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WO2019034042A1 - Biomarqueur de prédiction de la sensibilité à la gemcitabine et son utilisation - Google Patents

Biomarqueur de prédiction de la sensibilité à la gemcitabine et son utilisation Download PDF

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Publication number
WO2019034042A1
WO2019034042A1 PCT/CN2018/100371 CN2018100371W WO2019034042A1 WO 2019034042 A1 WO2019034042 A1 WO 2019034042A1 CN 2018100371 W CN2018100371 W CN 2018100371W WO 2019034042 A1 WO2019034042 A1 WO 2019034042A1
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acid
cancer
gemcitabine
akr1c1
pharmaceutically acceptable
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English (en)
Chinese (zh)
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杨岚
王凤
郭殿武
单佳祺
冯飞玉
郭文广
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Hangzhou Yuanchang Medical Sci-Tech Co Ltd
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Hangzhou Yuanchang Medical Sci-Tech Co Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens

Definitions

  • the present invention relates to the field of molecular biology and medicine, and in particular to biomarkers for predicting drug sensitivity of gemcitabine and uses thereof.
  • Gemcitabine is a commonly used anti-tumor chemotherapy drug in clinical practice.
  • Gemcitabine Hydrochloride is indicated for the treatment of inoperable advanced or metastatic pancreatic cancer and for the treatment of locally advanced or metastatic non-small cell lung cancer, in combination with paclitaxel, for the treatment of relapse after unassisted/neoadjuvant chemotherapy, unresectable, local recurrence or Metastatic breast cancer.
  • gemcitabine Even in the current emergence of targeted drugs and new immunotherapeutics, gemcitabine still has a wide range of clinical applications, especially in the field of pancreatic cancer, gemcitabine is the standard of treatment.
  • different patients have different sensitivity or effectiveness to gemcitabine, and there are primary and acquired drug resistance problems. Therefore, the search for effective gemcitabine drug sensitivity markers to guide the use of drugs, not only can avoid the patient's treatment due to improper drug selection delay, but also can monitor the drug treatment effect during the treatment process, to achieve rational drug use and individualized treatment purposes.
  • gemcitabine resistance is mainly related to its uptake and transport process disorders, intracytoplasmic activation, enzyme breakdown and DNA repair.
  • the research includes hENT1 (human balanced nucleoside transporter 1) and RRM1 (ribonucleotide reductase M1). ), RRM2 (ribonucleotide reductase M2), dCK (deoxycytidine kinase) and other genes or proteins.
  • the present invention seeks to find new and more accurate gemcitabine sensitivity Sexual predictive indicators.
  • the aldol.keto reductase (AKR) superfamily has 15 families, of which 15 are human AKR members. Most AKR members can catalyze a simple redox reaction with nicotinamide adenine dinucleotide phosphate NADP as a cofactor. They have a wide range of substrates, including sugars, fatty aldehydes, steroid hormones, prostaglandins and carcinogens. Therefore, members of the AKR superfamily may be enzymes that play important roles in life activities such as hormone synthesis, drug metabolism, inflammatory reactions, and carcinogen detoxification. Studies have shown that human AKR superfamily members are associated with a variety of tumor development, and their activity is closely related to tumor progression and therapeutic effects.
  • AKRlB10 is an early diagnostic marker for smoking-related non-small cell lung cancer, especially lung squamous cell carcinoma, and the role of AKR1C1 ⁇ 3 in the tolerance of multiple chemotherapeutic drugs in lung cancer makes it an important predictor of prognosis and also for the improvement of lung cancer drugs.
  • Sensitivity provides an effective target for action.
  • the present invention firstly discovered that the AKR1C1, AKR1C2, and AKR1C3 families of the aldosterone reductase (AKR) family members are associated with gemcitabine resistance.
  • the present invention investigated the correlation between gemcitabine drug sensitivity and AKR1C1 to C3 expression in 38 nude mouse tumor xenograft models. The results showed that among the 15 models with high expression of AKR1C1 ⁇ C3, 13 models showed poor efficacy and insensitivity of gemcitabine. Among the 23 models with low expression of AKR1C1 ⁇ C3, 19 models showed the efficacy of gemcitabine. Good, performance sensitivity.
  • biomarkers AKR1C1, AKR1C2, AKR1C3 for predicting drug sensitivity in the treatment of cancer with gemcitabine or a pharmaceutically acceptable salt thereof, and uses thereof.
  • the invention provides the use of AKR1C1, AKR1C2 or AKR1C3 as a biomarker for predicting drug sensitivity in the treatment of cancer with gemcitabine or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt comprises an acid addition salt of gemcitabine with an acid, for example, an acid addition salt of gemcitabine with an acid selected from the group consisting of inorganic acids such as hydrochloric acid, hydrofluoric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid , lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, Niacin, pamoic acid, pectic acid, persulf
  • inorganic acids such as
  • the pharmaceutically acceptable salt is gemcitabine hydrochloride.
  • the cancer is colon cancer, lung cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, liver cancer, breast cancer, cervical cancer.
