WO2017200263A1

WO2017200263A1 - Biomarker composition comprising lrp-1 as active ingredient, for diagnosis of radiation-resistant cancer or prediction of radiation therapy prognosis

Info

Publication number: WO2017200263A1
Application number: PCT/KR2017/005054
Authority: WO
Inventors: 최은경; 정성윤; 송시열; 이경진
Original assignee: 울산대학교 산학협력단; 재단법인 아산사회복지재단
Priority date: 2016-05-17
Filing date: 2017-05-16
Publication date: 2017-11-23

Abstract

The present invention relates to a biomarker composition comprising LRP-1 as an active ingredient, for the diagnosis of radiation-resistant cancer, and a method for diagnosing a radiation-resistant cancer using the same. The present invention identifies LRP-1, a binding partner protein to which a specific peptide sequence that specifically targets radiation-resistant colon cancer tissues actually binds, and having such basis, has suggested the possibility of a radiation therapy resistance-related factor for cancer.

Description

Biomarker composition for the diagnosis of radiation resistant cancer or for predicting the prognosis of radiation therapy comprising LRP-1 as an active ingredient

The present invention relates to a biomarker composition for diagnosing radiation-resistant cancer comprising low density lipoprotein receptor-related protein 1 (LRP-1) as an active ingredient, and a method for diagnosing radiation-resistant cancer using the same. In addition, the present invention relates to a biomarker composition for predicting radiotherapy prognosis of a cancer patient including LRP-1 as an active ingredient and a method for predicting radiotherapy prognosis of a cancer patient using the same.

The smallest unit of the human body, the cell, normally divides, grows and dies by intracellular control and maintains cell balance. If a cell is damaged for some reason, it is treated and recovered to act as a normal cell, but if it is not recovered, it dies on its own. However, cancer is defined as a condition in which abnormal cells, which are not controlled for such proliferation and suppression, proliferate excessively, invade surrounding tissues and organs, and cause mass formation and destruction of normal tissues for various reasons. Cancer is the proliferation of non-suppressive cells, which destroys the structure and function of normal cells and organs, so the diagnosis and treatment are of great importance.

On the other hand, there is a problem in the treatment according to the different treatment cases for each patient due to the difference in treatment responsiveness due to genetic differences of individual cancer patients. Accordingly, the development of cancer microenvironment and biomarkers according to radiation responsiveness is required for effective treatment of cancer patients, through which customized diagnosis and treatment for each patient can be realized.

The present invention is a biomarker composition for diagnosing radiation resistance cancer comprising LRP-1 as an active ingredient, a composition for diagnosing radiation resistance cancer comprising an agent capable of measuring the expression level of LRP-1 as an active ingredient, and a radiation resistant cancer diagnosis using the same. A method, a pharmaceutical composition for enhancing radiosensitivity to cancer cells comprising an LRP-1 protein expression or an activity inhibitor, and a method for screening a radiosensitizer for cancer cells by measuring the expression level of LRP-1 protein are provided.

The present invention also provides a biomarker composition for predicting radiotherapy prognosis of cancer patients comprising LRP-1 as an active ingredient, and a prognosis for cancer patients comprising an agent capable of measuring the expression level of LRP-1 as an active ingredient. The present invention provides a composition for predicting and a method for predicting the prognosis of radiation therapy of cancer patients using the same.

In order to solve the above problems, the present invention provides a low-density lipoprotein receptor-related protein 1 (LRP-1) or a biomarker composition for diagnosing radiation-resistant cancer comprising a gene encoding the same as an active ingredient. to provide.

The present invention also provides a composition for diagnosing radiation-resistant cancer comprising a formulation capable of measuring the expression level of LRP-1 as an active ingredient.

In addition, the present invention provides a method for measuring the expression level of LRP-1 to provide information necessary for the diagnosis of radiation resistant cancer.

The present invention also provides a pharmaceutical composition for enhancing radiation sensitivity to cancer cells comprising LRP-1 protein expression or activity inhibitor as an active ingredient.

