CN117242348A - Biomarkers for predicting sensitivity of rectal cancer to AN0025 combined radiation therapy/chemoradiotherapy (RT/CRT) treatment - Google Patents
Biomarkers for predicting sensitivity of rectal cancer to AN0025 combined radiation therapy/chemoradiotherapy (RT/CRT) treatment Download PDFInfo
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Abstract
The invention provides the use of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) in a blood sample of a patient suffering from rectal cancer and CD8, CD3& CD8, CD3& CD8& PD-1 in a tumor tissue sample as biomarkers for predicting the susceptibility of the patient to AN0025 combined radiation therapy/chemo-radiotherapy (RT/CRT) treatment and steps thereof, as well as methods for predicting the susceptibility of a rectal patient to AN0025 combined radiation therapy/chemo-radiotherapy (RT/CRT) treatment and methods for treating a patient suffering from rectal cancer using the use.
Description
Technical Field
The invention relates to the field of biology, and relates to a series of biomarkers which can be used for predicting the sensitivity of a rectal cancer patient to AN0025 combined radiotherapy/radiotherapy and chemotherapy (RT/CRT) treatment.
Background
Rectal cancer is one of the common malignant tumors of middle-aged and elderly people, and is well developed over 50 years old. With the change of eating habits and structures of people and the aging of population, the incidence rate of the people is on the rising trend. The main treatment modes of the rectal cancer include targeted therapy, gene therapy, traditional Chinese medicine therapy, immunotherapy and the like besides surgery, radiotherapy and chemotherapy. At present, surgical operation is still the first treatment and is the only means for radically treating rectal cancer. However, some patients cannot be treated by surgery, and some patients cannot be treated by repeated surgery, and for such patients, radiotherapy or radiotherapy and chemotherapy are main treatment methods, so as to improve survival rate and quality of life of the patients.
AN0025 is a highly selective, highly active antagonist of prostaglandin E2 (PGE 2) receptor 4 (EP 4) developed by Arnozaku medicine, which inhibits PGE2-EP4 mediated signaling pathways. Myeloid cells are the leading immune cells for tumor infiltration, and mainly include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which differentiate from immature monocytes. EP4 is 1 of 4 PGE2 receptors, expressed on myeloid cells, and plays a key role in promoting monocyte differentiation into TAM and MDSC in tumor microenvironment.
In cancer, the signal pathway composed of prostaglandin E2 (PGE 2) and its subtype 4 receptor (EP 4) can not only promote the occurrence of cancer, but also form a cancer microenvironment that promotes cancer progression and immunosuppression. cAMP generated by activation of PGE2/EP4 signaling pathway in T cells can activate cAMP-PKA signaling pathway, which can effectively inhibit the function of T cells. The PGE2/EP4 signaling pathway also negatively regulates DC maturation, inducing the formation of various immunosuppressive cells including M2 macrophages and myeloid suppressors (MDSCs)S et al.Front Immunol.2019；10:475)。
The compound of formula (I) (AN 0025) and pharmaceutically acceptable salts thereof are highly selective small molecule inhibitors of the E-type prostaglandin receptor 4. In preclinical studies, AN0025 was able to effectively reduce immunosuppressive cells in the tumor microenvironment by inhibiting PGE2/EP4 signaling pathways. AN0025 has been applied to a number of clinical strategies. In phase FIH (first in human) I clinical trials against a variety of advanced solid tumors, AN0025 has shown some single drug efficacy; in addition, AN0025 and radiotherapy and chemotherapy combined in the novel adjuvant therapy of rectal cancer show strong clinical efficacy (Wyrwicz et al, poster #540, ESMO2019).
Clinically, patients with rectal cancer have larger difference in sensitivity to AN0025 combined radiotherapy/radiotherapy and chemotherapy (RT/CRT) treatment. There is therefore a need to find one or several biomarkers in plasma and tissue samples that can predict the sensitivity of a patient to treatment.