  • the lung cancer includes non-small cell lung cancer including squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, large cell carcinoma, and the like, and the non-small cell lung cancer is preferably lung squamous cell carcinoma.
  • the present invention provides a method of predicting drug sensitivity in the treatment of cancer comprising a drug comprising gemcitabine or a pharmaceutically acceptable salt thereof.
  • the method comprises applying AKR1C1, AKR1C2 or AKR1C3 as a biomarker.
  • the method can also include detecting the amount of expression of AKR1C1, AKR1C2 or AKR1C3 in the patient or in an ex vivo sample.
  • a therapeutically effective amount of gemcitabine or a pharmaceutically acceptable salt thereof can be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable Adverse reactions.
  • Suitable active substances in the combination include conventional drugs suitable for chemotherapy or targeted therapy, such as alkylating agents, platinum compounds, DNA modifiers, topoisomerase inhibitors, microtubule modifiers, antimetabolites , anticancer antibiotics, hormones/antagonists, aromatase inhibitors, small molecule kinase inhibitors, photosensitizers, antibodies, cytokines, drug conjugates, vaccines or other drugs.
  • the pharmaceutically acceptable carrier can be a carrier that is relatively non-toxic and harmless to the patient at a concentration consistent with the effective activity of the active ingredient, such that any side effects caused by the carrier do not destroy the The beneficial effects of the active ingredients.
  • the pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt thereof is preferably an amount that produces a result or affects the particular condition being treated.
  • Gemcitabine or a pharmaceutically acceptable salt thereof can be administered in the following manner together with a pharmaceutically acceptable carrier well known in the art using any effective conventional dosage unit form including immediate release, sustained release and timed release formulations. : oral, parenteral, topical, nasal, ocular, sublingual, rectal, vaginal administration, etc.
  • the present invention provides a kit for predicting drug sensitivity in the treatment of cancer comprising gemcitabine or a pharmaceutically acceptable salt thereof, the kit comprising:
  • An agent that detects at least one of the expression levels of AKR1C1, AKR1C2, and AKR1C3 in an individual sample is an agent that detects at least one of the expression levels of AKR1C1, AKR1C2, and AKR1C3 in an individual sample.
  • the individual sample is selected from the group consisting of human cancer tissues, and specifically, may be selected from the group consisting of colon cancer, lung cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, liver cancer, breast cancer, and cervical cancer.
  • the present invention has the beneficial effects of using the aldosterone reductase (AKR) family member AKR1C1, AKR1C2 or AKR1C3 as a biomarker for predicting the drug sensitivity of gemcitabine in the treatment of cancer, thereby guiding clinical drug use, not only avoiding drug selection
  • the blindness avoids delaying the patient's condition due to improper drug selection, and can also monitor the therapeutic effect of the drug during the treatment process, and realize the rationality of the drug and the purpose of individualized treatment.
  • AKR1C1-C3 in clinical cancer cases further validates the high correlation between AKR1C1-C3 expression and gemcitabine efficacy, indicating the rationality, feasibility and height of using AKR1C1, AKR1C2 or AKR1C3 to predict the efficacy of gemcitabine in the treatment of cancer. Effectiveness.
  • Figure 1 shows the expression levels of AKR1C1 to C3 in different cells. GAPDH or ⁇ -tubulin is used as an internal reference. The higher the gray value of the strip, the higher the expression level of the corresponding protein.
  • Figure 9 Antitumor effect of gemcitabine in a MDA-MB-435 melanoma xenograft model.
  • a solid support such as a nitrocellulose membrane, a difluorinated resin membrane, etc.
  • the polypeptide acts as an antigen, and the corresponding antibody recognizes and binds to the antibody, and then reacts with the enzyme or the isotope-labeled secondary antibody, and develops the color of the substrate or autoradiography to detect the expression amount of the target protein.
  • AKR1C1 ⁇ C3 protein The expression of AKR1C1 ⁇ C3 protein in different cells was examined.
  • Cells human colon cancer cells CW-2, LoVo, HCT116, SW620, COLO 205, HT-29, RKO, DLD-1, NCI-H716, SW1116, SW948; human lung cancer cells NCI-H292, A549, NCI-H460, NCI-H1650, HCC827, NCI-H1299, NCI-H1975, SK-MES-1, NCI-H1437, NCI-H1944; human gastric cancer cells BGC-823, HGC-27, SGC-7901, KATO III, NCI-N87, SNU-1; human pancreatic cancer cells AsPC-1, BxPC-3, PANC-1, Capan-2, CFPAC-1, MIA PaCa-2, HPAF-II; human breast cancer cells BT-474, SK-BR-3 , MCF-7, T-47D, MDA-MB-231, MDA-MB-468; human ovarian cancer cell line SK-OV-3, NIH: OVCAR-3
  • AKR1C1 mouse monoclonal antibody (MAB6529) was purchased from R&D Systems, AKR1C2 rabbit polyclonal antibody (13035) from Cell Signaling Technology, AKR1C3 mouse monoclonal antibody (MAB7678) from R&D, GAPDH rabbit monoclonal antibody (2118) Purchased from Cell Signaling Technology, HRP- ⁇ -tubulin mouse monoclonal antibody (ab012) was purchased from Lianke Bio.
  • HRP-labeled goat anti-rabbit IgG and HRP-labeled horse anti-mouse IgG were purchased from Cell Signaling Technology.
