Methods of diagnosis and treatment of pancreatic cancer

Abstract

This disclosure describes how to treat and / or improve pancreatic cancer using a novel proteomic profile of the pancreatic cancer. In some embodiments, the treatment includes removing cancerous tissue after taking a biopsy from the patient. Optionally, the treatment includes administering anticancer agents to suppress the progression of pancreatic cancer. In further or alternative embodiments, the novel proteomic profile is used to monitor disease progression or remission.

Description

Technical Field

[0001] The present disclosure generally relates to the field of diagnosis and treatment of pancreatic cancer.

Background Art

[0002] (Background) Pancreatic cancer has a poor prognosis. This is often due to the difficulty of early detection. Usually, patients do not show symptoms until the cancer becomes incurable and / or metastasizes throughout the body. Furthermore, the tumor is located deep within the body, making it difficult to visualize.

[0003] For the purpose of early diagnosis of the disease, genetic testing is performed on patients with a family history of the disease. In such tests, changes in genes that cause hereditary diseases are examined. However, these tests have limitations in their ability to predict the risk of pancreatic cancer. For those found to be at risk of developing pancreatic cancer by genetic testing, endoscopic ultrasound or magnetic resonance imaging (MRI) is used to evaluate the possibility of pancreatic cancer. Through genetic analysis, doctors have been able to detect early treatable pancreatic cancer in the general population who are prone to developing pancreatic cancer, but such tests are not used for general population screening. (See American Cancer Society: www.cancer.org / cancer / pancreatic-cancer / detection-diagnosis-staging / detection.html).

[0004] Furthermore, there are few drugs that can treat pancreatic cancer. In the past few years, many targeted drugs such as ECFR inhibitors (erlotinib), VEGF and VEGFR inhibitors, phosphoinositide-3-kinase-mTOR pathway inhibitors, Janus kinase inhibitors, and Ras pathway inhibitors have been tested. Unfortunately, most of these drugs have had no effect on the treatment of the disease (Zhu et al., 2018, “Pancreatic cancer: challenges and opportunities”, BMC Medicine 16(214)).

[0005] Therefore, pancreatic cancer is not only difficult to detect early, but it is also one of the most difficult cancers to treat in humans.

[0006] Therefore, improved methods are needed for the diagnosis of pancreatic cancer, and / or for determining predispositions to developing the target pancreatic cancer, as well as for its treatment. There is also a need for screening and treatment of patients with early-stage pancreatic cancer (stage 1 or 2).

[0007] (overview) This disclosure provides a method for diagnosing and treating pancreatic cancer, or a method for treating pancreatic cancer.

[0008] This disclosure describes how to diagnose, treat, and / or improve pancreatic cancer using a novel proteomic profile of the pancreatic cancer. In some embodiments, treatment includes surgery to remove the tumor or, optionally, administration of anticancer agents to suppress the progression of pancreatic cancer, for example. In further or alternative embodiments, the novel proteomic profile is used to monitor disease progression and / or remission.

[0009] The proteome profile of pancreatic cancer includes at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-associated proteins selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter proteins, apolipoprotein M, gelzolin, adipocyte membrane-associated proteins, C1s complement factor, C4b complement factor or C6 complement factor, and fibronectin. In one embodiment, a subject is diagnosed with pancreatic cancer by determining whether one, two, three, four, five, six, or seven or more proteins are elevated compared to what is considered normal levels (e.g., baseline) in a subject(s) without pancreatic cancer, for example, whether they are elevated by at least 1.2 times, 1.4 times, 1.6 times, 1.8 times, or 2.0 times or more.

[0010] Surprisingly, compared to individuals negative for pancreatic cancer, subjects with early-stage pancreatic cancer (stage 1) were found to have elevated proteome profiles containing multiple of the aforementioned proteins or their peptide fragments. In some embodiments, the levels of pancreatic cancer-related proteins in the circulating blood of subjects with pancreatic cancer were elevated compared to individuals without pancreatic cancer. In further embodiments, the levels of pancreatic cancer-related proteins in the circulating blood of subjects were monitored as described herein, and if changes over time were detected, the subjects were identified for further evaluation. In certain embodiments, the concentrations of pancreatic cancer-related proteins were altered in the blood (e.g., serum, plasma), body fluids (e.g., cerebrospinal fluid, pleural fluid, amniotic fluid, semen, or saliva), urine, and / or feces of subjects with pancreatic cancer. While not intended to be theoretical, we believe that novel combinations of pancreatic cancer-related proteins are involved in the development of pancreatic cancer. Treatment methods may further include the step(s) of obtaining a biopsy to positively confirm the presence of pancreatic cancer, followed by surgery and / or administration of a pancreatic cancer drug. Typically, treatment involves a combination of biopsy and surgery after a positive diagnosis.

[0011] According to one aspect of the present disclosure, a method for treating pancreatic cancer in a subject, the method comprising (i) obtaining a proteome profile from the subject, the proteome profile being obtained in advance by: (a) providing a biological sample obtained from the subject; (b) measuring the concentration level of one or a combination of at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; (c) measuring the concentration level of the pancreatic cancer-related protein or peptide fragment from the obtained sample at an earlier time point than the pancreatic cancer-negative reference value and / or obtained from the subject. A method is provided comprising: (ii) comparing the concentration level of a reference pancreatic cancer-related protein or its peptide fragment from a sample obtained; (ii) identifying a subject at risk of having pancreatic cancer if the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample differs from the pancreatic cancer-negative reference value and / or from a sample obtained from the subject at an earlier time; (iii) optionally taking a biopsy from a subject identified as at risk of having pancreatic cancer in step (ii); (iv) analyzing the biopsy to determine whether cancer cells are present; (v) identifying the subject as having pancreatic cancer if the subject was identified as at risk of having pancreatic cancer based on the proteome profile in step (ii) and cancer cells are present during the biopsy; and (vi) optionally removing cancerous tissue from the subject's pancreas and / or bile duct(or bile duct(s)) if the subject is identified as having pancreatic cancer.

[0012] A further aspect of the present disclosure relates to a method for diagnosing and treating pancreatic cancer in a subject, the method comprising: (a) providing a biological sample obtained from the subject; (b) measuring the concentration level of one or more of at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; and (c) pancreatic cancer-related proteins or peptide fragments from the obtained sample. A method is provided which includes: (d) comparing the concentration level of a fragment with the concentration level of a reference pancreatic cancer-related protein or peptide fragment from a pancreatic cancer-negative reference value and / or from a sample obtained earlier from the subject; (e) identifying the subject as having pancreatic cancer or being at risk of having pancreatic cancer if the concentration level of the pancreatic cancer-related protein or peptide fragment from the obtained sample differs from the concentration level of a reference pancreatic cancer-negative reference value and / or from a sample obtained earlier from the subject; and (f) optionally treating or having subjects identified as having pancreatic cancer treated with a pancreatic cancer treatment plan which optionally includes surgery and / or administration of chemotherapeutic agents or radiotherapy.

[0013] A further aspect of the present disclosure relates to a method for diagnosing and treating pancreatic cancer in a subject, the method comprising: (a) providing a biological sample obtained from the subject; (b) measuring or having a spectroscopic unit measure the concentration levels of a combination of pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1; apolipoprotein A-II; plasma protease C1 inhibitor; L-selectin; tetranectin; phospholipid transporter; apolipoprotein M; gelzolin; adipocyte membrane-related proteins; C1s complement factor; C4b complement factor; C6 complement factor; and fibronectin; and (c) measuring the concentration levels of pancreatic cancer-related proteins or peptide fragments measured by the spectroscopic unit in a pancreatic cancer-negative subject. A method is provided which includes: (d) comparing or having a comparison made between the concentration level of a reference pancreatic cancer-related protein or its peptide fragment from a sample obtained earlier from the subject and / or from a sample obtained earlier from the subject; (e) identifying the subject as having pancreatic cancer or being at risk of having pancreatic cancer if the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample differs from the concentration level of a reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative sample and / or from a sample obtained earlier from the subject; and (f) optionally treating or having the subject identified as having pancreatic cancer treated with a pancreatic cancer treatment plan which optionally includes surgery and / or administration of chemotherapeutic agents or radiotherapy.

