WO2020019095A1 - Protéine rage (récepteur des produits finaux de glycation avancée) utilisée comme biomarqueur de sensibilité tumorale et pour l'évaluation de la d'une thérapie radiologique et radiomimétique - Google Patents

Protéine rage (récepteur des produits finaux de glycation avancée) utilisée comme biomarqueur de sensibilité tumorale et pour l'évaluation de la d'une thérapie radiologique et radiomimétique Download PDF

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WO2020019095A1
WO2020019095A1 PCT/CL2019/050062 CL2019050062W WO2020019095A1 WO 2020019095 A1 WO2020019095 A1 WO 2020019095A1 CL 2019050062 W CL2019050062 W CL 2019050062W WO 2020019095 A1 WO2020019095 A1 WO 2020019095A1
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rage
cancer
expression
therapy
treatment
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Spanish (es)
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Armando ROJAS RUBIO
Erik Marcelo MORALES MEJÍAS
Ileana GONZÁLEZ BONET
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Universidad Católica Del Maule
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • 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

Definitions

  • PROTEIN RAGE (RECEIVER OF FINAL PRODUCTS OF ADVANCED GLICACY) AS BIOMARCATOR OF TUMOR SENSITIVITY AND ASSESSMENT OF RADIOLOGICAL THERAPY AND
  • Radiotherapy is a clinical modality that uses ionizing radiation to treat malignant neoplasms and sometimes benign diseases.From its inception, the goal of radiotherapy has been to cure cancer locally without excessive side effects.
  • Radiation therapy is presented as one of the most potent and most used cancer treatment options. Currently, it is an essential component of treatment for more than half of newly diagnosed cancer patients, where approximately 60-65% of cancer patients require radiation therapy as the sole treatment or in combination with surgery and / or chemotherapeutic drugs.
  • the most important factors that affect the results of radiotherapy are the type of tumor, its location and its extent, the affected anatomical area and the geometric accuracy with which a calculated radiation dose is administered.
  • External beam radiation therapy is the most frequent form of radiation therapy, where an external source of radiation is aimed at a particular area of the body.
  • a computer is used to calculate the position of the source and the amount of time needed to administer the correct dose of radiation to the tumor.
  • the treatment can be administered at a high dose rate (HDR) or a low dose rate (LDR) .
  • HDR high dose rate
  • LDR low dose rate
  • the dose rate in LDR ranges from 0.4 to 2.0 Gy / h, while the dose in HDR is> 12 Gy / h.
  • HDR brachytherapy is usually an outpatient procedure that lasts only a few minutes, while with LDR brachytherapy, the patient is treated with radiation administered at a continuous rate for several hours or days.
  • Permanent brachytherapy also called seed implantation, involves placing radioactive seeds or pellets (approximately the size of a grain of rice) on or near the tumor and leaving them there permanently, because after several weeks or months, the level Implant radioactivity finally decreases to zero.
  • drugs or radiomimetic agents are added, which are those that mimic the effects of radiation in terms of their effect generating breaks in the double strand of DNA, as in the case of certain drugs that are used in cancer chemotherapy, such as cisplatin, carboplatin, oxalaplatin doxorubicin, daunorubicin, neocarzinostatin, bleomycin, among others.
  • Ionizing radiation detecting equipment like other measuring devices, works because of some effect on the matter produced by the phenomenon to be measured. In the particular case of these radiations this effect is ionization.
  • the measuring instruments are similar to other detection equipment in their operational characteristics. However, this measurement is not related to the effect on treated tissues, therefore, there is a need to develop methodologies that allow estimating the sensitivity or response to treatment with radiological therapy and / or radiomimetic drugs, since in the case of these drugs there are also no systems that allow quantifying or directly correlating their effect on the treated tumor or tissue.
  • Eukaryotic cells have developed a sophisticated response to the different types of potential damage that the DNA molecule can suffer, not only in its ability to detect damage but also to repair it efficiently.
  • the effectiveness of DNA repair mechanisms is currently considered one of the most important determinants of tumor radiosensitivity to this therapeutic modality, since ionizing radiation induces different forms of DNA repair, especially in the repair of double strand breaks (DSB) in DNA.
  • DSB double strand breaks