Disclosure of Invention
Based on the above, the present invention provides a series of biomarker applications, aiming at solving the problem of predicting the sensitivity of a rectal cancer patient to AN0025 combined radiotherapy/radiotherapy and chemotherapy (RT/CRT) treatment, so as to screen a rectal cancer patient group more suitable for using the treatment scheme, and further improving the pertinence of the therapy.
In order to achieve the above object, the present invention adopts the following technical scheme. All data and samples of the present invention were from a test run in the united states under the accession number clinical three.gov ID: clinical trial of NCT03152370, and all published information about this clinical trial is incorporated by reference into the present invention.
In one aspect, the invention provides the use of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) in a blood sample of a patient with rectal cancer as a biomarker for predicting the patient's susceptibility to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment.
In one aspect, the invention provides the use of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) as a biomarker in a blood sample of a patient suffering from rectal cancer in the preparation of a product for predicting the susceptibility of the patient to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) therapy.
In one aspect, the present invention provides the above application comprising the steps of:
step 1: carrying out centrifugal treatment on a peripheral blood sample to be tested of a rectal cancer patient to collect plasma;
step 2: detecting the concentration of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) in said plasma;
step 3: if the plasma detection concentration is higher than the reference value, the rectal cancer patient is considered to be sensitive to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment; otherwise, it is insensitive.
In another aspect, the invention provides the use of CD8, CD3& CD8& PD-1 in a tumor tissue sample of a patient with rectal cancer as a biomarker for predicting the patient's susceptibility to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment.
In another aspect, the invention provides the use of CD8, CD3& CD8& PD-1 as a biomarker in a tumor tissue sample of a patient with rectal cancer for the manufacture of a product for predicting the susceptibility of the patient to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment.
In another aspect, the present invention provides the above application comprising the steps of:
step 1: treating tumor tissue samples of patients with rectal cancer according to an ELISE method;
step 2, detecting the expression quantity of CD3, CD8 and PD-1 in the tissue sample;
step 3: if the detected CD8, CD3& CD8, CD3& CD8& PD-1 expression levels are above the reference value, then the patient with rectal cancer is considered to be susceptible to AN0025 combination radiation/chemo-radiotherapy (RT/CRT) treatment; otherwise, it is insensitive.
In yet another aspect, the invention provides a method of predicting susceptibility of a colorectal patient to AN0025 combined radiation therapy/chemoradiotherapy (RT/CRT) treatment comprising selecting one or more of the patient's blood biomarkers IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) described above, and/or as one or more of the patient's tumor tissue biomarkers CD8, CD3& CD8& PD-1.
In yet another aspect, the present invention also provides a method of treating a patient suffering from rectal cancer comprising the steps of:
step 1: the method of claim 7, wherein colorectal patient sensitivity to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment is predicted;
step 2: if the rectal cancer patient is predicted to be sensitive to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment, a therapeutically effective amount of AN0025 combined radiation/chemo-radiotherapy (RT/CRT) is administered to the rectal cancer patient.
In another aspect, the invention provides a method of treating a patient having colorectal cancer in need thereof, comprising: administering to the rectal cancer patient a therapeutically effective amount of AN0025 combined radiation/chemo-radiotherapy (RT/CRT), wherein the patient is predicted to be susceptible to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment by the foregoing method.
In yet another aspect, the present invention provides a method of treating a patient having colorectal cancer in need thereof, comprising: administering to the patient with rectal cancer a therapeutically effective amount of AN0025 in combination with radiation therapy/chemotherapy (RT/CRT), wherein the detected concentration of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) in the patient's blood sample is above its reference value and/or the expression level of CD8, CD3& CD8& PD-1 in the patient's tumor tissue sample is above its reference value. Where "reference value" refers to a particular value to which a test value is compared to determine whether a patient is responsive or sensitive to AN0025 associated radiation therapy/chemoradiotherapy (RT/CRT) therapy, such as may be obtained by clinical statistical analysis.