[0014] In one embodiment, the treatment of pancreatic cancer comprises reducing the blood levels of one or more pancreatic cancer-related proteins or peptide fragments in a subject diagnosed with pancreatic cancer.

[0015] According to any one of the aforementioned embodiments or models, the adjustment of the blood levels of one or more pancreatic cancer-related proteins or their peptide fragments in the subject is carried out until the levels of pancreatic cancer-related proteins or their peptide fragments in the subject are reduced to a predetermined level.

[0016] According to any one of the embodiments described above, the identifying step is performed when it is determined that the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or their peptide fragments from the obtained sample are elevated by about 10% or more, 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more compared to the concentration level of the reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative reference value and / or compared to the concentration level in a sample previously obtained from the subject.

[0017] According to any one of the aforementioned embodiments or models, measuring the concentration levels of pancreatic cancer-related proteins or peptide fragments involves measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

[0018] According to any one of the aforementioned embodiments or models, at least the concentration level of tetranectin is measured.

[0019] According to any one of the aforementioned aspects or embodiments, the sample obtained is blood or urine.

[0020] According to any one of the aforementioned embodiments or models, the obtained sample is serum or plasma.

[0021] According to any one of the aforementioned aspects or embodiments, the sample obtained is urine.

[0022] According to any one of the aforementioned embodiments or models, pancreatic cancer-related proteins or their peptide fragments are measured by a spectroscopic technique, which is selected from the group consisting of liquid chromatography, gas chromatography, liquid chromatography-mass spectroscopy, gas chromatography-mass spectroscopy, high-performance liquid chromatography-mass spectroscopy, capillary electrophoresis-mass spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, Raman spectroscopy, and infrared spectroscopy.

[0023] According to any one of the aforementioned aspects or embodiments, the spectroscopic technique includes mass spectrometry.

[0024] According to any one of the aforementioned aspects or embodiments, the comparison of the concentration level of pancreatic cancer-related proteins or their peptide fragments from the obtained sample with the concentration level of a reference value includes the use of multivariate statistical analysis.

[0025] According to any one of the aforementioned aspects or embodiments, the multivariate statistical analysis is selected from principal component analysis (PCA) or partial least squares latent structure discriminant analysis (PLS-DA).

[0026] A method for monitoring proteins or peptide fragments in a subject and treating pancreatic cancer in the subject, comprising: (a) providing a first biological sample obtained from the subject at a first time point; (b) evaluating a first pancreatic cancer-related proteome profile by measuring the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; and (c) relating the first pancreatic cancer-related proteome profile to a reference pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample. (d) comparing the first pancreatic cancer-related proteome profile with a reference pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample, and determining that the first difference indicates pancreatic cancer; (e) providing a second biological sample obtained from the subject at a second time point after the first time point; (f) evaluating the second pancreatic cancer-related proteome profile by measuring the concentration levels of pancreatic cancer-related proteins or their peptide fragments from the second biological sample; (g) comparing the second pancreatic cancer-related proteome profile with a reference pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample; (h) determining that the first pancreatic cancer-related proteome profile with a reference pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample, and determining that the second difference indicates pancreatic cancer; and (i) determining that there is a risk of progression of pancreatic cancer or having pancreatic cancer based on at least some of the first and second differences.(j) When a subject is identified as having pancreatic cancer, optionally treating the subject according to a pancreatic cancer treatment plan that optionally includes surgery and / or administration of an anti-cancer therapeutic agent or radiation therapy, or causing such treatment to be performed. A method is provided that includes this.;

[0027] According to the foregoing aspect, the period between the first time point and the second time point is at least 1 month, at least 2 months, at least 3 months, or at least 6 months.

[0028] According to the foregoing aspect or an embodiment thereof, measuring the concentration level of a pancreatic cancer-related protein or a peptide fragment thereof from the first and / or second biological sample includes measuring at least one, at least two, at least three, or each of L-selectin, tenectin, lipid transport protein, and fibronectin.

[0029] According to the foregoing aspect or an embodiment thereof, at least the concentration level of tenectin is measured.

[0030] According to the foregoing aspect or an embodiment thereof, the first sample, the second sample, or both are blood or urine, or both samples are of the same specimen type and are selected from serum, plasma, or urine.

[0031] A diagnostic kit for pancreatic cancer comprising: (a) a detector configured to detect the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1; apolipoprotein A-II; plasma protease C1 inhibitor; L-selectin; tetranectin; phospholipid transport protein; apolipoprotein M; gelzolin; adipocyte membrane-related protein; C1s complement factor; C4b complement factor; C6 complement factor; and fibronectin; and (b) apolipoprotein A1; apolipoprotein A-II; plasma protease C1 inhibitor; L-selectin; tetranectin at control levels corresponding to a control group of pancreatic cancer-negative subjects. (a) a composition comprising phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; (c) a multivariate analysis system configured to analyze the difference between the concentration level of a pancreatic cancer-related protein or its peptide fragment and a control level; and (d) optionally providing instructions for a method for diagnosing pancreatic cancer, the method comprising measuring the level of a pancreatic cancer-related protein or its peptide fragment from a obtained biological sample using a detector, and comparing the obtained level of the pancreatic cancer-related protein or its peptide fragment to a control level of a pancreatic cancer-related protein or its peptide fragment obtained from a pancreatic cancer-negative subject and / or from a sample obtained from the subject at an earlier time point.

[0032] According to one embodiment of the foregoing aspects of the present disclosure, the detector includes a multiproteome detector configured to measure levels of pancreatic cancer-related proteins or peptide fragments thereof, including apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport proteins, apolipoprotein M, gelzolin, adipocyte membrane-related proteins, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin.

[0033] In the aforementioned embodiments or in some embodiments of those embodiments, the detector is configured to measure the concentration level of pancreatic cancer-related proteins or peptide fragments, including at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

[0034] In the aforementioned embodiments or some embodiments of those embodiments, the detector is configured to measure at least tetranectin.

[0035] A further aspect of the present disclosure relates to a computer-implemented method for processing a biological sample of a subject, diagnosing pancreatic cancer, and treating pancreatic cancer, the computer-implemented method comprising: (a) receiving a biological sample obtained from a subject; (b) processing the sample in a spectroscopic unit directly or wirelessly connected to a processing device, the processing device having memory for storing measurement data from the spectroscopic unit; (c) measuring the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin, and storing the measurement data in a processor; and (d) optionally using multivariate statistical analysis of the stored measurement data to determine pancreatic cancer-negative samples. (e) comparing the results with a reference value in memory; (f) storing the results from the obtained sample in a processing device corresponding to at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from the group consisting of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin, wherein if the measured data representing the level of pancreatic cancer-related proteins or peptide fragments differs from the concentration level of reference pancreatic cancer-related proteins or peptide fragments from a pancreatic cancer-negative sample, the results identify the subject as having pancreatic cancer or being at risk of having pancreatic cancer; (f) displaying the results on an electronic display directly or wirelessly connected to the processor for subjects identified as having pancreatic cancer, being at risk of having pancreatic cancer, or being predisposed to developing pancreatic cancer;(g) A computer implementation method is provided which includes, optionally, treating or having a subject identified as having pancreatic cancer treated with a pancreatic cancer plan that optionally includes surgery and / or administration of anticancer agents or radiation therapy.