  • the molecules involved in the DNA signaling response pathways, which detect and repair the lesions generated, are excellent candidates for evaluation as radiosensitivity biomarkers, since cells with poor repair mechanisms have less able to repair the DSB induced by Ionizing radiation and, therefore, are more sensitive to irradiation, according to radiosensitivity syndromes, such as talengiectasis ataxia.
  • DNA repair biomarkers highlight variations in the response to DNA damage as a function of radiation dose
  • An intrinsic radiosensitivity biomarker of the tumor would be extremely valuable for the personalization of the therapy, helping to make decisions among the radical treatment options, so as to avoid the toxicity of radiotherapy in patients who are likely to benefit from radiotherapy.
  • radiosensitivity biomarkers According to an article published in Clinical Oncology (Vol. 27, N Q 10, p. 561-569, 2015] official journal of The Royal College of Radiologists (United Kingdom), there are no biomarkers predictive of radiosensitivity or benefit of radiotherapy. There would be several biomarkers that look promising, but that require more clinical evaluations.As radiotherapy is a widely used treatment modality, radiosensitivity biomarkers have the potential to improve treatment outcomes for a large number of patients and, therefore, , would have a great effect on cancer practice. This would also be extensive for biomarkers to assess the usefulness of therapies using radiomimetic drugs.
  • a biomarker composition for diagnosing radiation resistant cancer containing a protein 1 related to the low density lipoprotein receptor (LRP-1) as an active ingredient, and a method is described in KR20170129620. to diagnose radiation resistant cancer using it.
  • LRP-1 is analyzed, which is a binding protein to which a specific peptide sequence bound to radiation-resistant colorectal cancer tissues binds.
  • LRP1 is a member of the low-density lipoprotein receptor (LDLR) family and is highly expressed in hepatocytes, adipocytes, neurons, vascular smooth muscle cells, fibroblasts and macrophages, so Therefore, this marker would not only be expressed in cancer but also in various types of healthy tissues / cells, which reduces the sensitivity and specificity of the method.
  • LDLR low-density lipoprotein receptor
  • WO2017186882 describes a method for predicting the response to an antitumor treatment comprising determining the level of expression of the TIMP3 gene, evaluating the amount of mRNA as a predictive biomarker of the response to DNA repair inhibitors.
  • This method is related to a predictive marker of response for therapy with DNA repair inhibitors.
  • it is a pharmacological approach to enhance the effect of cytostatics.
  • the drug Lynparza olaparib
  • PARP poly-ADP-ribose polymerase
  • Document US2016024594 describes the methods that allow classifying patients into groups to receive an optimized radiation treatment based on the signature of the patient's specific biomarker, which includes markers that have been shown to correlate with TGF-b expression and are associated with tumor aggressiveness, radioresistance and unfavorable prognosis.
  • the biomarkers evaluated are selected from CD44, MMP9, ALDH1A1, Vimentin, hyaluronan, beta-catenin, MFG-E8 and CD68.
  • the expression of TGF-beta is related to radio resistance without mentioning mimetic radios.
  • Fig.lA H2AX induction results as a marker for DSB DNA repair in cisplatin-treated MKN74 cells.
  • This Figure shows the response to cisplatin (left) compared to the control (right). Because there is a different response between both conditions, it should be normalized using a protein that does not change its expression (histone H1) to show that Changes are specific for nuclear RAGE and for the gold standard of double chain breaks (phospho-H2AX)
  • Fig. 1B Difference between wild-type cells compared to silenced RAGE cells, where the latter have higher viability rates after drug treatment.
  • Fig. 2 Immunostaining of nuclear RAGE in gastric biopsies of subjects infected with H. pylori, where nuclear level expression is shown.
  • the method of the present invention is based on the ability of the nuclear protein RAGE (Receptor for Advanced Glycation End Products] to interact with other biomarkers alone or in combinations thereof, selected from the ATM protein (Mutated Ataxia Telangectasia), histone H2AX, the MDC-1 protein (Mediator of the Damage Control Point in DNA 1), and the DNA repair protein RAD51; preferably to interact with the biomarker corresponding to the ATM protein, and where its association is essential for repair Efficient double chain DNA breaks.
  • the nuclear protein RAGE Receptor for Advanced Glycation End Products
  • the receptor for advanced glycation end products is a 55 KDa protein that belongs to the pattern recognition receptor group.
  • This protein was initially described as a receptor for advanced glycation end products (AGE), which are formed non-enzymatically by the interaction of non-reducing sugars, such as glucose with the amino groups present in proteins, the formation of AGEs can also occur by the self-oxidation of glucose and the peroxidation of lipids that generate dicarbonyl derivatives that , in turn, can interact with proteins, lipids and nucleic acids to form AGEs.