In yet another aspect, the invention also provides a kit for predicting susceptibility of a patient with rectal cancer to AN0025 combined radiation therapy/chemo-radiotherapy (RT/CRT) treatment, said kit comprising one or more of the patient's blood biomarkers as described above, and/or one or more of the patient's tumor tissue biomarkers as described above.
Drawings
FIG. 1 shows the content of each biomarker in a blood sample of a patient with complete pathology relief (pCR)/complete clinical relief (cCR) without complete relief (non-CR), Y-axis unit pg/mL.
FIG. 2 shows the proportion of positive cells of each biomarker to total cells in tumor tissue samples of patients with complete pathology remission (pCR)/complete clinical remission (cCR) without complete remission (non-CR), with the Y-axis representing the percentage.
Detailed Description
Definition of terms：
Unless otherwise indicated herein, the terms used herein have the conventional meaning in the art to which they pertain.
In the present invention, a "biomarker" is equivalent to a biomarker or molecular marker, and is any gene or protein whose expression level in a tissue or cell is altered compared to the expression level of a normal or healthy cell or tissue, (used alone or in combination with other qualitative terms such as breast cancer markers, breast cancer specific markers, control markers, exogenous markers, endogenous markers) refers to parameters that are measurable, computable or otherwise obtainable, related to any molecule or combination of molecules, and that can be used as an indicator of a biological and/or chemical state. In the present invention, a "marker" refers to a parameter associated with one or more biomolecules (i.e., a "biomarker") such as naturally or synthetically produced nucleic acids (i.e., individual genes, as well as coding and non-coding DNA and RNA) and proteins (e.g., peptides, polypeptides). "marker" in the present invention also includes reference to a single parameter that may be calculated or otherwise obtained by considering expression data from two or more different markers.
Those skilled in the art will recognize that the utility of the present invention is not limited to quantifying the gene expression of any particular variant of the marker genes of the present invention.
The IL-1alpha/IL-4/IL-18/IL-27a/EGF/HGF/VEGF-D/SCF/IFN-gamma/MCP-1 (CCL 2)/CCL 11 (Eotaxin) of the invention is a blood sample biomarker, encompassing the IL-1alpha/IL-4/IL-18/IL-27a/EGF/HGF/VEGF-D/SCF/IFN-gamma/MCP-1 (CCL 2)/CCL 11 (Eotaxin) protein sequences as well as amino acid sequences of variants and/or homologs thereof, as well as fragments of such sequences having at least 80%, at least 85%, at least 90% or at least 95% homology, provided that the variant protein (including isoforms), homolog protein and/or fragment is subject to one or more IL-1/IL-4/IL-18/IL-27 a/EGF/HGF/VEGF-D/gamma/MCP-1 (CCL 2)/IFN-gamma/CCL 11 (CCL xi) specific antibodies recognizing the protein (CCL 11).
The CD3/CD8/PD-1 of the invention are tissue sample biomarkers that encompass the CD3/CD8/PD-1 protein sequences as recorded in databases such as uniprot, and also encompass amino acid sequences that are variants and/or homologs thereof, as well as proteins that have at least 80%, at least 85%, at least 90%, or at least 95% homology to fragments of such sequences, provided that variant proteins (including isoforms), homolog proteins, and/or fragments are recognized by one or more CD3/CD8/PD-1 specific antibodies.
To determine whether an amino acid or nucleic acid sequence has some degree of identity to an amino acid or nucleic acid sequence as described herein, the skilled artisan can use means and methods well known in the art, such as alignment, either manually or by using computer programs known in the art or described herein. According to the present invention, the term "identical" or "percent identity" in the context of two or more amino acid or nucleic acid sequences refers to two or more sequences or subsequences that are the same, or a specified percentage of amino acid residues or nucleotides are the same, as determined using sequence comparison algorithms known in the art or by manual alignment and visual inspection, when compared and aligned for maximum correspondence over a comparison window or over a specified region, as sequences having, for example, 60% to 95% or more sequence identity. Such definitions also apply to the complement of the test sequence. Preferably, the identity described exists over a region of at least about 15 to 25 amino acids or nucleotides in length, more preferably over a region of about 50 to 100 amino acids or nucleotides in length.