  • the cells were cultured in a 25 cm 2 flask, and cells were collected at 80-90% coverage, and 200-300 ⁇ l of RIPA lysate (50 mM Tris ⁇ HCl, 150 mM NaCl, 1% NP-40, 1% SDS, was added according to the number of cells. 1 ⁇ protease inhibitor Cocktail), vortexed and placed on ice for 30 min. After centrifugation at 14,000 rpm for 10 min at 4 ° C, the supernatant was taken and quantified using a BSA protein quantitative assay kit. Add 5 ⁇ loading buffer and bring to a boil.
  • RIPA lysate 50 mM Tris ⁇ HCl, 150 mM NaCl, 1% NP-40, 1% SDS
  • AKR1C1 ⁇ C3 were highly expressed in COLO 205 cells; AKR1C1 and AKR1C2 were moderately high expression in NCI-H716 cells, AKR1C3 was highly expressed; and three proteins in HCT 116, RKO and DLD-1 cells were observed. Low expression; AKR1C1 and AKR1C2 were underexpressed in CW-2, LoVo, SW620, HT-29, SW1116 and SW948 cells, and AKR1C3 was moderately or highly expressed.
  • AKR1C1 ⁇ C3 were highly expressed in A549, NCI-H460, SK-MES-1, NCI-H1437 and NCI-H1944 cells; NCI-H292, NCI-H1650, NCI-H1299 and NCI-H1975 cells AKR1C1 ⁇ C3 were all expressed low; in HCC827 cells, AKR1C1 ⁇ C3 were all expressed low.
  • AKR1C1 ⁇ C3 was highly expressed in SGC-7901 cells; AKR1C1 ⁇ C3 was down-regulated in HGC-27 and SNU-1; AKR1C1 was moderately expressed in BGC-823 cells, low to moderate expression of AKR1C2, and high expression of AKR1C3.
  • AKR1C1 and AKR1C2 proteins were underexpressed and AKR1C3 was moderately expressed.
  • AKR1C1 ⁇ C3 were highly expressed in AsPC-1 and BxPC-3 cells; AKR1C1 ⁇ C3 were down-regulated in PANC-1 and Capan-2; low to moderate expression of AKR1C1 and AKR1C2 in CFPAC-1 cells AKR1C3 is highly expressed; in MIA PaCa-2 cells, AKR1C1 is moderately expressed, AKR1C2 and AKR1C3 are underexpressed; in HPAF-II cells, AKR1C1 is underexpressed, AKR1C2 is low to moderately expressed, and AKR1C3 is highly expressed.
  • AKR1C1 ⁇ C3 were down-regulated in BT-474, MCF-7, T-47D, MDA-MB-231 and MCF7 cells; AKR1C1 and AKR1C2 were underexpressed in SK-BR-3 cells, and AKR1C3 was Moderate expression; AKR1C1 and AKR1C2 are highly expressed in MDA-MB-468 cells, and AKR1C3 is moderately expressed.
  • AKR1C1 ⁇ C3 were all expressed in NIH:OVCAR-3 and A2780 cells; AKR1C1 ⁇ C3 were highly expressed in SK-OV-3 cells.
  • AKR1C1 ⁇ C3 were down-regulated in BEL-7402 cells; AKR1C1 and AKR1C2 were low to moderately expressed in Hep G2 cells, and AKR1C3 was highly expressed.
  • AKR1C1 and AKR1C2 were both lowly expressed and AKR1C3 was highly expressed.
  • Gemcitabine hydrochloride was purchased from Meilun Bio, matrigel was purchased from Corning, USA (Cat. No. 354262), and BALB/c nude mice were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.
  • tumors were grown to 100-200 mm3, they were divided into two groups, namely, control group and gemcitabine-administered group, with 6 animals in each group.
  • Gemcitabine hydrochloride was administered at a dose of 120 mg/kg, administered intraperitoneally, on the first and fourth days of each week.
  • V0 is the measured tumor volume at the time of sub-cage administration (ie, d0)
  • Vt is the tumor volume at each measurement.
  • T/C% TRTV/CRTV*100%
  • TRTV average RTV of the treatment group
  • CRTV mean RTV of the vehicle control group.
  • Gemcitabine showed differences in its efficacy in different xenograft models.
  • the anti-tumor effect of gemcitabine in different nude mice xenograft models was significantly different.
  • gemcitabine significantly inhibited the growth of HCT-116, HT-29, CW-2, LoVo, RKO, and DLD-1 xenografts, T/C% ⁇ 20 %;
  • the inhibitory effect of gemcitabine was poor, T/C%>40%; in the NCI-H716 model, the inhibitory effect of gemcitabine was intermediate, and the T/C% was about 38%. .
  • gemcitabine has a significant inhibitory effect on NCI-H1650, NCI-H1975 and NCI-H1299 xenografts in nude mice, T/C ⁇ 20%; whereas for A549, NCI- H460, NCI-H1437 and NCI-H1944 were poorly inhibited (see Figure 3) with T/C > 40%.
  • gemcitabine has a significant inhibitory effect on the growth of NCI-N87, HGC-27 and SNU-1 xenografts, T/C ⁇ 20%; but inhibition of BGC-823 and SGC-7901 xenografts Poor effect, T / C > 50%.
  • gemcitabine has a significant inhibitory effect on Capan-2, PANC-1, and CFPAC-1 xenografts, T/C ⁇ 20%; inhibition of BxPC-3 and AsPC-1 xenografts Poor, T/C>40%.
  • gemcitabine has a poor inhibitory effect on HeLa xenograft tumors, with a T/C >50%.
  • Gemcitabine also showed strong antitumor activity in the MDA-MB-435 melanoma model (see Figure 9) with T/C ⁇ 20%.
  • AKR1C1 to C3 can be used as biomarkers for predicting drug sensitivity in the treatment of cancer with gemcitabine or a pharmaceutically acceptable salt thereof.
  • AKR1C1 rabbit polyclonal antibody (ab192785) was purchased from abcam
  • AKR1C2 antibody (AM05295PU-N) was purchased from Origene
  • AKR1C3 antibody (ab49680) was purchased from abcam
  • BOND III automatic dyeing machine was purchased from Leica (Germany).
  • the paraffin sample was sliced to a thickness of about 4 ⁇ m. After drying in an oven, it was placed in a BOND III automatic dyeing machine for immunohistochemistry.
  • the primary antibody was diluted 1:200, the incubation time was 15 min, and the BOND Polymer Refine incubation time was 8 min.
  • the expression level of AKR1C1 ⁇ C3 in different samples was determined by scoring the tissue sections under the light microscope.
  • AKR1C1 ⁇ C3 The expression of AKR1C1 ⁇ C3 in lung squamous cell carcinoma is correlated with the efficacy of gemcitabine (Table 1).