The present invention also provides a method for screening a radiation sensitivity enhancer for cancer cells by measuring the expression level of LRP-1 protein.

The present invention also provides a biomarker composition for predicting the prognosis of radiation therapy in cancer patients comprising LRP-1 or a gene encoding the same as an active ingredient.

In another aspect, the present invention provides a composition for predicting the prognosis of the radiation therapy of cancer patients comprising a formulation capable of measuring the expression level of LRP-1 as an active ingredient.

In addition, the present invention provides a method of measuring the expression level of LRP-1 to provide information necessary for predicting the prognosis of radiation therapy in cancer patients.

The present invention relates to a biomarker composition for diagnosing radiation-resistant cancer or predicting prognosis for radiation-resistant cancer, comprising LRP-1 as an active ingredient, wherein the binding partner protein actually binds to a specific peptide sequence that specifically targets radiation-resistant colorectal cancer tissue. Phosphorus LRP-1 was elucidated and based on this, the possibility of radiotherapy resistance-related factors for cancer or radiotherapy prognostic predictors of cancer patients was suggested.

1 shows the results of biopanning in human-derived colorectal cancer cDNA library. A total of three biopanning processes were performed, and it was confirmed that the number of phages increased specifically as the number of times increased.

Figure 2 is a result showing a schematic diagram for the construction of a mouse model transplanted with patient colorectal cancer tissue.

3 shows the results of verifying seven candidate groups showing significant mRNA expression differences among the 14 binding partner protein candidate groups screened.

Figure 4 is a result of confirming the difference in expression at the protein level for the two candidate groups selected in the mRNA expression difference with or without irradiation. Only LRP-1 of the two candidate groups confirmed the difference in expression and indicated only the result. Radiation Resistance and Sensitivity Two cases each were checked for protein expression according to irradiation or not.

5 shows the histological results of LRP-1 in radiation-resistant and sensitive colorectal cancer.

Figure 6 shows the results of the binding of LRP-1 and TPSFSKI peptide using immunoprecipitation method. Lysate: 0 Gy / 2 Gy Irradiated Colorectal Cancer Tissue Extract Protein, IP (B5 phage): 0 Gy / 2 Gy Irradiated Colorectal Cancer Tissue Extract Protein from Immune Sedimentation with Specific Peptide Phage, IP (wt phage): 0 Gy / Immune Sedimentation with Peptide-free Phage from 2 Gy Irradiated Colorectal Cancer Tissue Extracted Proteins, IP (w / o Ab): 0 Gy / 2 Gy Irradiated Immune Sedimented Without Antibodies from Colorectal Cancer Tissue Extracted Proteins, phage lysate: radiation resistant colorectal cancer Peptide phage extract protein targeted at irradiation in tissue, Antibody: LRP-1 antibody.

FIG. 7 shows the results of LRP-1 expression in 4 patients with colorectal cancer tissues (2 cases of radiation resistance and 2 cases of radiation sensitivity). It was confirmed that LRP-1 was overexpressed in the radiation-resistant case, but not in the sensitive case, while confirming that the cancer tissue was identical to that of the cancer tissue extracted from the patient's cancer-grafted mouse model.

FIG. 8 is a result of verifying the expression of LRP-1 by receiving cancer tissue from 20 patients with poor treatment prognosis as a patient who performed radiation therapy among colon cancer patients. It was confirmed that LRP-1 was overexpressed in cancer tissue of patients with poor prognosis.

9 is a result of confirming the prognosis of the patient who performed radiation treatment in actual colon cancer patients through in silico analysis. When the expression of LRP-1 was high, it was confirmed through clinical data that the prognosis of radiotherapy was not good.

The present invention provides a low-marker lipoprotein receptor-related protein 1 (LRP-1) or a biomarker composition for diagnosing radiation-resistant cancer comprising a gene encoding the same as an active ingredient.

"Low density lipoprotein receptor-related protein 1" (LRP-1) of the present invention is described in NCBI accession no. NM_002332, but is not limited thereto.