  • AGE receptor for advanced glycation end products
  • the research group of the present invention described the presence of this protein in the cell nucleus, without clarifying its function. Recently, a group from the University of Heidelberg reported that this receptor effectively reaches the cell nucleus and that its function in this new location is not linked to the known pathophysiological inflammatory response, but it has an essential function for efficient DNA repair and, in particular, with the repair of double chain breaks (DSB)
  • RAGE is vital for DNA repair, so the loss of RAGE produces higher levels of cell dysfunction and cellular senescence, so the method of the present invention Based on this finding, it will be possible to evaluate and determine the sensitivity or response to treatment with radiological therapy and / or radiomimetic drugs in a patient affected with a tumor.
  • the advantage of the present invention is given in part because RAGE binds with ATM, forming a complex.
  • the results with ATM previously known in the state of the art lacked to simultaneously evaluate the RAGE protein and therefore the results when using only ATM were not a good prediction method, nor was it obvious to correlate it with RAGE or other biomarkers.
  • the present invention describes an in vitro method for predicting the utility of therapy for a patient affected with a tumor to respond to a treatment with radiotherapy or radiomimetic drugs using RAGE (hereinafter, nuclear RAGE) as a biomarker, optionally based on its ability to interact with ATM or other biomarkers, such as H2AX, MDC-1, RAD51 or combinations thereof, and where their association is essential for efficient DNA repair of double stranded tears.
  • RAGE nuclear RAGE
  • nuclear RAGE is detected in the nucleus of the tumor cells in samples obtained from the patient, preferably samples obtained from biopsies. More specifically, the method detects the presence of any polymorphic RAGE variant described in the nucleus of any tumor cell.
  • the detection of RAGE expression is preferably performed by immunohistochemical techniques, quantifying the signal intensity and correlated with an empirical evaluation, validated with the help of an oncologist, to have a baseline reference.
  • the method for the detection of RAGE expression comprises the following steps:
  • the step of incubating with the corresponding secondary antibodies is performed.
  • Normalization is performed when there is a complex mixture of biomolecules, for example, when an analysis is performed on a biopsy or whole tissue that has been included in paraffin.
  • Nuclear RAGE is associated in any polymorphic form or variant with the presence or positive signal of the following proteins in any polymorphic form or variant thereof or combinations thereof: H2AX, MDC-1, ATM, RAD51.
  • a positive signal compared to the control value is an indication that a patient is likely to respond to treatment. These are then indicators that the repair process is working, corresponding to a positive control that the damaged cell is repairing DNA damage.
  • the indicated markers can also be evaluated by immunohistochemistry, selecting the primary antibody for the corresponding marker, where, optionally a positive signal for an additional marker selected from H2AX, MDC-1, ATM, RAD51 or combinations thereof, will be correlated in in conjunction with the results of RAGE expression to determine the sensitivity to therapy.
  • the method of the present invention may include one or more additional RAGE markers selected from H2AX, MDC-1, ATM, RAD51 or combinations of them, to expand the coverage and / or sensitivity of the method.
  • a preferred embodiment of the present invention comprises the correlation of positive results for RAGE in conjunction with positive results for ATM.
  • the detection could be done, in addition to the immunohistochemical techniques already mentioned, by ELISA, mass spectrometry, proteomic techniques, flow cytometry, or others.
  • the method according to the present invention could be executed according to the most appropriate detection techniques available at the time of executing the invention, without thereby limiting or altering the scope of the same.
  • This method is useful for assessing the sensitivity or response to treatment with radiological therapy and / or radiomimetic drugs in a patient affected with a tumor associated with a cancer selected from the group consisting of melanoma, glioblastoma, breast cancer, prostate cancer, cancer of testis, colon cancer, lung cancer, gastrointestinal cancer, liver cancer and head and neck cancer.
  • any other type of cancer where first-line therapy is based on the use of radiation or radiomimetic drugs, where the therapy generates rupture in the double strand of DNA.
