claim 2 , wherein the Interferon-Stimulated Gene (ISG) comprises at least one RIG1-like receptor (RLR) family member.

4 . The method of claim 3 , wherein ionizing radiation induced cytotoxic IFNβ production is substantially maintained in the subject at levels substantially found prior to the administration of the ionizing radiation.

5 . The method of claim 4 , wherein Mitochondrial Antiviral Signaling Protein (MAVS)-dependent induction of endogenous IFNβ production is maintained in the subject at substantially the same level found in the subject prior to the administration of the ionizing radiation.

6 . The method of claim 3 , wherein the RIG1-like receptor (RLR) family member comprises RIG1 (Retinoic Acid-inducible Gene 1).

7 . The method of claim 3 , wherein the RIG1-like receptor (RLR) family member comprises LGP2 (Laboratory of Genetics and Physiology 2).

8 . The method of claim 3 , wherein the RIG1-like receptor (RLR) family member comprises MDA5 (Melanoma Differentiation-Associated Protein 5).

9 . The method of claim 2 , wherein the suppressing of the Interferon-Stimulated Gene (ISG) results in at least one of: suppression of growth or proliferation of the cancer, cell death of the cancer, or sensitization of the cancer to the ionizing radiation and/or chemotherapy.

10 . The method of claim 2 , wherein the suppressing of production of the Interferon-Stimulated Gene comprises suppression of expression of at least one Cytoplasmic Pattern-recognition Receptor (PRR) protein.

11 . The method of claim 10 , wherein the PPR protein comprises at least one of RIG1, LGP2, and MDA5.

12 . The method of claim 1 , wherein the method of treating cancer comprises maintaining the activation of Type I Interferon in the subject to maintain ionizing radiation and chemotherapy sensitization in the subject.

13 . The method of claim 12 further comprising administering to the subject a therapeutic amount of an agent that maintains the activation of Type I Interferon in the subject, wherein the agent comprises at least one of a shRNA, a siRNA, a micro-RNA mimic, an antisense oligonucleotide, a chemical, and a protein inhibitor.

14 . The method of claim 13 , wherein the agent down-regulates cytoplasmic DNA-sensoring pathway-exonuclease TREX1 (Three Prime Repair Exonuclease 1).

15 . The method of claim 13 , wherein the agent up-regulates at least one of DAI (DNA-dependent Activator of IFN regulatory factors), IFI16 (Gamma-interferon-inducible protein Ifi-16), and Aim2 (Interferon-inducible protein AIM2).

16 . The method of claim 1 , wherein the primary RNA or DNA sensor comprises at least one of RIG1, MDA5, DAI, IFI16, Aim2, and cGAS.

17 . The method of claim 1 , wherein the major adaptor protein of the RNA/DNA-dependent pathway of IFN production comprises at least one of MAVS and STING.

18 . The method of claim 1 , wherein the two apical repressors of the RNA/DNA-dependent pathway of IFN production comprises at least one of LGP2 and TREX1.

19 . The method of claim 1 , wherein the ionizing radiation comprises at least one of brachytherapy, external beam radiation therapy, and radiation from cesium, iridium, iodine, and cobalt.

20 . The method of claim 1 , wherein the method of treating cancer comprises inducing the Type I Interferon production in the subject to maintain ionizing radiation and/or chemotherapy sensitization in the subject.

21 . The method of claim 20 further comprising administering to the subject a therapeutic amount of an agent that induces the Type 1 Interferon production in the subject.

22 . The method of claim 21 , wherein the agent enhances STING signaling.

23 . The method of claim 22 , wherein the agent increases cGAS levels in the subject.

24 . The method of claim 23 , wherein the agent enhances expression of a cGAS gene in a cancerous cell in the subject.

25 . The method of claim 22 , wherein the agent is cGAMP.

26 . The method of claim 21 , wherein the agent activates at least one endosomal toll-like receptor (TRL) comprising at least one of TLR3, TLR7, TLR8 and TLR9.

27 . The method of claim 26 , wherein the agent interacts with at least one adaptor protein comprising at least one of myeloid differentiation primary-response protein 88 (MyD88) and TIR-domain-containing adaptor protein inducing IFN-β (TRIF).

28 . The method of claim 20 , wherein the method comprises administering an agent to the subject that increases levels of cGAS in a cancerous cell.

29 . The method of claim 28 , wherein the cGAS levels are equal to or greater than about 100% of a cancerous state control cell.

30 . The method of claim 29 , wherein the agent is delivered to the cancerous cell by a pharmaceutical carrier.

31 . The method of claim 30 , wherein the pharmaceutical carrier comprises at least one of a nanocarrier, a conjugate, a nucleic-acid-lipid particle, a vesicle, a exosome, a protein capsid, a liposome, a dendrimer, a lipoplex, a micelle, a virosome, a virus like particle, and a nucleic acid complexes.

32 . The method of claim 31 , wherein the agent is delivered into a cytosol of a dendritic cell.

33 . A pharmaceutical composition for treating cancer in a subject in need thereof, comprising: a therapeutically effective amount of an agent that regulates endogenous IFNbeta (IFNβ) production in the subject and at least one of:
a) suppresses at least one of a product or expression of an Interferon-Stimulated Gene (ISG) in the subject;
b) maintains activation of Type I Interferon in the subject;
c) induces activation of Type I Interferon in the subject; and
d) maintains radio/chemoprotection of normal non-disease state tissue in the subject by suppression of at least one of:
i) a primary RNA or DNA sensor;
ii) a major adaptor protein of a RNA/DNA-dependent pathway of IFN production, or
iii) up-regulation or activation or gene transfer of two apical repressors of a RNA/DNA-dependent pathway of IFN production; and

optionally, one or more pharmaceutically acceptable carriers, diluents and excipients.

34 . The pharmaceutical compositi

Assignees

• Univ Chicago

Inventors

• Deng Liufu
• Fu Yang-Xin
• Khodarev Nikolai
• Weichselbaum Ralph

Classifications

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C12N2320/30

  Special therapeutic applications · CPC title

• C12N15/1138 Primary

  against receptors or cell surface proteins · CPC title

• A61N5/1077

  Beam delivery systems · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title