Preferably, the biomarker composition may further include a conventionally known radiation resistant biomarker, and conventionally known radiation resistant biomarkers include, but are not limited to, CD133, CD144 and CD24.

Preferably, the LRP-1 may bind to a peptide consisting of the amino acid sequence of SEQ ID NO: 1 (TPSFSKI), and the "TPSFSKI" peptide is a peptide targeting a radiation resistant colorectal cancer, and the applicant of Korea It is disclosed in detail in patent application 10-2015-0106580.

As used herein, the term “diagnosis” refers to determining the susceptibility of an object to a particular disease or condition, determining whether an object currently has a particular disease or condition, or as long as a person has a particular disease or condition. Determining the prognosis of the object, or therametrics (eg, monitoring the condition of the object to provide information about treatment efficacy).

In addition, the present invention provides a composition for diagnosing radiation-resistant cancer comprising a formulation capable of measuring the expression level of LRP-1 as an active ingredient.

In detail, the agent capable of measuring the expression level of LRP-1 includes a primer or probe specifically binding to the LRP-1 gene, an antibody, peptide, aptamer specifically binding to the LRP-1 protein. Or a compound, but is not limited thereto.

The present invention also provides a kit for diagnosing radiation-resistant cancer comprising the composition.

As used herein, the term "primer" refers to a nucleic acid sequence having a short free 3-terminal hydroxyl group, which is capable of forming base pairs with complementary templates and acting as a starting point for template strand copying. Refers to the sequence. Primers can initiate DNA synthesis in the presence of four different nucleoside triphosphates and reagents for polymerization (ie, DNA polymerase or reverse transcriptase) at appropriate buffers and temperatures. PCR conditions, sense and antisense primer lengths may be appropriately selected according to techniques known in the art.

As used herein, the term "probe" refers to a nucleic acid fragment such as RNA or DNA, which is short to several bases to hundreds of bases capable of specifically binding other than mRNA, and is labeled so that the presence or absence of a specific mRNA is expressed. You can check the amount. The probe may be manufactured in the form of an oligonucleotide probe, a single strand DNA probe, a double strand DNA probe, an RNA probe, or the like. Selection of appropriate probes and hybridization conditions may be appropriately selected according to techniques known in the art.

As used herein, the term “antibody” refers to a specific immunoglobulin directed to an antigenic site as is known in the art. The antibody in the present invention means an antibody that specifically binds to LRP-1 of the present invention, and the antibody can be prepared according to conventional methods in the art. Forms of such antibodies include polyclonal antibodies or monoclonal antibodies, including all immunoglobulin antibodies. The antibody means a complete form having two full length light chains and two full length heavy chains. In addition, the said antibody also contains special antibodies, such as a humanized antibody.

In addition, the kit of the present invention includes an antibody that specifically binds to a marker component, a secondary antibody conjugate conjugated with a label that is developed by reaction with a substrate, a color substrate solution to be color-reacted with the label, a wash solution, It may include an enzyme stopping solution and the like, and may be prepared in a number of separate packaging or compartments containing the reagent components used.

As used herein, the term "peptide" has the advantage of high binding power to the target material, and no degeneration occurs even during thermal / chemical treatment. In addition, the small size of the molecule can be used as a fusion protein by attaching to other proteins. Specifically, since it can be used by attaching to a polymer protein chain, it can be used as a diagnostic kit and drug delivery material.

As used herein, the term "aptamer" refers to a particular kind of single-stranded nucleic acid (DNA, RNA or modified nucleic acid) that has a stable tertiary structure and which is capable of binding with high affinity and specificity to a target molecule. It means a kind of polynucleotide consisting of). As described above, aptamers are composed of polynucleotides that can bind specifically to antigenic substances like antibodies, but are more stable than proteins, simple in structure, and easy to synthesize. Can be.

In addition, the present invention comprises the steps of (1) measuring the mRNA expression level or LRP-1 protein expression level of LRP-1 gene from a sample isolated from cancer patients; (2) comparing the mRNA expression level of the LRP-1 gene or the expression level of the LRP-1 protein with a control sample; And (3) determining that the LRP-1 gene mRNA expression level or LRP-1 protein expression level is higher than that of the control sample, wherein the LRP-1 gene is determined to be radiation resistant cancer. do.