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Abstract

La présente invention concerne une application d'AKR1C1, AKR1C2 ou AKR1C3 pour une utilisation en tant que biomarqueur pour prédire la sensibilité à un médicament dans le traitement de cancers avec de la gemcitabine ou un sel pharmaceutiquement acceptable de celle-ci. Les cancers pouvant être le cancer du côlon, du poumon, de l'estomac, du pancréas, de l'ovaire, du foie, du sein et du col de l'utérus et un mélanome. En adoptant la solution technique de la présente invention pour guider la médication clinique, le recours à l'aveugle dans la sélection de médicament peut être évité, évitant ainsi des retards de traitement dus à une sélection de médicament incorrecte, et l'effet thérapeutique des médicaments peut être surveillé pendant des processus de traitement, ce qui permet d'atteindre l'objectif d'une utilisation de médicament appropriée et d'un traitement individualisé.
PCT/CN2018/100371 2017-08-14 2018-08-14 Biomarqueur de prédiction de la sensibilité à la gemcitabine et son utilisation Ceased WO2019034042A1 (fr)

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JP5143841B2 (ja) * 2006-10-10 2013-02-13 ロス アラモス ナショナル セキュリティー，エルエルシー 高度な薬物開発及び製造
EP2009114A1 (fr) * 2007-06-29 2008-12-31 Bayer Schering Pharma Aktiengesellschaft Procédés, kits et composés pour déterminer la réactivité au traitement d'un trouble pathologique par épothilones

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YANG, ZHIYONG ET AL.: "Expression and Implication of Dihydroliol Dehydrogenase in Non-small Cell Lung Cancer", MEDICAL RECAPITULATE, vol. 17, no. 10, 20 May 2011 (2011-05-20), pages 1497 - 1499 *

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