"rectal cancer" in the present invention refers to a malignant tumor of the digestive tract that occurs in the colon or rectum. Colorectal cancer occurs when cells in the inner wall of the colon abnormally manifest or grow as polyps. If polyps are untreated they can become cancerous. Including but not limited to various pathological types of adenocarcinoma, squamous carcinoma, etc.
The term "radiation therapy", also called "radiotherapy", according to the present invention, refers to the medical use of ionizing radiation, in particular for the treatment of cancer. Preferably, the medical use of ionizing radiation in the treatment of cancer results in the reduction and/or killing of cancer cells in a subject. Radiation therapy may be administered by any means known to those skilled in the art. Examples of radiation utilized in radiation therapy include, but are not limited to, photon radiation, ionizing radiation, or charged particle radiation, such as X-rays or protons. Examples of radiation therapies include (but are not limited to): external radiotherapy or teletherapy; brachytherapy or sealed beam source therapy; and systemic radioisotope therapy or non-encapsulated source radiation therapy.
The term "chemotherapy" as used herein, also known as "chemotherapy", refers to the treatment of a subject with a chemotherapeutic agent, wherein the chemotherapeutic agent includes chemotherapeutic agents commonly used so far for cancer patients, such as may be taxane, paclitaxel, docetaxel, cabazitaxel, gemcitabine, carboplatin, cisplatin, oxaliplatin, fluorouracil, capecitabine, or tegafur (tegafur), or any functional analog thereof. Preferably, the chemotherapeutic agent of the invention is selected from capecitabine or folinic acid/5-fluoropyrimidine/oxaliplatin (mFOLFOX-6).
The term "radiotherapy" as used herein refers to the simultaneous or different time points of administration of radiation therapy and chemotherapy to a patient to treat cancer.
"treating," "treating" and "treatment" refer to reducing, inhibiting and/or reversing the progression of a disease (e.g., tumor/cancer) in a subject in need thereof. The term "treatment" includes any sign of successful treatment or amelioration of a disease, including any objective or subjective parameter, such as alleviation; moderating; reduced symptoms or greater tolerance to injury, pathology or condition in the subject; delay or slow down the rate of development, etc. Measurement of treatment or improvement may be based on, for example, the results of physical, pathological, and/or diagnostic examinations as known in the art. Treatment may also refer to reducing the risk of onset or onset of disease, or reducing disease recurrence (e.g., extending the time to recurrence) than would occur without such measures. In the medical field, such treatment is also referred to as "prophylaxis".
The term "subject" refers to mammalian subjects, and particularly human subjects, including male or female subjects, and includes neonatal, infant, toddler, adolescent, adult or geriatric subjects, and further includes various ethnicities and races, such as caucasian, african and asian.
The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic or organic acid salts of the compounds of formula I of the present invention. These salts may be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free form with a suitable organic or inorganic acid, respectively, and isolating the salt so formed. Representative acid salts include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclosulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, maritime benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalate (napthylate), 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, gluconate, stearate, succinate, tanninate, tartrate, tosylate, trifluoroacetate and cinnabar. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride/chloride salt.
The terms "pharmaceutically acceptable" and "pharmaceutically acceptable" are used interchangeably herein to refer to the types generally accepted by those skilled in the pharmaceutical arts. Such as pharmaceutically acceptable salts, pharmaceutically acceptable carriers, and the like.
The term "effective amount" or "therapeutically effective amount" refers to an amount effective to treat a disease as recorded by clinical testing and evaluation, patient observation, and the like. An "effective amount" may further mean an amount that causes a detectable change in biological or chemical activity. The detectable change may be detected and/or further quantified by one of ordinary skill in the relevant mechanisms or methods. Furthermore, an "effective amount" may refer to an amount that maintains a desired physiological state (i.e., reduces or prevents significant decline and/or promotes improvement of the condition). An "effective amount" may further refer to a therapeutically effective amount.