Specifically, the method of measuring the mRNA expression level is RT-PCR, competitive RT-PCR (Real-time RT-PCR), RNase protection assay (RPA; RNase protection assay ), Northern blotting and DNA chips are used, but are not limited to these.

Specifically, the method of measuring the protein expression level is Western blot, ELISA (enzyme linked immunosorbent asay), radioimmunoassay (RIA), radioimmunodiffusion, Ouchterlony immunodiffusion method, Rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, FACS and protein chips are used, but are not limited thereto.

As used herein, the term "sample isolated from cancer patients" refers to tissues, cells, whole blood, serum, plasma, which differ from the control group in the expression level of the LRP-1 gene or LRP-1 protein, which is a biomarker for radiation-resistant cancer diagnosis. Samples such as saliva, sputum, cerebrospinal fluid, or urine include, but are not limited to.

In the present specification, "radiation-resistant cancer diagnosis" is intended to determine whether cancer cells are radiation-resistant or sensitive for the prediction of radiation treatment strategies and radiation treatment effects of cancer patients.

Specifically, the LRP-1 protein expression inhibitor may be an antisense nucleotide, small interfering RNA (siRNA) or short hairpin RNA (shRNA) that complementarily binds to the mRNA of the LRP-1 gene. The LRP-1 protein activity inhibitor may be, but is not limited to, a compound, a peptide, a peptide mimetics, an aptamer, an antibody, or a natural product that specifically binds to the LRP-1 protein.

The pharmaceutical composition of the present invention may include chemicals, nucleotides, antisenses, siRNA oligonucleotides, and natural extracts as active ingredients. The pharmaceutical compositions or complex preparations of the present invention may be prepared using pharmaceutically acceptable and physiologically acceptable auxiliaries in addition to the active ingredients, which may include excipients, disintegrants, sweeteners, binders, coatings, swelling agents, lubricants. Solubilizers such as lubricants and flavoring agents can be used. The pharmaceutical composition of the present invention may be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to the active ingredient for administration. Acceptable pharmaceutical carriers in compositions formulated in liquid solutions are sterile and physiologically compatible, including saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.

Pharmaceutical formulation forms of the pharmaceutical compositions of the present invention may be granules, powders, coated tablets, tablets, capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and sustained release formulations of the active compounds, and the like. Can be. The pharmaceutical compositions of the present invention may be administered in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, sternum, transdermal, nasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. Can be administered. An effective amount of the active ingredient of the pharmaceutical composition of the present invention means an amount required to prevent or treat a disease. Thus, the type of disease, the severity of the disease, the type and amount of the active and other ingredients contained in the composition, the type of formulation and the age, body weight, general health, sex and diet of the patient, time of administration, route of administration and composition It can be adjusted according to various factors including the rate of secretion, the duration of treatment, and the drug used concurrently. For example, in the case of an adult, when administered once or several times a day, the composition of the present invention is administered once or several times a day, when the compound is 0.1ng / kg to 10g / kg, a polypeptide, In the case of proteins or antibodies, 0.1ng / kg ~ 10g / kg, antisense nucleotides, siRNA, shRNAi, miRNA can be administered at a dose of 0.01ng / kg ~ 10g / kg.

In addition, the present invention (1) contacting the test substance to cancer cells; (2) measuring the level of expression or activity of LRP-1 protein in cancer cells in contact with the test substance; And (3) provides a method for screening a radiation sensitivity enhancer for cancer cells comprising the step of selecting a test substance with reduced expression or activity of the LRP-1 protein compared to the control sample.

As used to refer to the screening method of the present invention, the term "test material" refers to an unknown candidate used in screening to examine whether it affects the expression level of a gene or affects the expression or activity of a protein. do. The sample includes, but is not limited to, chemicals, nucleotides, antisense-RNAs, small interference RNAs (siRNAs), and natural extracts.

