Modulation of Insulin Like Growth Factor I Receptor Expression in Cancer

a technology of insulin like growth factor and receptor, applied in the field of cancer treatment, can solve problems such as limited tissue, and achieve the effect of inhibiting expression and reducing transcription and/or translation

Inactive Publication Date: 2015-12-03
ANTISENSE THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes using an antisense oligonucleotide to reduce the size and growth of tumors or cancers in subjects. The oligonucleotide can target specific genes that are involved in the growth of cancer cells. By inhibiting the expression of these genes, the tumor can be made smaller and not grow as quickly. This approach has shown promise in animal studies and is now being tested in clinical trials.

Problems solved by technology

Further, it is not clear what the hurdles for therapeutic activity might be, such as 1) limited tissue and cellular penetration of the antisense oligonucleotide, 2) undesirable activities including hyperglycemia, or interference or modulation of the immune system in a way that affects its activity.

Method used

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  • Modulation of Insulin Like Growth Factor I Receptor Expression in Cancer
  • Modulation of Insulin Like Growth Factor I Receptor Expression in Cancer
  • Modulation of Insulin Like Growth Factor I Receptor Expression in Cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Nucleoside Phosphoramidites

[0191]The following compounds, including amidites and their intermediates were prepared as described in U.S. Pat. No. 6,426,220 and WO 02 / 36743: -Dimethoxytrityl-thymidine intermediate for 5-methyl dC amidite, 5′-O-Dimethoxytrityl-2′-deoxy-5-methylcytidine intermediate for 5-methyl-dC amidite, 5′-O-Dimethoxytrityl-2′-deoxy-N4-benzoyl-5-methylcytidine penultimate intermediate for 5-methyl dC amidite, [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N4-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (5-methyl dC amidite), 2′-Fluorodeoxyadenosine, 2′-Fluorodeoxyguanosine, 2′-Fluorouridine, 2′-Fluorodeoxycytidine, 2′-O-(2-Methoxyethyl) modified amidites, 2′-O-(2-methoxyethyl)-5-methyluridine intermediate, 5′-O-DMT-2′-O-(2-methoxyethyl)-5-methyluridine penultimate intermediate, [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE T amidite), 5...

example 2

Oligonucleotide and Oligonucleoside Synthesis

[0192]The antisense compounds used in accordance with this invention may be conveniently and routinely made by the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides, such as, the phosphorothioates and alkylated derivatives.

[0193]Oligonucleotides: Unsubstituted and substituted phosphodiester (P═O) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.

[0194]Phosphorothioates (P═S) are synthesized similar to phosphodiester oligonucleotides with the following exceptions: thiation are effected by utilizing a 10% w / v solution of 3,H-1,2-benzodithiole-3-on...

example 3

RNA Synthesis

[0206]In general, RNA synthesis chemistry is based on the selective incorporation of various protecting groups at strategic intermediary reactions. Although one of ordinary skill in the art will understand the use of protecting groups in organic synthesis, a useful class of protecting groups includes silyl ethers. In particular, bulky silyl ethers are used to protect the 5′-hydroxyl in combination with an acid-labile orthoester protecting group on the 2′-hydroxyl. This set of protecting groups is then used with standard solid-phase synthesis technology. It is important to lastly remove the acid labile orthoester protecting group after all other synthetic steps. Moreover, the early use of the silyl protecting groups during synthesis ensures facile removal when desired, without undesired deprotection of 2′ hydroxyl.

[0207]Following this procedure for the sequential protection of the 5′-hydroxyl in combination with protection of the 2′-hydroxyl by protecting groups that are...

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PUM

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Abstract

Provided herein are methods, compounds, and compositions for reducing expression of an IGF-IR mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions that inhibit expression of IGF-IR in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate the tumor or cancer, or a symptom thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority benefit of U.S. provisional patent application Ser. No. 61 / 105,367, filed Oct. 14, 2008; U.S. provisional patent application Ser. No. 61 / 187,510, filed Jun. 16, 2009; and U.S. provisional patent application Ser. No. 61 / 233,772, filed Aug. 13, 2009. The contents of each application listed in this paragraph are fully incorporated by reference herein.FIELD OF THE INVENTION[0002]The present invention provides methods for the treatment of cancer. In one example, the present invention provides methods for the treatment of prostate cancer.BACKGROUND OF THE INVENTION[0003]The insulin-like growth factor receptor (IGF-IR) is composed of two types of subunits: an alpha subunit (a 130-135 kDa protein that is entirely extracellular and functions in ligand binding) and a beta subunit (a 95-kDa transmembrane protein, with transmembrane and cytoplasmic domains). The IGF-IR binds insulin-like growth factor I (IGF-I), or IG...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/113A61K45/06A61K31/337A61K31/7088
CPCC12N15/1138A61K31/7088C12N2320/30A61K31/337C12N2310/11A61K45/06A61K31/7052A61P35/00A61K2300/00
Inventor TACHAS, GEORGEATLEY, LYNNE MAREEWRAIGHT, CHRISTOPHER J.
Owner ANTISENSE THERAPEUTICS LTD
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