WO2012039972 specifically sets forth the compounds of formula I of the present invention, which compounds or pharmaceutically acceptable salts thereof and processes for their preparation are disclosed in the examples of WO2012/039972, which is incorporated herein by reference in its entirety.
In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1: blood tumor markers
Materials and methods
Materials: blood samples were obtained from a multicenter clinical trial performed in the united states under the test accession number clinical trimals. Gov ID: NCT03152370.
Sample collection:
whole blood samples, blood for mRNA analysis and PD plasma samples were collected as follows: baseline, week 3 (day 15, before initiation of radiation therapy), week 3 (day 19, end of radiation therapy), week 5 (day 29, beginning of chemotherapy/mid-AN 0025 treatment), week 7 (mid-43 chemotherapy), week 10 (day 70, end of AN0025 treatment) and weeks 14-16 (pre-operative).
The experimental method comprises the following steps:
the ELISA method is adopted:
first antigen coating
1. An antigen solution of appropriate concentration is prepared using carbonate-bicarbonate buffer or PBS.
2. 0.2ml of the above solution was added to each well of the microtiter plate.
Incubate for 30 min at 3.37℃or overnight (complete coverage is required) at 4 ℃.
4. The coating was removed and washed three times with PBS-T.
Second primary anti-reaction
1. Monoclonal primary antibodies were diluted with PBS-T. The optimal concentration should be determined using titration.
2. 0.2ml of diluted monoclonal antibody was added to each well. The negative control should be a species diluted in PBS-T and isotype matched nonspecific immunoglobulin.
3. Incubate at room temperature for 2 hours.
4. The washing step is the same as the antigen coating step 4.
Final secondary antibody binding
1. The enzyme-bound secondary antibody was diluted with PBS-T. 0.2ml of the solution was added to each well. The optimal concentration should be determined using titration.
2. Incubate at room temperature for 2 hours.
3. The washing step is the same as the antigen coating step 4.
Calculation/evaluation method:
the patient group with optimal curative effect and the patient group with poor curative effect are compared by adopting statistical analysis, and whether the expression of the specific biomarker is different or not is judged. A total of 45 different kinds of biomarkers were detected, including: BDNF, EGF, CCL11 (Eotaxin), FGF-2, GM-CSF, GRO alpha (CXCL 1), HGF, IFN alpha, IFN gamma, IL-1alpha, IL-1beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8 (CXCL 8), IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A (CTLA-8), IL-18, IL-21, IL-22, IL-23, IL-27A, IL-31, IP-10 (CXCL 10), LIF, MCP-1 (CCL 2), MIP-1alpha (CCL 3), MIP-1beta (CCL 4), NGF beta, PDGF-BB, plGF-1, TES (CCL 5), SCF, SDF-1alpha,TNF alpha,TNF beta,VEGF-A, VEGF-D.
Experimental results
Finally, in blood samples, we found that the following 11 biomarkers differ (to a statistically significant level of 0.10) between the best efficacy patient group (complete pathologic relief or complete clinical relief) and the poorly efficacy patient group (not seen complete relief), which can be predictive of patient sensitivity to therapy: IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gama, CCL2, CCL-11.
The test results are shown in figure 1, where the 11 biomarker levels in serum of patients with complete pathological remission (pCR) or complete clinical remission (cCR) were statistically significantly lower than those of the group of patients without complete remission (non-CR). Among these 11 biomarker detection values were significantly lower in both pCR and cCR patients than in patients that did not achieve complete remission (non-CR). It was therefore suggested that these 11 biomarkers could be used to predict whether a patient could obtain pCR/cCR.
Example 2: tissue tumor markers
Materials and methods
Materials: tissue samples were obtained from a multicenter clinical trial performed in the united states under the test accession number clinical trials. Gov ID: NCT03152370.