[0036] In the aforementioned embodiments or some embodiments of those embodiments, the displayed results are contained within a user interface, which is a dashboard.

[0037] In the aforementioned embodiments or some embodiments of those embodiments, the displayed results are part of the multi-omics information displayed on the user interface.

[0038] In the embodiments described above or in some embodiments of those embodiments, the spectroscopic unit includes, or is operably connected to, a detector configured to measure the concentration levels of pancreatic cancer-related proteins or peptide fragments, and is optionally configured to measure at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

[0039] In the aforementioned embodiments or some embodiments of those embodiments, the detector is configured to measure at least tetranectin.

[0040] A further aspect of the present disclosure relates to a method for diagnosing and treating pancreatic cancer in a subject, the method comprising: (a) providing a biological sample obtained from the subject; (b) measuring the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin; and (c) measuring the concentration levels of pancreatic cancer-related proteins from the obtained sample. A method is provided which includes: (d) comparing the concentration level of the protein or its peptide fragment with the concentration level of a reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative sample and / or a sample obtained at an earlier time from the subject; (f) identifying the subject as having pancreatic cancer or being at risk of having pancreatic cancer if the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample differs from the concentration level of a reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative sample and / or a sample obtained at an earlier time from the subject; and (e) optionally treating or having the identified subject treated with a pancreatic cancer treatment plan or radiotherapy.

[0041] In the aforementioned embodiments or in some embodiments of those embodiments, measuring the concentration levels of pancreatic cancer-related proteins or their peptide fragments from a first and / or second biological sample includes measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

[0042] In the aforementioned embodiments or some embodiments of those embodiments, at least the concentration level of tetranectin is measured.

[0043] A further aspect of the present disclosure relates to a method for diagnosing and treating pancreatic cancer in a subject, the method comprising: (a) providing a first biological sample obtained from the subject; and (b) at a first time point, selecting from the obtained sample at least one selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin. (a) measuring the concentration levels of at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments; (c) comparing the concentration levels of pancreatic cancer-related proteins or peptide fragments from the obtained sample to the concentration levels of reference pancreatic cancer-related proteins or peptide fragments from a pancreatic cancer-negative sample and / or a sample obtained from the subject at an earlier time; (d) at a second time point, apolipoprotein A1; apolipoprotein A-II, (a) Measuring the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter, apolipoprotein M, gelzolin, adipocyte membrane-related proteins, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin; (e) Comparing the concentration levels of pancreatic cancer-related proteins or peptide fragments from the obtained samples at a second time point to the concentration levels of reference pancreatic cancer-related proteins or peptide fragments from pancreatic cancer-negative samples and / or samples obtained at a first time point or earlier from the subject; (f) Identifying the subject as having pancreatic cancer or being at risk of having pancreatic cancer if the concentration levels of pancreatic cancer-related proteins or peptide fragments from the first and second obtained samples differ from the concentration levels of reference pancreatic cancer-related proteins or their peptide fragments from pancreatic cancer-negative samples and / or from the sample obtained at the first time point;(g) A method is provided which includes, optionally, treating or having a subject identified as having pancreatic cancer treated using a pancreatic cancer treatment plan.

[0044] In the embodiments described above or in some embodiments of those embodiments, the identifying step (f) is performed when it is determined that the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or their peptide fragments from the obtained sample are elevated by about 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% compared to the concentration levels of reference pancreatic cancer-related proteins or their peptide fragments from a pancreatic cancer-negative sample.

[0045] In the aforementioned embodiments or in some embodiments of those embodiments, the identifying step (f) is performed when it is determined that the concentration levels of at least three, at least four, or at least five pancreatic cancer-related proteins or their peptide fragments from the obtained sample are elevated by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% or more compared to the concentration levels of reference pancreatic cancer-related proteins or their peptide fragments from a pancreatic cancer-negative sample.

[0046] In the aforementioned embodiments or in some embodiments of those embodiments, measuring the concentration levels of pancreatic cancer-related proteins or their peptide fragments from a first and / or second biological sample includes measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

[0047] In the aforementioned embodiments or some embodiments of those embodiments, at least the concentration level of tetranectin is measured.

[0048] In the aforementioned embodiments or some embodiments of those embodiments, the obtained sample is blood or urine, or serum, plasma or urine.

[0049] In the aforementioned embodiments or some embodiments of those embodiments, pancreatic cancer-related proteins or their peptide fragments are measured by spectroscopic techniques, which are selected from the group consisting of liquid chromatography, gas chromatography, liquid chromatography-mass spectroscopy, gas chromatography-mass spectroscopy, high-performance liquid chromatography-mass spectroscopy, capillary electrophoresis-mass spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, Raman spectroscopy, and infrared spectroscopy.

[0050] In the aforementioned embodiments or in some embodiments of those embodiments, the comparison of the concentration levels of pancreatic cancer-related proteins or their peptide fragments from the obtained samples with the concentration levels of reference pancreatic cancer-related proteins or their peptide fragments from pancreatic cancer-negative samples includes multivariate statistical analysis.

[0051] In the aforementioned embodiments or in some embodiments of those embodiments, measuring the concentration levels of pancreatic cancer-related proteins or their peptide fragments from a second biological sample includes measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, and phospholipid transporter proteins, and if the measured levels of L-selectin, tetranectin, and / or phospholipid transporter proteins in the second biological sample are elevated by at least 10%, 15%, 20%, or 25% compared to the respective concentration levels measured at a first time point, the subject is identified as having pancreatic cancer or being at risk of having pancreatic cancer.

[0052] In the aforementioned embodiments or in some embodiments of those embodiments, at least the concentration level of fibronectin is measured, and if the measured level of fibronectin in the second biological sample is increased or decreased by at least 10%, 15%, 20%, or 25% compared to the respective concentration levels measured at the first time point, the subject is identified as having pancreatic cancer or being at risk of having pancreatic cancer.

[0053] In a further embodiment, a proteolytic sample for use in mass spectrometry to diagnose a target pancreatic cancer is provided, comprising one or a combination of peptide fragments of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin.

[0054] In a further embodiment, a proteolytic sample is provided containing peptide fragments of L-selectin, tetranectin, phospholipid transport proteins, and / or fibronectin for use in mass spectrometry for diagnosing a target pancreatic cancer.

[0055] In some embodiments of any one of the aforementioned embodiments, the method further includes obtaining a biopsy sample from a subject identified as being at risk of having pancreatic cancer after measurement of pancreatic cancer proteins or fragments thereof, and, if cancer cells are identified in the sample, surgically removing the cancerous tissue from the subject's pancreas and / or bile ducts.

[0056] In some embodiments of any one of the aforementioned embodiments or its manifestations, the subject is identified as having pancreatic cancer (e.g., stage 1) if the level of tetranectin is increased over time or elevated above the control at a single point in time, as measured at two or more time points within a period of one month to three years. Such embodiments may further include measuring the concentration of at least one of L-selectin and phospholipid transport proteins, and the level of at least one of L-selectin and phospholipid transport proteins is increased over time or elevated above the control at a single point in time, as measured at two or more time points within a period of one month to three years. In some embodiments, the method or kit further includes measuring fibronectin. In some embodiments, the method further includes measuring at least one of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, or a combination thereof.

[0057] All features of the exemplary embodiments described herein can be combined with each other if they are not mutually exclusive. Elements of one embodiment can be used in other embodiments without further description. Other aspects and features of this disclosure will be obvious to those skilled in the art by referring to the following description of specific embodiments together with the accompanying drawings. [Modes for carrying out the invention]

[0058] (Detailed explanation) A detailed description of one or more embodiments of the present invention is given below. While the present invention is described in relation to such embodiments, it is not limited to the specific embodiments described herein. The scope of the present invention is limited only by the claims and their equivalents. For a complete understanding of the present invention, numerous specific details are provided below. These details are provided for illustrative purposes only, and the present invention can be carried out according to the claims without some or all of these specific details.