  • the method considers using a biological sample obtained from a biopsy of the patient undergoing radiotherapy or chemotherapy with radiomimetic drugs.
  • the inventors of the present invention are preparing the evaluation of tumors of patients with gastric and colorectal cancer.
  • the method of the present invention offers a reliable and efficient methodology to evaluate the sensitivity or response to the oncological treatment that generates rupture in the double strand of the DNA, by means of radiotherapy or radiomimetic drugs.
  • the methodology of the present invention is based on a biological base that is capable of supporting chemo and radiotherapy, the principle originates from the fact that it was detected that accidental exposure to ionizing radiation was capable of damaging DNA, where The main injury generated was the double chain rupture.
  • both radiotherapy and chemotherapy with radiomimetic drugs originate in principle from the ability of chemical or physical agents to damage DNA. Therefore, the methodology of the present invention is based on the biological premise that both therapies generate the same biological event, so that biomarkers selected alone or in combination with them, are able to detect the sensitivity and therapeutic efficacy of radiotherapy and chemotherapy with radiomimetic drugs.
  • the present invention provides a kit to evaluate the sensitivity or response to treatment with radiological therapy and / or radiomimetic drugs by detecting nuclear RAGE by immunohistochemical technique comprising:
  • anti-IgG conjugates of the primary antibody species labeled with Alexa_Fluor, or peroxidase enzyme.
  • Example 1 Immunohistochemistry to determine RAGE expression
  • PBS phosphate buffered saline
  • the primary antibody is incubated overnight at 4 ° C in a humid chamber. The next day, 3 washes are performed with PBS-Tween20, incubating the corresponding Alexa Fluor, at room temperature and dark for 1 hour. 3 washes are done with PBS-Tween20, finishing with the assembly of the samples with ProLong-DAPI medium.
  • the samples are observed after 24 hours in the Zeiss AxioScopeAl fluorescence microscope, for image capture, which will be processed by the ZEN2 software.
  • the presence or positive signal of RAGE allows us to consider that the tissue sample is sensitive to cisplatin therapy, by detecting that there is repair of the breaks produced by said double-chain radiomimetic drug.
  • Example 2A Evaluation in gastric cancer cell model. Cisplatin
  • MKN74 adenocarcinoma cells were treated with 10 mM cisplatin for 24 hours. After treatment, cells were harvested and nuclear fractions were isolated with the CelLytic TM NuCLEAR TM extraction kit according to the manufacturer's instructions.
  • the protein (20 pg) was electrophoresed in 10% SDS-polyacrylamide gels and subsequently transferred to a polyvinylidene difluoride membrane, after blocking with 0.05% Tris / Tween 20 buffered saline ( TBS-T] containing 0.2% casein, the membrane was incubated with primary antibodies, at the dilutions recommended by the manufacturer (Abcam], in blocking solution at 4 ° C overnight.
  • cisplatin is capable of inducing double breakage chain, managing to induce classic DSB DNA repair markers, such as phospho- H2AX, also known as H2AX.
  • An early cellular response to DSBs is the rapid phosphorylation of H2AX, in Ser-139 to produce gH2AC.
  • Example 2B Evaluation in gastric cancer cell model. Cisplatin and Etoposide.
  • the RAGE gene was silenced using the lentiviral particle technique with three RAGE-specific constructs that code for shRNA type structures (Santa Cruz Biotechnology, Inc.].
  • the coverslips were subjected to 3 washes of 5 minutes each with PBS IX, then fix the samples with cold methanol for 20 minutes at -20 ° C. 3 washes were performed with PBS IX to continue blocking with 1% PBS-BSA for 1 hour at room temperature. Next, the primary antibody, diluted in blocking buffer, was incubated overnight at 4 ° C and in a humid chamber. The next day, 3 washes were performed with PBS-tween20, 0.2%, and incubated at room temperature and dark for 1 hour with the Alexa conjugate correspondent. 3 washes are done with PBS-Tween20, finishing with the assembly of the samples with ProLong medium with DAPI. The samples are observed after 24 hours in the Zeiss ScopeAl fluorescence microscope and using the ZEN2 software.
  • Immunofluorescent labeling for phosphorylated H2AX protein is extraordinarily weak, suggesting that wild-type adenocarcinoma cells have sufficient capacity to repair lesions induced by treatment with both drugs, however, silenced cells for RAGE they show an intense immunofluorescent labeling for gamma-H2AX, which means that the treatment with the drugs generated a significant number of double-chain tears.
  • Nuclear RAGE immunostaining signals were recorded in gastric biopsies of subjects infected with H. pylori, which is a pathogen capable of inducing double chain tears in gastric epithelial cells.