Sample collection:
the subjects will take samples from tumor biopsies as follows: 1) Pretreatment (screening or baseline). The tumor material available for archiving may be submitted as a pretreatment biopsy provided that the local pathology review defined in the laboratory manual meets minimum requirements. If the archived tumor material is not available or meets minimum requirements, a new tumor biopsy must be performed according to local institutional practices; 2) Pre-radiotherapy (week 2 [ days 10-14 ]); 3) End of treatment (optional week 10 +/-2); 4) During surgery (weeks 14-16).
The experimental method comprises the following steps:
the ELISA method is adopted:
first antigen coating
1. An antigen solution of appropriate concentration is prepared using carbonate-bicarbonate buffer or PBS.
2. 0.2ml of the above solution was added to each well of the microtiter plate.
Incubate for 30 min at 3.37℃or overnight (complete coverage is required) at 4 ℃.
4. The coating was removed and washed three times with PBS-T.
Second primary anti-reaction
1. Monoclonal primary antibodies were diluted with PBS-T. The optimal concentration should be determined using titration.
2. 0.2ml of diluted monoclonal antibody was added to each well. The negative control should be a species diluted in PBS-T and isotype matched nonspecific immunoglobulin.
3. Incubate at room temperature for 2 hours.
4. The washing step is the same as the antigen coating step 4.
Final secondary antibody binding
1. The enzyme-bound secondary antibody was diluted with PBS-T. 0.2ml of the solution was added to each well. The optimal concentration should be determined using titration.
2. Incubate at room temperature for 2 hours.
3. The washing step is the same as the antigen coating step 4.
Calculation/evaluation method:
the patient group with optimal curative effect and the patient group without curative effect are compared by adopting statistical analysis, and whether the expression of the specific biomarker is different or not is judged. A total of 6 different combinations of different kinds of biomarkers were detected, including: CD163, CD3, CD4, CD8, PD-1, PD-L1.
Experimental results
Finally, in tissue samples, we found that the following 3 biomarker combinations differed (reaching a statistically significant level of 0.10) between the best efficacy patient group (complete pathologic relief or complete clinical relief) and the poorly efficacy patient group (not seen complete relief), which could be predictive of patient sensitivity to therapy: CD8, CD3& CD8& PD-1. Wherein "CD8" indicates positive for CD8 detection, "CD3& CD8" indicates positive for both CD3 and CD8 detection, and "CD3& CD8& PD-1" indicates positive for all of CD3, CD8 and PD-1 detection.
The test results are shown in FIG. 2: the combination of these 3 types of biomarkers in tumor tissue of patients with complete pathological remission (pCR) or complete clinical remission (cCR) was statistically significantly higher than in the group of patients without complete remission (non-CR). Wherein, the patients with positive detection of CD8, the patients with positive detection of CD3 and CD8 combination and the patients with positive detection of CD3, CD8 and PD-1 can obtain better curative effect in treatment. This also suggests that 3 combinations of CD8, CD3& CD8& PD-1 may be used to predict the efficacy of a patient population.
In practical applications, one or more of the blood biomarkers as depicted in fig. 1 and one or more of the tumor tissue biomarkers as depicted in fig. 2 of a patient with rectal cancer may be selected in combination to further increase the accuracy of predicting the sensitivity of the patient with rectal cancer to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment.
Claims (13)
1. Use of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) in a blood sample of a patient suffering from rectal cancer as a biomarker for predicting the sensitivity of the patient to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment.
2. Use of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) as biomarkers in a blood sample of a patient suffering from rectal cancer for the preparation of a product for predicting the susceptibility of the patient to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment.
3. The use according to claim 1 or 2, comprising the steps of:
step 1: carrying out centrifugal treatment on a peripheral blood sample to be tested of a rectal cancer patient to collect plasma;
step 2: detecting the concentration of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) in said plasma;
step 3: if the plasma detection concentration is higher than the reference value, the rectal cancer patient is considered to be sensitive to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment; otherwise, it is insensitive.
4. Use of CD8, CD3& CD8& PD-1 in a tumor tissue sample of a patient with rectal cancer as a biomarker for predicting the sensitivity of the patient to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment.