[0059] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art relating to the present invention. Except as used herein, and unless otherwise stated or required by context, the following terms shall have the definitions set forth below.

[0060] Articles such as "a" and "an" used within a claim are understood to mean one or more of the things described or described in the claim.

[0061] Regarding samples, the term "pancreatic cancer negative" generally refers to biological samples from individuals who have not had pancreatic cancer or who do not have a predisposition to develop pancreatic cancer.

[0062] The terms “baseline” or “control” generally refer to values ​​corresponding to the concentration of a protein or its peptide fragment in individuals who do not have pancreatic cancer or who are not predisposed to developing pancreatic cancer, or values ​​derived from a population of such individuals and / or published data.

[0063] The term "pancreatic cancer treatment plan" generally refers to interventions tailored to the individual with pancreatic cancer. The objectives of this plan may include, but are not limited to, one or more of the following: symptom relief or prevention, delaying or halting the progression or worsening of pancreatic cancer, and achieving remission of pancreatic cancer.

[0064] In some embodiments, “pancreatic cancer treatment plan” refers to a treatment procedure involving one or more appropriate therapeutic agents, such as chemotherapeutic agents, administered to the patient (e.g., changes in pancreatic cancer-related proteome levels).

[0065] The terms "comprises," "comprising," "include," "includes," "including," "contain," "contains," and "containing" have a non-restrictive meaning, meaning they can add other steps and sections that do not affect the end result. The terms above include the terms "consist of" and "essentially become from."

[0066] The term “pancreatic cancer-related proteome” or “proteome profile” generally refers to a profile of proteins associated with pancreatic cancer, including multiple proteins such as apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter proteins, apolipoprotein M, gelzolin, adipocyte membrane-related proteins, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin, or any combination thereof.

[0067] In relation to comparing protein levels in a sample to a reference, the phrase "reference value derived therefrom" refers to a value obtained from a sample or from multiple subjects that do not have pancreatic cancer. For example, the reference value may be derived from statistical data previously collected from subjects that do not have pancreatic cancer.

[0068] The terms "prevent" and "prevent" are used interchangeably and generally refer to any activity that leads to a reduction in the risk of developing pancreatic cancer in the target group.

[0069] The term "subject" generally refers to vertebrates such as mammals. The term "mammal" is defined as an individual belonging to the class Mammalia. In some embodiments, the subject is a human.

[0070] The term “treating” or “treatment” generally refers to interventions performed in response to pancreatic cancer or its associated symptoms. The goals of treatment may include, but are not limited to, one or more of the following: palliative care or prevention of pancreatic cancer, delaying or halting the progression or worsening of pancreatic cancer, and achieving remission of pancreatic cancer. In certain embodiments, “treatment” refers to surgery and / or administration of therapeutic agents for the treatment of pancreatic cancer. Such treatments may further include radiation therapy.

[0071] The term "pancreatic cancer treatment drug" refers to any therapeutic agent or prodrug used to treat or slow the progression of pancreatic cancer. The drug may be included in a pharmaceutical formulation and may optionally contain excipients.

[0072] In this specification, the term “biopsy” as used in relation to determining whether a subject has pancreatic cancer refers to a composition comprising, but not limited to, cells and / or fluids from one or more of the subject’s duodenum, bile duct, pancreas, and / or pancreatic duct.

[0073] The terms “preferred” or “preferred” refer to a non-restrictive example of the disclosure and should not be interpreted as restrictive.

[0074] In relation to a method or process, the term “computerized implementation” means that all or most of the steps of the method are performed by electronic data processors and / or distributed computing such as cloud computing.

[0075] In all embodiments of this disclosure, all percentages, concentrations, part counts, and ratios are based on the total weight of the composition of this disclosure unless otherwise specified. All such weights for the listed components are based on effective levels and therefore do not include solvents or by-products that may be present in commercial products unless otherwise stated. Modeling data

[0076] In one embodiment, 1 to 50, 2 to 40, or 5 to 30 biomarkers are evaluated based on pancreatic cancer modeling data. Such data is used to assess whether specific biomarkers can predict pancreatic cancer.

[0077] In one embodiment, modeling data is obtained from data of a test group and a control group of pancreatic cancer patients, and the data from each group is subjected to computer-implemented calculations including computer-generated receiver operating characteristic (ROC) curve analysis, principal component analysis (PCA) plots, and latent structure discriminant analysis (PLS-DA) models and / or variable importance (VIP) plots, thereby obtaining a set of at least two, three, four, five, six, seven, eight, nine, or ten identified biomarkers that contribute to the diagnosis, development, or regression of pancreatic cancer compared to other biomarkers measured. In some embodiments, the disclosure is based on identifying a subject at risk of having pancreatic cancer by determining whether a biological sample from a patient has elevated or decreased levels of a novel combination of proteins or fragments that the inventors have identified as predictive of the presence of pancreatic cancer. The identified subject is then subjected to one or more steps, including obtaining a biopsy (e.g., cells and / or fluids from the duodenum, bile duct(s), pancreas, and / or pancreatic duct) and analyzing the biopsy for the presence of cancer cells.

[0078] In some embodiments, biomarkers are pre-selected from a proteome profile obtained from computer modeling. In some non-limiting examples, at least two, three, four, or five proteomic biomarkers are measured. In further embodiments, up to 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, or 20 proteomic biomarkers are identified based on computer modeling. Optionally, this includes the selection of metabolome biomarkers in addition to proteomic biomarkers.

[0079] In some embodiments, biomarkers are selected from computer modeling based on metabolic profiles, further optionally based on assigning weights to biomarkers within a proteome profile, where the weights are based on the marker's ability to diagnose and / or assess pancreatic cancer progression.

[0080] Methods of diagnosis and treatment of pancreatic cancer In one embodiment, the disclosure relates to methods for the (e.g., early) diagnosis and treatment of pancreatic cancer and any related conditions in a subject. In some embodiments, the disclosure provides, at least in part, the identification of proteins or peptide fragments thereof that provide etiological data related to pancreatic cancer, and provides opportunities for objective protein-based or peptide-based diagnosis of pancreatic cancer that may lead to more effective treatment. Given the complexity of the interaction between genetics and environment, proteomic profiling may, optionally combined with other profiling methods (e.g., genomic profiling and / or metabolic profiling) to provide an approach for developing diagnostic tests that can help to better understand pancreatic cancer and aid in personalized treatment decisions. In one embodiment, the method includes proteomic analysis within a multi-omics analysis that includes proteomic analysis and genomic analysis and / or metabolome analysis. Multi-omics-based analysis offers the advantage of not only identifying biomarker profiles derived from an individual's genetic characteristics, but also capturing the interactions of an individual's current lifestyle behaviors (e.g., smoking, alcohol consumption, sleep behavior, physical activity), gut microbiota, diet, and environmental factors that contribute to the unique protein profiles of pancreatic cancer patients. Combining this with early diagnosis and pancreatic cancer treatment planning offers the further advantage of improved treatment outcomes. This specification describes a method that provides the identification of novel proteomic profiles in pancreatic cancer patients, which is useful for the diagnosis and treatment of pancreatic cancer patients. Therefore, this disclosure represents an advance in the art.

[0081] This disclosure identifies a novel proteomic profile of pancreatic cancer in subjects with pancreatic cancer. The proteomic profile of pancreatic cancer includes at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-associated proteins selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter proteins, apolipoprotein M, gelzolin, adipocyte membrane-associated proteins, C1s complement factor, C4b complement factor or C6 complement factor, and fibronectin.