As used herein, the term “prognostic prediction” refers to the act of predicting the progress and outcome of a disease in advance. More specifically, the prognosis prediction may vary according to the physiological or environmental condition of the patient, and is interpreted to mean all actions for predicting the progress of the disease after treatment in consideration of the condition of the patient. Can be.

For the purposes of the present invention, the prognosis prediction may be interpreted as an act of predicting disease-free survival rate or survival rate of cancer patients by predicting the progress and cure of the disease in advance after radiation treatment of cancer patients. For example, predicting "good prognosis" indicates a high level of disease-free survival or survival after cancer treatment, meaning that cancer patients are more likely to be treated, and predicting "prognosis is poor." The low disease-free survival rate or survival rate of cancer patients after radiation is indicated, which means that the cancer is more likely to recur or die from cancer.

In another aspect, the present invention provides a kit for predicting the prognosis of the radiation treatment of cancer patients comprising the composition.

In addition, the present invention comprises the steps of (1) measuring the mRNA expression level or LRP-1 protein expression level of LRP-1 gene from a sample isolated from cancer patients; (2) comparing the mRNA expression level of the LRP-1 gene or the expression level of the LRP-1 protein with a control sample; And (3) determining that the prognosis of radiation therapy is worse when the mRNA expression level of the LRP-1 gene or the expression level of the LRP-1 protein is higher than that of the control sample. Provide a way to.

As used herein, the term "cancer" or "cancer cell" refers to breast cancer, cervical cancer, glioma, brain cancer, melanoma, lung cancer, bladder cancer, prostate cancer, leukemia, kidney cancer, liver cancer, colon cancer, pancreatic cancer, gastric cancer, gallbladder cancer, ovarian cancer, It may be, but is not limited to, lymphoma, osteosarcoma, uterine cancer, oral cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, skin cancer, hematologic cancer, thyroid cancer, parathyroid cancer, or ureter cancer.

Hereinafter, examples will be described in detail to help understand the present invention. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Example 1 cDNA Library Screening from Human Colon Cancer

T7Select ^® Human colon tumor cDNA Library specific peptide sequence that purchased the target radiation-resistant colon cancer (Novagen); screened a binding partner protein (TPSFSKI Korea Patent Application No. 10-2015-0106580 call). Specifically, three biopanning processes were repeated to design a binding partner protein candidate group, thereby selecting candidate groups to bind more specifically. After a total of three biopanning procedures, probable candidate information was obtained using sequencing and BLAST. The candidate group information is shown in FIG. 1.

<실시예 2> 환자 대장암 조직 이식 마우스 모델 구축Example 2 Construction of a Mouse Colon Tissue Transplant Mouse Model

Radiation resistant case tissue among patient colorectal cancer tissues was passaged to nude mice. Cancer tissues were implanted one by one under the thigh. The growth of the cancer tissue was observed up to about 1 month (4 weeks), and when the size of the cancer tissue grew to about 100 mm ³ , the cancer tissue was irradiated locally with 2 Gy and after 24 hours recovery time. It was used for the experiment. As a control group of the irradiation group, a mouse model (0 Gy) which was not irradiated only in the same mouse model was also prepared. In addition, radiation-resistant colorectal cancer cases as well as radiation-sensitive colorectal cancer cases were transplanted and passaged in the same manner, and irradiation was performed under the same conditions. A schematic diagram relating to mouse model construction is shown in FIG. 2.

<실시예 3> 결합 상대 단백질 후보군의 유의적 mRNA 발현 차 확인<Example 3> Significant mRNA expression difference of binding partner protein candidate group confirmed

Q-PCR was used to identify significant differences in mRNA expression according to radiation-sensitive, resistant colorectal cancer cases and irradiation. Primers for 14 binding partner protein candidate genes obtained through screening were prepared. In addition, cancer tissue was extracted from the model constructed in Example 2 and cryopreserved, and then mRNA was purified and cDNA was synthesized, respectively. Quantitative PCR (Q-PCR) was performed and seven candidate groups with significant expression differences were selected among the 14 candidate groups depending on the irradiation. As a result of confirming the reproducibility of the candidate group, two candidate groups having the largest significant difference in expression were demonstrated, and the results are shown in FIG. 3.