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Abstract

La présente invention concerne l'utilisation de la protéine nucléaire RAGE (Receptor for Advanced Glycation End Products) comme biomarqueur dans une méthode in vitro d'évaluation, de détermination ou de prédiction de la sensibilité ou de la réponse au traitement dans le cadre d'une thérapie radiologique (radiothérapie) et/ou d'une thérapie avec médicaments radiomimétiques (chimiothérapie), c'est-à-dire, une thérapie produisant des ruptures dans la double chaîne d'ADN chez un patient atteint d'une tumeur. La protéine RAGE peut être utilisée comme biomarqueur unique ou en association avec d'autres biomarqueurs.
PCT/CL2019/050062 2018-07-26 2019-07-24 Protéine rage (récepteur des produits finaux de glycation avancée) utilisée comme biomarqueur de sensibilité tumorale et pour l'évaluation de la d'une thérapie radiologique et radiomimétique WO2020019095A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2008012023A (es) * 2006-03-21 2008-10-01 Wyeth Corp Metodos para prevenir y tratar enfermedades amiloidogenicas.
WO2011106084A1 (fr) * 2010-02-24 2011-09-01 Biodesix, Inc. Sélection de patient cancéreux pour l'administration d'agents thérapeutiques utilisant une analyse par spectrométrie de masse
EP2650013A1 (fr) * 2012-04-10 2013-10-16 Deutsches Krebsforschungszentrum Inhibiteurs du récepteur de produit terminal de glycosylation (RAGE) pour une utilisation dans le traitement du cancer induit par l'inflammation et/ou les lésions
WO2016033489A2 (fr) * 2014-08-28 2016-03-03 Ndsu Research Foundation Compositions et procédés permettant de réduire l'interaction entre un récepteur des produits de glycation avancée (rage) et ses ligands

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2008012023A (es) * 2006-03-21 2008-10-01 Wyeth Corp Metodos para prevenir y tratar enfermedades amiloidogenicas.
WO2011106084A1 (fr) * 2010-02-24 2011-09-01 Biodesix, Inc. Sélection de patient cancéreux pour l'administration d'agents thérapeutiques utilisant une analyse par spectrométrie de masse
EP2650013A1 (fr) * 2012-04-10 2013-10-16 Deutsches Krebsforschungszentrum Inhibiteurs du récepteur de produit terminal de glycosylation (RAGE) pour une utilisation dans le traitement du cancer induit par l'inflammation et/ou les lésions
WO2016033489A2 (fr) * 2014-08-28 2016-03-03 Ndsu Research Foundation Compositions et procédés permettant de réduire l'interaction entre un récepteur des produits de glycation avancée (rage) et ses ligands

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ARUMUGAM, T. ET AL.: "S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis", CLINICAL CANCER RESEARCH, vol. 18, no. 16, 15 August 2012 (2012-08-15), pages 4356 - 4364, XP055681886 *
BHATTACHARYA, S. ET AL.: "Repurposing DNA repair factors to eradicate tumor cells upon radiotherapy", TRANSLATIONAL CANCER RESEARCH, vol. 6, no. S5, 1 July 2017 (2017-07-01), pages S822 - S839, XP055681890 *
KUMAR, V. ET AL.: "Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair", NUCLEIC ACIDS RESEARCH, vol. 45, no. 18, 13 October 2017 (2017-10-13), pages 10595 - 10613, XP055681885 *
LECLERC, E. ET AL.: "The role of S1 00 proteins and their receptor RAGE in pancreatic cancer", BIOCHIMICA ET BIOPHYSICA ACTA (BBA)-MOLECULAR BASIS OF DISEASE, vol. 1852, no. 12, December 2015 (2015-12-01), pages 2706 - 2711, XP055681889 *
MORALES, E. ET AL.: "Lesiones gástricas en pacientes infectados con Helicobacter pylori: expresión de RAGE (receptor de productos de glicosilización avanzada) y otros inmunomarcadores", REVISTA MEDICA DE CHILE, vol. 141, no. 10, 2013, pages 1240 - 1248, XP055681882 *

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