5. Use of CD8, CD3& CD8& PD-1 as biomarker in a tumor tissue sample of a patient with rectal cancer for the manufacture of a product for predicting the susceptibility of the patient to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment.
6. Use according to claim 4 or 5, comprising the steps of:
step 1: treating tumor tissue samples of patients with rectal cancer according to an ELISE method;
step 2, detecting the expression quantity of CD3, CD8 and PD-1 in the tissue sample;
step 3: if the detected CD8, CD3& CD8, CD3& CD8& PD-1 expression levels are above the reference value, then the patient with rectal cancer is considered to be susceptible to AN0025 combination radiation/chemo-radiotherapy (RT/CRT) treatment; otherwise, it is insensitive.
7. A method of predicting the susceptibility of a colorectal patient to AN0025 combined radiation therapy/chemoradiotherapy (RT/CRT) treatment comprising selecting one or more of the patient's blood biomarkers according to any of claims 1-3 and/or one or more of the patient's tumor tissue biomarkers according to any of claims 4-6.
8. A method of treating a patient with rectal cancer comprising the steps of:
step 1: the method of claim 7, wherein colorectal patient sensitivity to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment is predicted;
step 2: if the rectal cancer patient is predicted to be sensitive to AN0025 combined radiation/chemo-radiotherapy (RT/CRT) treatment, a therapeutically effective amount of AN0025 combined radiation/chemo-radiotherapy (RT/CRT) is administered to the rectal cancer patient.
9. A method of treating a patient having rectal cancer in need thereof, comprising: administering to the rectal cancer patient a therapeutically effective amount of AN0025 combined radiation/chemo-radiation (RT/CRT), wherein the patient is predicted to be susceptible to AN0025 combined radiation/chemo-radiation (RT/CRT) treatment by the method of claim 7.
10. A method of treating a patient having rectal cancer in need thereof, comprising: administering to the patient with rectal cancer a therapeutically effective amount of AN0025 in combination with radiation therapy/chemotherapy (RT/CRT), wherein the detected concentration of IL-1alpha, IL-4, IL-18, IL-27a, EGF, HGF, VEGF-D, SCF, IFN-gamma, MCP-1 (CCL 2) or CCL11 (Eotaxin) in the patient's blood sample is above its reference value and/or the expression level of CD8, CD3& CD8& PD-1 in the patient's tumor tissue sample is above its reference value.
11. A kit for predicting sensitivity of a patient with rectal cancer to AN0025 combined with radiotherapy/radiotherapy (RT/CRT) treatment, said kit comprising one or more of the patient's blood biomarkers according to any one of claims 1-3, and/or one or more of the patient's tumor tissue biomarkers according to any one of claims 4-6.
12. The method or use or kit of any one of the preceding claims, wherein AN0025 in combination with radiotherapy/chemoradiotherapy (RT/CRT) is a compound of the structure of formula (I) or a pharmaceutically acceptable salt, AN isotopic isomer, a stereoisomer thereof.
13. The method or use or kit of any of the preceding claims, wherein the radiation therapy in combination with radiation therapy/chemo-radiation (RT/CRT) of AN0025 comprises radiation therapy and chemo-therapy, wherein the chemo-therapy is selected from one or more of capecitabine or folinic acid/5-fluoropyrimidine/oxaliplatin.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2022109360863 | 2022-08-04 | ||
| CN202210936086 | 2022-08-04 | ||
| PCT/CN2023/109888 WO2024027599A1 (en) | 2022-08-04 | 2023-07-28 | Biomarker for predicting sensitivity of rectal cancer to treatment with an0025 in combination with radiotherapy/chemoradiotherapy (rt/crt) |
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| CN117242348A true CN117242348A (en) | 2023-12-15 |
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| CN202380010282.0A Pending CN117242348A (en) | 2022-08-04 | 2023-07-28 | Biomarkers for predicting sensitivity of rectal cancer to AN0025 combined radiation therapy/chemoradiotherapy (RT/CRT) treatment |
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- 2023-07-28 CN CN202380010282.0A patent/CN117242348A/en active Pending
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