<< 실시예Example 4> 결합 상대 단백질 후보군의 방사선 조사 여부에 따른 단백질 발현 차 확인 4> Confirmation of protein expression difference according to the irradiation of binding partner protein candidate group

Western boltting was performed to demonstrate significant expression differences at the protein level for the two candidate groups verified according to mRNA expression differences. Proteins were extracted from cryopreserved tissues, and the difference in protein expression according to irradiation was confirmed using antibodies of each candidate group. Of the two candidate groups, only LRP-1 was able to verify the significant difference in protein expression according to irradiation, and one other candidate group was excluded from the candidate group because the protein level could not be confirmed regardless of the irradiation. In addition to the radiation-resistant colorectal cancer case used in the screening and continued verification step, the addition of two radiation-sensitive colorectal cancer cases and one radiation-resistant colorectal cancer case was added to confirm the difference in protein expression. In the case of LRP-1, no significant difference in expression was observed in the radiation-sensitive case, and in the other radiation-resistant colorectal cancer cases, the expression difference was significantly verified. The results are shown in FIG. 4.

<실시예 5> LRP-1의 조직학적 검증Example 5 Histological Validation of LRP-1

IHC staining was performed for histological validation of LRP-1, which identified significant expression differences in mRNA and protein levels. Tissue sections were prepared for each of the two cases of radiation-resistant and susceptible colorectal cancer with or without irradiation. The tissue sections were stained with LRP-1 antibody and then examined for their presence. By confirming homology with the protein expression difference verification in Example 4, it was supported that LRP-1 is a binding partner protein of the TPSFSKI peptide. This is shown in FIG. 5.

<실시예 6> TPSFSKI 펩타이드 파아지와 LRP-1의 실제 결합 여부 규명Example 6 Identification of Actual Binding of TPSFSKI Peptide Phage to LRP-1

Based on indirectly verifying that LRP-1 is a binding partner protein of the TPSFSKI peptide sequence in Examples 3 to 5, an immunoprecipitation assay was performed to directly determine whether LRP-1 binds to the actual TPSFSKI sequence. Was carried out. Proteins were extracted from the colorectal cancer tissues of each case according to irradiation and immunoprecipitation was performed using LRP-1 and M13 antibodies and IgG bead. Immune sedimentation was confirmed by western boltting, through which LRP-1 was directly identified as a binding partner protein of TPSFSKI peptide. The results are shown in FIG. 6.

<실시예 7> 실제 환자 대장암 조직에서 LRP-1의 발현 여부 확인Example 7 Confirmation of Expression of LRP-1 in Actual Colorectal Cancer Tissues

The cancer tissue utilized in Example 4 thru | or Example 6 is the cancer tissue extracted from the mouse colon cancer tissue transplantation mouse model. The expression of LRP-1 and differences in case-specific expression were evaluated in the colorectal cancer tissues of the original owner of the cancer tissue. With the approval of the relevant institution, the patient's actual cancer tissue paraffin slice slides were provided by Asan Medical Center's Pathology Department, and histological verification was performed by IHC staining technique. As a result, the results related to Example 4 and FIG. 5 were obtained, and it was verified that LRP-1 could be applied to actual clinical practice. The results are shown in FIG.

<실시예 8> 방사선 저항성 대장암 환자 암조직에서 LRP-1의 발현 여부 검증 <Example 8> Verification of the expression of LRP-1 in cancer tissue of radiation-resistant colorectal cancer patients

In addition to Example 7, the expression of LRP-1 was verified in 20 cases of colorectal cancer tissues of patients with poor radiotherapy prognosis. The verification method was verified by the IHC staining technique in the same manner as in Example 7, and as a result, it was confirmed that LRP-1 overexpressed in cancer tissues of colon cancer patients with poor prognosis. In addition, we analyzed the prognosis according to LRP-1 expression in colorectal cancer patients who received radiotherapy through clinical data analysis. As a result, it was confirmed that the prognosis was very poor when the expression of LRP-1 was high. The results are shown in FIGS. 8 and 9.

