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1. WO2012064286 - TARGETING METABOLIC ENZYMES IN HUMAN CANCER

Publication Number WO/2012/064286
Publication Date 18.05.2012
International Application No. PCT/SG2011/000400
International Filing Date 11.11.2011
IPC
A61K 38/12 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38Medicinal preparations containing peptides
04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
12Cyclic peptides
A61K 48/00 2006.01
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61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
48Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
A61K 31/195 2006.01
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61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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31Medicinal preparations containing organic active ingredients
185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
19Carboxylic acids, e.g. valproic acid
195having an amino group
A61P 35/00 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
CPC
A61K 31/395
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61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
A61K 31/519
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
495having six-membered rings with two ; or more; nitrogen atoms as the only ring heteroatoms, e.g. piperazine ; or tetrazines
505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
519ortho- or peri-condensed with heterocyclic rings
A61K 31/713
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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31Medicinal preparations containing organic active ingredients
70Carbohydrates; Sugars; Derivatives thereof
7088Compounds having three or more nucleosides or nucleotides
713Double-stranded nucleic acids or oligonucleotides
A61K 38/177
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61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38Medicinal preparations containing peptides
16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
17from animals; from humans
177Receptors; Cell surface antigens; Cell surface determinants
A61K 38/191
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38Medicinal preparations containing peptides
16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
17from animals; from humans
19Cytokines; Lymphokines; Interferons
191Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
A61K 45/06
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61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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45Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Applicants
  • AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH [SG]/[SG] (AllExceptUS)
  • LIM, Bing [CA]/[SG] (UsOnly)
  • ZHANG, Wencai [CN]/[SG] (UsOnly)
Inventors
  • LIM, Bing
  • ZHANG, Wencai
Agents
  • YU SARN AUDREY & PARTNERS
Priority Data
201008288-111.11.2010SG
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) TARGETING METABOLIC ENZYMES IN HUMAN CANCER
(FR) CIBLAGE D'ENZYMES MÉTABOLIQUES DANS UN CANCER HUMAIN
Abstract
(EN)
Targeting metabolic enzymes in human cancer Abstract Lung cancer is a devastating disease and a major therapeutic burden with poor prognosis. The functional heterogeneity of lung cancer (different tumor formation ability in bulk of tumor) is highly related with clinical chemoresistance and relapse. Here we find that, glycine dehydrogenase (GLDC), one of the metabolic enzyme involved in glycine metabolism, is overexpressed in various subtypes of human lung cancer and possibly several other types of cancers. GLDC was found to be highly expressed in tumor-initiating subpopulation of human lung cancer cells compared with non-tumorigenic subpopulation. By array studies we showed that normal lung cells express low levels of GLDC compared to xenograft and primary tumor. Functional studies showed that RNAi inhibition of GLDC inhibits significantly the clonal growth of tumor-initiating cells in vitro and tumor formation in immunodeficient mice. Overexpression of GLDC in non-tumorigenic subpopulation convert the cells to become tumorigenic. Furthermore, overexpression of GLDC in NIH/3T3 cells and human primary lung fibroblasts can transform these cells, displaying anchorage-independent growth in soft agar and tumor-forming in mice. Not only is GLDC is expressed human lung cancer, it is also up-regulated in other types of cancer, such as colon cancer. RNAi knockdown of GLDC in colon cancer cell line, CACO-2 cells, can also inhibit the tumor formation in mice. Thus GLDC maybe a new metabolic target for treatment of lung cancer, and other cancers.
(FR)
Le cancer du poumon est une maladie particulièrement grave dont le pronostic thérapeutique est généralement pessimiste. L'hétérogénéité fonctionnelle du cancer du poumon, avec une capacité de formation de tumeurs différentes au cœur de la tumeur, est fortement corrélée à la chimiorésistance clinique et à la rechute. Nous avons découvert dans la présente invention que la glycine déshydrogénase (GLDC), l'une des enzymes métaboliques impliquées dans le métabolisme de la glycine, est surexprimée dans divers sous-types de cancer du poumon humain et peut-être dans plusieurs autres types de cancer. Il a été découvert que la GLDC était fortement exprimée dans la sous-population tumorigène de cellules cancéreuses du poumon humain par rapport à la sous-population non tumorigène. En étudiant des ensembles de cellules, nous avons démontré que les cellules pulmonaires normales expriment la GLDC à un faible niveau par rapport à une xénogreffe et une tumeur primaire. Des études fonctionnelles ont démontré que l'inhibition de l'ARNi de la GLDC inhibe significativement la croissance clonale des cellules tumorigénes in vitro et la formation tumorale chez des souris immunodéficientes. La surexpression de GLDC dans la sous-population non tumorigène convertit les cellules en cellules tumorigènes. En outre, la surexpression de GLDC dans les cellules NIH/3T3 et les fibroblastes pulmonaires primaires humains peut transformer ces cellules, qui présentent alors une croissance indépendante de leur ancrage dans un milieu semi-rigide de type soft agar et aboutissent à la formation de tumeurs chez la souris. Non seulement la GLDC est exprimée dans le cancer du poumon humain, mais elle est également régulée à la hausse dans d'autres types de cancer, par exemple le cancer du côlon. Le knock-down de l'ARNi de la GLDC dans une lignée cellulaire de cancer du côlon, CACO-2, peut également inhiber la formation tumorale chez la souris. Ainsi, la GLDC peut être une nouvelle cible métabolique pour le traitement du cancer du poumon et d'autres cancers.
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