[0082] The protein apolipoprotein A1 is identified herein as a biomarker for pancreatic cancer, and in some embodiments, its level is elevated to approximately 1.2 to 10 times or more compared to the median level of reference apolipoprotein A1 in pancreatic cancer-negative individuals. In some embodiments, an elevation of 1.2 times or more in apolipoprotein A1 levels identifies the subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer. Apolipoprotein A1 is currently considered a tumor suppressor. Apolipoprotein A1 (ApoA1) is a protein involved in lipid metabolism, and its potential role in pancreatic cancer has been studied.

[0083] Alternatively or additionally, the protein apolipoprotein A-II is identified herein as a biomarker for pancreatic cancer, and in some embodiments, its level is elevated to approximately 1.2 to 10 times or more compared to the median reference apolipoprotein A-II level in pancreatic cancer-negative individuals. In some embodiments, an elevation of 1.2 times or more in apolipoprotein A-II levels identifies the subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0084] Alternatively or additionally, the protein plasma protease C1 inhibitor can also be measured as a biomarker for pancreatic cancer. Levels of plasma protease C1 inhibitor may be elevated by approximately 1.2 to 10 times or more compared to the median plasma protease C1 inhibitor level in pancreatic cancer-negative individuals. In some embodiments, an elevation of 1.2 times or more in plasma protease C1 inhibitor levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer. Plasma protease inhibitor 1 (C1 inhibitor) is a protein involved in regulating the complement system, a component of the immune system.

[0085] Alternatively or additionally, the protein L-selectin can also be measured as a biomarker for pancreatic cancer. L-selectin is a cell adhesion molecule expressed on the surface of immune cells and is involved in the migration of these cells to inflammatory sites.

[0086] In some embodiments, L-selectin levels increase by approximately 1.2 to 10 times or more compared to the median reference L-selectin level in individuals that are pancreatic cancer-negative. In some embodiments, an increase of 1.2 times or more in L-selectin levels identifies the subject as having pancreatic cancer, for example, stage 1 or 2 pancreatic cancer.

[0087] Alternatively or additionally, the protein tetranectin can also be measured as a biomarker for pancreatic cancer. Tetranectin, also known as plasminogen-activator inhibitor-tissue factor pathway inhibitor-2, is a protein involved in blood clotting and has also been shown to have antitumor properties. Tetranectin is produced by various types of cells in the body, including endothelial cells, platelets, and monocytes. It is also found in various tissues, including the liver, lungs, and placenta. In some embodiments, tetranectin levels are elevated by approximately 1.2 to 10 times or more compared to the median reference tetranectin level in pancreatic cancer-negative individuals. In some embodiments, an elevation of 1.2 times or more in tetranectin levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0088] Alternatively or additionally, proteins, specifically phospholipid transport proteins, can also be measured as biomarkers for pancreatic cancer. In some embodiments, the level of phospholipid transport proteins increases by approximately 1.2 to 10 times or more compared to the median level of reference phospholipid transport proteins in individuals that are negative for pancreatic cancer. In some embodiments, an increase of 1.2 times or more in the level of phospholipid transport proteins identifies the subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0089] Alternatively or additionally, the protein apolipoprotein M can be measured as a biomarker for pancreatic cancer, and in some embodiments, levels are elevated to approximately 1.2 to 10 times or more compared to the median level of reference apolipoprotein M in pancreatic cancer-negative individuals. In some embodiments, an elevation of 1.2 times or more in apolipoprotein M levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0090] Alternatively or additionally, C1s complement factor can be measured as a biomarker for pancreatic cancer, and in some embodiments, it is elevated to levels of approximately 1.2 to 10 times or more compared to the median reference C1s complement factor in individuals that are pancreatic cancer-negative. In some embodiments, an elevation of 1.2 times or more in C1s complement factor levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0091] Alternatively or additionally, C4b complement factor can be measured as a biomarker for pancreatic cancer, and in some embodiments, it is elevated to levels of approximately 1.2 to 10 times or more compared to the median C4b complement factor in individuals that are pancreatic cancer-negative. In some embodiments, an elevation of 1.2 times or more in C4b complement factor levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0092] Alternatively or additionally, C6 complement factor can be measured as a biomarker for pancreatic cancer, and in some embodiments, it is elevated to levels of approximately 1.2 to 10 times or more compared to the median reference C6 complement factor in individuals that are pancreatic cancer-negative. In some embodiments, an elevation of 1.2 times or more in C6 complement factor levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0093] Alternatively or additionally, the protein gelzolin can also be measured as a biomarker for pancreatic cancer. Gerzolin has an established role in cell motility and, in some embodiments, is elevated to levels of approximately 1.2 to 10 times or more compared to the median reference gelzolin level in pancreatic cancer-negative individuals. In some embodiments, an elevation of 1.2 times or more in gelzolin levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0094] Alternatively or additionally, the protein adipocyte membrane-related protein can also be measured as a biomarker for pancreatic cancer. Adipocyte membrane-related protein, also known as adipophyllin, is a protein expressed in lipid droplets, which are organelles that store lipids such as fat. Because adipophyllin is expressed in adipose (fat) tissue, weight loss may lower its levels in the blood. Regular physical activity is known to reduce adipose tissue and lower adipophyllin levels in the blood. Consuming a diet low in fat and high in fiber, fruits, and vegetables may help lower adipophyllin levels in the blood. Certain drugs, such as statins used to lower cholesterol levels, have been shown to lower adipophyllin levels in the blood, and in some embodiments, levels rise to approximately 1.2 to 10 times or more compared to the median level of reference adipocyte membrane-related protein in pancreatic cancer-negative individuals. In some embodiments, a rise of 1.2 times or more in adipocyte membrane-related protein levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0095] Alternatively or additionally, the protein fibronectin can be measured as a biomarker for pancreatic cancer, and in some embodiments, levels are elevated to approximately 1.2 to 10 times or more compared to the median reference fibronectin level in pancreatic cancer-negative individuals. In some embodiments, an elevation of 1.2 times or more in fibronectin levels identifies a subject as having pancreatic cancer, e.g., stage 1 or 2 pancreatic cancer.

[0096] In one embodiment, the disclosure provides a method for diagnosing and treating pancreatic cancer in a subject. The method comprises step (a) providing a biological sample obtained from a subject such as a human. According to the method disclosed herein, any type of biological sample taken from anywhere in the subject's body can be examined, including but not limited to blood (including, but not limited to, serum or plasma), cerebrospinal fluid ("CSF"), pleural fluid, urine, feces, sweat, tears, exhaled condensate, saliva, vitreous fluid, tissue samples, amniotic fluid, chorionic villi samples, brain tissue, etc., and biopsies of any solid tissue such as tumors, adjacent normal tissue, smooth muscle and skeletal muscle, adipose tissue, liver, skin, hair, brain, kidney, pancreas, lungs, etc. In one embodiment, the biological sample is obtained from blood. Pancreatic cancer-related proteins can be extracted from the biological source using any number of extraction / purification procedures commonly used in quantitative analytical chemistry.

[0097] The method further comprises step (b) measuring the concentration levels of at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-related proteins or peptide fragments selected from the group consisting of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin. In certain embodiments, the method comprises measuring at least eight, nine, ten, eleven, twelve, thirteen, or fifteen pancreatic cancer-related proteins or fragments from the obtained sample.

[0098] In certain embodiments, the method may further include measuring the concentration levels of one or more additional pancreatic cancer-related proteins or peptide fragments, including but not limited to any of the proteins known in the art, in addition to the aforementioned proteins. Such markers include carbohydrate antigen 19-9 (CA 19-9) (see Goonetilleke and Siriwardena, 2007, Eur J Surg Oncol. 33(3): 266-70, which is incorporated herein by reference), CA 242, hCG beta, CA 72-4, and carcinoembryonic antigen (CEA) (see Louhimo et al., 2004, Oncology, 66(2): 125-31, which is incorporated herein by reference).