As described above, the present invention has been described in detail, and it should be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims

Low density lipoprotein receptor-related protein 1 (LRP-1) or a biomarker composition for diagnosing radiation-resistant cancer comprising a gene encoding the same as an active ingredient.
The biomarker composition of claim 1, wherein the biomarker composition further comprises at least one protein selected from the group consisting of CD133, CD144, and CD24, or a gene encoding the same.
According to claim 1, The LRP-1 is a radiation resistant cancer diagnostic biomarker composition, characterized in that for binding to the peptide consisting of the amino acid sequence of SEQ ID NO: 1.
The biomarker composition for diagnosing radiation-resistant cancer according to any one of claims 1 to 3, wherein the cancer is colorectal cancer.
Radiation-resistant cancer diagnostic composition comprising a formulation capable of measuring the expression level of LRP-1 as an active ingredient.
According to claim 5, The agent capable of measuring the expression level of LRP-1 is a primer or probe specifically binding to the LRP-1 gene, an antibody, peptide, specifically binding to the LRP-1 protein, Radiation-resistant cancer diagnostic composition, characterized in that the aptamer or compound.
According to claim 5, The cancer is radiation-resistant cancer diagnostic composition, characterized in that the colorectal cancer.
A radiation-resistant cancer diagnostic kit comprising the composition of any one of claims 5 to 7.
(1) measuring the mRNA expression level of LRP-1 gene or the expression level of LRP-1 protein from a sample isolated from cancer patients;

(2) comparing the mRNA expression level of the LRP-1 gene or the expression level of the LRP-1 protein with a control sample; And

(3) a method of providing information necessary for diagnosing radiation resistant cancer comprising determining that the LRP-1 gene mRNA expression level or LRP-1 protein expression level is higher than a control sample.
10. The method of claim 9, wherein said cancer is colorectal cancer.
A pharmaceutical composition for enhancing radiosensitivity to cancer cells comprising LRP-1 protein expression or activity inhibitors as an active ingredient.
12. The method of claim 11, wherein the LRP-1 protein expression inhibitor comprises antisense nucleotides, small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) that complementarily bind to the mRNA of the LRP-1 gene. Pharmaceutical composition for enhancing radiation sensitivity to cancer cells, characterized in that any one selected from the group consisting of.
The method of claim 11, wherein the LRP-1 protein activity inhibitor is any one selected from the group consisting of compounds, peptides, peptide mimetics, aptamers, antibodies and natural products that specifically bind to LRP-1 protein A pharmaceutical composition for enhancing radiation sensitivity to cancer cells.
The pharmaceutical composition of claim 11, wherein the cancer cells are colorectal cancer cells.
(1) contacting the test substance with cancer cells;

(2) measuring the level of expression or activity of LRP-1 protein in cancer cells in contact with the test substance; And

(3) A method for screening a radiation sensitivity enhancer for cancer cells, the method comprising selecting a test substance having a decreased expression or activity level of the LRP-1 protein compared to a control sample.
The method of claim 15, wherein the cancer cells are colorectal cancer cells.
Biomarker composition for predicting radiotherapy prognosis of cancer patients comprising LRP-1 or a gene encoding the same as an active ingredient.
A composition for predicting the prognosis of radiation therapy in cancer patients comprising a formulation capable of measuring the expression level of LRP-1 as an active ingredient.
20. A kit for predicting the prognosis of radiation therapy in cancer patients comprising the composition of claim 18.
(1) measuring the mRNA expression level of LRP-1 gene or the expression level of LRP-1 protein from a sample isolated from cancer patients;

(2) comparing the mRNA expression level of the LRP-1 gene or the expression level of the LRP-1 protein with a control sample; And

(3) providing information necessary for predicting the prognosis of the radiation therapy of cancer patients, including determining that the prognosis of radiation therapy is poor when the mRNA expression level of the LRP-1 gene or the expression level of the LRP-1 protein is higher than that of the control sample. Way.