[0099] The methods described herein further include step (c) comparing the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample with the concentration level of the reference pancreatic cancer-related protein or its peptide fragment from a reference sample(may be pancreatic cancer-negative) or a reference value obtained therefrom. Those skilled in the art will understand that for comparison, a reference can be established as a value representing the level of the pancreatic cancer-related protein or its peptide fragment in a population without pancreatic cancer. Various criteria may be used to determine whether to include and / or exclude specific subjects in the reference population, including the age of the subjects (e.g., the reference subjects may be in the same age group as the subjects requiring treatment) and the sex of the subjects (e.g., the reference subjects may be in the same sex as the subjects requiring treatment). In certain embodiments, the reference is from a pancreatic cancer-negative sample or the mean of a group of samples. In another embodiment, the concentration level of the reference pancreatic cancer-related protein or its peptide fragment is obtained from a patient population.

[0100] The methods described herein further include step (d) identifying a subject has pancreatic cancer if the concentration level of a pancreatic cancer-related protein or its peptide fragment from a obtained sample differs from the concentration level of a reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative sample(s) or a reference value obtained therefrom. In certain embodiments, step (d) is performed when it is determined that the concentration level of at least one pancreatic cancer-related protein or its peptide fragment from a obtained sample differs from the concentration level of at least one reference pancreatic cancer-related protein from a pancreatic cancer-negative sample(s) or a reference value obtained therefrom by about 10% or more, 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more. In certain embodiments, the identifying step (d) is performed when it is determined that the concentration levels of at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-related proteins or peptide fragments from the obtained sample differ by about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% or more compared to the concentration levels of reference pancreatic cancer-related proteins or fragments from a pancreatic cancer-negative sample or a reference value obtained therefrom.

[0101] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least apolipoprotein A1 from the obtained sample is lower than the concentration level of reference apolipoprotein A1 from or derived from a pancreatic cancer-negative sample(s). In some embodiments, the concentration level of apolipoprotein A1 from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference apolipoprotein A1 obtained or induced from or derived from a pancreatic cancer-negative sample(s). In some embodiments, the concentration level of apolipoprotein A1 from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference apolipoprotein A1 from or derived from a pancreatic cancer-negative sample(s).

[0102] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least apolipoprotein A-II from the obtained sample is lower than the concentration level of reference apolipoprotein A-II from a pancreatic cancer-negative sample(s) or a reference value obtained therefrom. In some embodiments, the concentration level of apolipoprotein A-II from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference apolipoprotein A-II from a pancreatic cancer-negative sample(s) or a reference value obtained therefrom. In some embodiments, the concentration level of apolipoprotein A-II from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference apolipoprotein A-II from a pancreatic cancer-negative sample(s) or a reference value obtained therefrom.

[0103] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least plasma protease C1 inhibitor from the obtained sample is lower than the concentration level of reference plasma protease C1 inhibitor from a pancreatic cancer-negative sample(s) or a reference value obtained therefrom. In some embodiments, the concentration level of plasma protease C1 inhibitor from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more higher than the concentration level of reference plasma protease C1 inhibitor from a pancreatic cancer-negative sample(s) or a reference value obtained therefrom. In some embodiments, the concentration level of plasma protease C1 inhibitor 1 from the obtained sample is approximately 20% or more, approximately 30% or more, approximately 40% or more, approximately 50% or more, approximately 60% or more, or approximately 70% or more lower than the concentration level of reference plasma protease C1 inhibitor from pancreatic cancer-negative sample(s) or a reference value obtained therefrom.

[0104] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least L-selectin from the obtained sample is lower than the concentration level of reference L-selectin from a pancreatic cancer-negative sample. In some embodiments, the concentration level of L-selectin from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference L-selectin from a pancreatic cancer-negative sample. In some embodiments, the concentration level of L-selectin from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference L-selectin from a pancreatic cancer-negative sample.

[0105] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least tetranectin from the obtained sample is lower than the concentration level of reference tetranectin from a pancreatic cancer-negative sample. In some embodiments, the concentration level of tetranectin from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference tetranectin from a pancreatic cancer-negative sample. In some embodiments, the concentration level of tetranectin from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference tetranectin from a pancreatic cancer-negative sample.

[0106] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least phospholipid transporter protein from the obtained sample is lower than the concentration level of reference phospholipid transporter protein from a pancreatic cancer-negative sample. In some embodiments, the concentration level of phospholipid transporter protein from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference phospholipid transporter protein from a pancreatic cancer-negative sample. In some embodiments, the concentration level of phospholipid transporter protein from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference phospholipid transporter protein from a pancreatic cancer-negative sample.

[0107] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least apolipoprotein M from the obtained sample is lower than the concentration level of reference apolipoprotein M from a pancreatic cancer-negative sample. In some embodiments, the concentration level of apolipoprotein M from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference apolipoprotein M from a pancreatic cancer-negative sample. In some embodiments, the concentration level of apolipoprotein M from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference apolipoprotein M from a pancreatic cancer-negative sample.

[0108] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least gelzolin from the obtained sample is lower than the concentration level of reference gelzolin from a pancreatic cancer-negative sample. In some embodiments, the concentration level of gelzolin from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference gelzolin from a pancreatic cancer-negative sample. In some embodiments, the concentration level of gelzolin from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference gelzolin from a pancreatic cancer-negative sample.

[0109] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least adipocyte membrane-related protein from the obtained sample is lower than the concentration level of adipocyte membrane-related protein from a reference pancreatic cancer-negative sample. In some embodiments, the concentration level of adipocyte membrane-related protein from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of adipocyte membrane-related protein from a reference pancreatic cancer-negative sample. In some embodiments, the concentration level of adipocyte membrane-related protein from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of adipocyte membrane-related protein from a reference pancreatic cancer-negative sample.

[0110] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least C1s complement factor from the obtained sample is lower than the concentration level of reference C1s complement factor from a pancreatic cancer-negative sample. In some embodiments, the concentration level of C1s complement factor from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference C1s complement factor from a pancreatic cancer-negative sample. In some embodiments, the concentration level of C1s complement factor from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference C1s complement factor from a pancreatic cancer-negative sample.

[0111] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least C4b complement factor from the obtained sample is lower than the concentration level of reference C4b complement factor from a pancreatic cancer-negative sample. In some embodiments, the concentration level of C4b complement factor from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference C4b complement factor from a pancreatic cancer-negative sample. In some embodiments, the concentration level of C4b complement factor from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference C4b complement factor from a pancreatic cancer-negative sample.

[0112] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least C6 complement factor from the obtained sample is lower than the concentration level of reference C6 complement factor from a pancreatic cancer-negative sample. In some embodiments, the concentration level of C6 complement factor from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference C6 complement factor from a pancreatic cancer-negative sample. In some embodiments, the concentration level of C6 complement factor from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference C6 complement factor from a pancreatic cancer-negative sample.

[0113] In certain embodiments, the identifying step (d) is performed when it is determined that the concentration level of at least fibronectin from the obtained sample is lower than the concentration level of reference fibronectin from a pancreatic cancer-negative sample. In some embodiments, the concentration level of fibronectin from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference fibronectin from a pancreatic cancer-negative sample. In some embodiments, the concentration level of fibronectin from the obtained sample is about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more, compared to the concentration level of reference fibronectin from a pancreatic cancer-negative sample.

[0114] The methods described herein further include step (e) treating subjects identified as having pancreatic cancer using a pancreatic cancer treatment plan.

[0115] In any particular embodiment of the method described herein, the comparison of the concentration level of at least one pancreatic cancer-related protein from the obtained sample, or a value obtained therefrom, with the concentration level of a reference pancreatic cancer-related protein from a pancreatic cancer-negative sample, involves using multivariate statistical analysis. In one embodiment, the multivariate statistical analysis is selected from principal component analysis ("PCA") or partial least squares latent structure discriminant analysis ("PLS-DA"). In certain embodiments, a computer is used for the statistical analysis. Data for the statistical analysis can be extracted from the chromatogram (i.e., the spectrum of the mass signal) using software for statistical methods known in the art.

[0116] In some embodiments, the disclosure relates to methods for monitoring the progression of pancreatic cancer in a subject and for treating pancreatic cancer. In one embodiment, the method includes quantifying pancreatic cancer-related proteins or peptide fragments thereof at one or more time points after the initiation of treatment in order to monitor the progression or regression of pancreatic cancer in a subject. Therefore, the method is to (a) provide a first biological sample obtained from the subject at a first time; (b) evaluate the first pancreatic cancer-related proteome profile by measuring the concentration levels of at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; (c) compare the first pancreatic cancer-related proteome profile with a reference pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample; and (d) compare the first pancreatic cancer-related proteome profile with the pancreatic cancer-related proteome profile from a reference pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample. (i) determining that there is a first difference between the pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample and a reference pancreatic cancer-related proteome profile, and that the first difference indicates pancreatic cancer; (e) providing a second biological sample obtained from the subject at a second time after the first time; (f) evaluating the second pancreatic cancer-related proteome profile by measuring the concentration levels of pancreatic cancer-related proteins or peptide fragments from the obtained second sample; (g) comparing the second pancreatic cancer-related proteome profile with the reference pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample; (h) determining that there is a second difference between the first pancreatic cancer-related proteome profile and the reference pancreatic cancer-related proteome profile from a pancreatic cancer-negative sample, and that the second difference indicates pancreatic cancer; (i) determining the progression or regression of pancreatic cancer based at least partially on the first and second differences; and (j) treating the subject according to a pancreatic cancer treatment plan.

[0117] In certain embodiments of the above method, the period between the first time and the second time is at least one month, at least two months, at least three months, at least six months, at least nine months, or at least twelve months, preferably at least three months. In some embodiments, the subject is treated before the first two biological samples are obtained. In other embodiments, the treatment is administered to the subject within the interval(s) between the collection of the biological samples. In certain embodiments, the first biological sample, the second biological sample, or both are blood or urine, preferably serum, plasma, or urine.

[0118] This disclosure also provides a method for diagnosing and treating pancreatic cancer in a subject. The method comprises (a) providing a biological sample obtained from the subject; and (b) at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-related proteins selected from the group consisting of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin. (c) measuring the concentration level of the protein or its protein fragment; (d) comparing the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample with the concentration level of a reference pancreatic cancer-related protein or its fragment from a pancreatic cancer-negative sample; (e) identifying the subject as having pancreatic cancer if the concentration level of the pancreatic cancer-related protein or its fragment from the obtained sample differs from the concentration level of a reference pancreatic cancer-related protein or its fragment from a pancreatic cancer-negative sample; and (f) treating the identified subject with a pancreatic cancer treatment plan.

[0119] This disclosure also provides a method for diagnosing and treating pancreatic cancer in a subject, the method comprising (a) providing a biological sample obtained from the subject; and (b) selecting from the obtained sample at least one and at least two from the group consisting of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin. (c) Measuring the concentration levels of at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-related proteins or fragments; (d) Comparing the concentration levels of pancreatic cancer-related proteins or fragments from the obtained sample to the concentration levels of reference pancreatic cancer-related proteins or fragments from a pancreatic cancer-negative sample or baseline; (e) Apolipoprotein A1; Apolipoprotein A-II; Plasma protease C1 inhibitor; L-selectin; Tetranectin; Phospholipid transport protein; A (a) measuring the concentration levels of at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-related proteins or fragments selected from the group consisting of polypoprotein M, gelzolin, adipocyte membrane-related proteins, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; (b) comparing the concentration levels of pancreatic cancer-related proteins or fragments from the obtained sample to the concentration levels of reference pancreatic cancer-related proteins or fragments from a pancreatic cancer-negative sample or baseline; (c) identifying a subject as having pancreatic cancer if the concentration levels of pancreatic cancer-related proteins or fragments from the obtained sample differ from the concentration levels of reference pancreatic cancer-related proteins or fragments from a pancreatic cancer-negative sample, and the concentration levels of pancreatic cancer-related proteins or fragments from the obtained sample differ from the concentration levels of reference pancreatic cancer-related proteins or fragments from a pancreatic cancer-negative sample or baseline; and (d) treating the identified subject with a pancreatic cancer treatment plan.

[0120] In certain embodiments of the above method, the identifying step (f) is performed when it is determined that the concentration levels of at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-related proteins or fragments from the obtained sample differ by about 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% compared to the concentration levels of reference pancreatic cancer-related proteins or fragments from a pancreatic cancer-negative sample or baseline.

[0121] Method for quantifying pancreatic cancer-related proteins or their peptide fragments In one embodiment, pancreatic cancer-related proteins or peptide fragments thereof are measured by spectroscopic techniques, which are selected from the group consisting of liquid chromatography, gas chromatography, liquid chromatography-mass spectroscopy, gas chromatography-mass spectroscopy, high-performance liquid chromatography-mass spectroscopy, capillary electrophoresis-mass spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, Raman spectroscopy, and infrared spectroscopy.

[0122] In certain embodiments, the measurement of concentration levels of pancreatic cancer-related proteins or their peptide fragments can be performed by methods including, but not limited to, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (e.g., LC-MS, LC-MS-MS, LC-MRM, LC-SIM, and LC-SRM). In certain embodiments, the mass spectrometry is multiple reaction monitoring mass spectrometry, parallel reaction monitoring mass spectrometry, matrix-assisted laser desorption / ionization (MALDI) mass spectrometry, or data-independent acquisition mass spectrometry. In yet another embodiment, the multiple reaction monitoring mass spectrometry is immunomultiple reaction monitoring mass spectrometry, immunoparallel reaction monitoring mass spectrometry, immuno-MALDI, or immunodata-independent acquisition mass spectrometry.

[0123] In one embodiment, a procedure involving mass spectrometry includes introducing a protein sample into a mass spectrometry unit, subsequently fragmenting it within the mass spectrometry unit, recording the mass of the fragments, and providing them for analysis.

[0124] In some embodiments, a mass spectrometry process for determining whether pancreas-related proteins are elevated includes enzymatically or chemically digesting proteins or peptide fragments of a sample obtained from a subject into peptide fragments. The peptide fragments are optionally separated and / or ionized and captured by mass spectrometry. Digestion may include proteolytic digestion, which involves treating a preparation containing pancreatic cancer-related proteins with an acid, a base, or an enzyme such as trypsin or other proteolytic enzymes. One embodiment includes shotgun proteomics quantification, which aims to hydrolyze or cleave whole proteins in complex mixtures such as serum, urine, and cell lysates into peptides, followed by multidimensional HPLC-MS to generate a global profile of the protein mixture as genomic "shotgun" sequencing.

[0125] Accordingly, according to one aspect of the present disclosure, a method is provided for determining whether there is an increase in pancreatic cancer-related proteins or peptide fragments thereof in a sample obtained from a subject, wherein the pancreatic cancer-related proteins or peptide fragments thereof are selected from at least one of pancreatic cancer-related proteins or peptide fragments thereof, including apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin, and the method involves enzymatically or chemically digesting the protein or peptide fragment in the sample obtained from the subject to obtain peptide fragments, and the peptide The process includes generating peptide fragments, optionally subjecting the solution containing the peptide fragments to one or more treatments, including liquid chromatography or other processes, followed by introduction into a mass spectrometer to quantify the peptide fragments, determining the concentration of the peptide fragment(s) by comparing it to a baseline such as reference values(s) (e.g., peptide standard values), evaluating whether the fragments are elevated compared to the baseline or reference values(s), identifying the subject as having pancreatic cancer or a predisposition to developing pancreatic cancer if one or more peptides are elevated compared to the baseline or reference values, and optionally treating or having the subject undergo treatment for pancreatic cancer, including chemotherapy drugs approved for use in the treatment of pancreatic cancer.

[0126] The protein or its peptide fragments are fragmented within the mass spectrometry unit, and the mass of each fragment is recorded and provided for analysis.

[0127] Baseline is the normal level of a protein or peptide obtained from subjects or populations of subjects without pancreatic cancer. The standard may include one or more pancreatic cancer-related proteins or peptide fragments at concentrations corresponding to such normal levels. The standard may be values ​​obtained from samples previously acquired from subjects without pancreatic cancer. The standard may include one or more of the following: apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter proteins, apolipoprotein M, gelzolin, adipocyte membrane-related proteins, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin or fragments thereof.

[0128] In another embodiment, a set of reference values ​​is provided that include one or more pancreatic cancer-related peptide fragments at concentrations corresponding to normal levels. The reference values ​​may include any combination of peptide fragments obtained from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter proteins, apolipoprotein M, gelzolin, adipocyte membrane-related proteins, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin.

[0129] Pancreatic cancer treatment Before treatment for pancreatic cancer, patients typically undergo a biopsy to confirm the presence of the cancer. The biopsy can be a percutaneous biopsy, endoscopic biopsy, or surgical biopsy. In a percutaneous biopsy, a hollow needle is inserted through the skin into the pancreas to collect a sample of the tumor. The procedure can be facilitated by imaging studies such as ultrasound or CT scans. Endoscopic biopsy involves inserting an endoscope through the throat and small intestine to the pancreas. Endoscopic ultrasound is used to guide the needle through the tumor, and a sample is taken from the bile duct or pancreatic duct, or cells are removed from the bile duct or pancreatic duct using a brush. A surgical biopsy may be performed if it is desired to determine if the pancreatic cancer has spread. Surgical biopsies can be performed using laparoscopy (keyhole surgery). Optionally, additional tests are performed to evaluate whether the cancer cells taken from the biopsy have mutations in specific genes. If mutations in genes related to pancreatic cancer are found, targeted therapy may be part of the pancreatic treatment plan. Proteome profile assessment data may be used in conjunction with this information.

[0130] Imaging tests may be performed to facilitate diagnosis. Imaging tests may use X-rays, magnetic fields, sound waves, or radioactive materials to visualize tumors. Examples of imaging tests include computed tomography (CT) scans, magnetic resonance imaging, ultrasound, cholangiopancreatography such as magnetic resonance cholangiopancreatography or percutaneous transhepatic cholangiography, positron emission tomography (PTSC) scans, or angiography.

[0131] A pancreatic treatment plan may include surgery to remove the tumor.

[0132] A pancreatic cancer treatment plan may include, alternatively or additionally, one or more therapeutic agents to treat pancreatic cancer. Examples of such therapeutic agents include Abraxane (paclitaxel albumin-stabilized nanoparticle formulation), Afinitor (everolimus), capecitabine, erlotinib hydrochloride, everolimus, 5-FU (fluorouracil injection), fluorouracil, gemcitabine, MRTX1133 targeting the Kras G12D variant, and / or olaparib. Pancreatic cancer treatment may also include, additionally or alternatively, radiotherapy to reduce tumor size.

[0133] In one embodiment, one or more therapeutic agents are incorporated into a delivery medium such as lipid nanoparticles. The therapeutic agents incorporated into the delivery medium such as lipid nanoparticles may contain one or more RNA sequences of the pancreatic cancer biomarkers described above, or RNA sequences of biomarkers related to the pancreatic biomarkers described above, and can be used to suppress the effects of these diseases or reduce their levels. kit

[0134] The proteome profiles described herein may be used in tests, assays, methods, and kits for the diagnosis, prediction, adjustment, or monitoring of pancreatic cancer, including ongoing evaluation, monitoring, and / or sensitivity assessment. This disclosure includes a kit for diagnosing pancreatic cancer by measuring and identifying at least one pancreatic cancer-related protein or fragment associated with pancreatic cancer. Accordingly, the kit measures the concentration levels of at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic cancer-related proteins or fragments selected from the group consisting of (a) apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin in a pancreatic cancer-negative subject. The method includes (c) a detector configured to detect at a control level corresponding to a control group, a multivariate analysis system configured to analyze the difference between the concentration level of pancreatic cancer-related protein or its peptide fragments and a control level, and (d) optionally, instructions for a pancreatic cancer diagnostic method, wherein the method includes using the detector to measure the level of pancreatic cancer-related protein or its peptide fragments from a obtained biological sample, and comparing the obtained level of pancreatic cancer-related protein or its peptides with a control level of pancreatic cancer-related protein or its peptides obtained from a pancreatic cancer-negative subject. In one embodiment, the pancreatic cancer diagnostic method includes a multi-metabolite detector configured to measure the level of pancreatic cancer-related protein or its peptides. The detector is part of a mass spectrometry unit and can optionally communicate operably with a chromatography unit such as a liquid chromatography unit.

[0135] In some embodiments, the kit may be for measuring pancreatic cancer-related proteins or fragments thereof by physical separation techniques (as described above herein). In some embodiments, the kit may, in non-limiting examples, be for measuring pancreatic cancer-related proteins or peptides by methodologies other than physical separation techniques, such as colorimetric, enzymatic, and immunological methodologies. The kit may also include one or more suitable negative and / or positive controls. The kits of this disclosure may include other reagents, such as buffers and solutions for performing the tests. Computer implementation method

[0136] This disclosure also relates to a computer-implemented method for processing a biological sample, diagnosing pancreatic cancer, and treating said pancreatic cancer. The computer-implemented method further enables monitoring the progression of pancreatic cancer over multiple time points to support more effective treatment planning.

[0137] The computer implementation method includes receiving a biological sample from a subject and processing the sample with a spectroscopic unit connected directly, wirelessly, or using any appropriate communication technology to a processing device, wherein the processing device has memory for storing measurement data from the spectroscopic unit, and measuring the levels of at least one, at least two, at least three, at least four, at least five, at least six, or at least seven pancreatic-related proteins or fragments selected from the group consisting of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related proteins, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin, and storing the measurement data in a processor. The processing device includes one or more data storage devices which may be configured or adapted to store data related to the method. For example, the data storage device may be configured or adapted to store measurement data from the spectroscopic unit. The data storage device may also include computer program code stored therein. The program code of this embodiment may include program code for executing at least the steps of the method at runtime.

[0138] The computer implementation method further involves using multivariate statistical analysis to compare the stored measurement data with values ​​in memory representing pancreatic cancer-negative samples, and selecting at least one, at least two, at least three, or at least four from the group consisting of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transporter protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin. The process involves storing results corresponding to at least five, at least six, or at least seven pancreatic cancer-related proteins or fragments in a processing device, wherein if measurement data representing the level of pancreatic cancer-related proteins or fragments differs from the concentration value of a reference pancreatic cancer-related protein or fragment from a pancreatic cancer-negative sample, the results identify the subject as having pancreatic cancer, and for subjects identified as having pancreatic cancer or being predisposed to developing pancreatic cancer, the results of a pancreatic cancer treatment plan are displayed on an electronic display directly or wirelessly connected to the processor.

[0139] The displayed results or treatment plan may include electronic text, optionally accompanied by graphical icons. Optionally, the graphical icons may be part of an electronic dashboard to display the results in a simplified format and / or provide treatment recommendations based on the results.

[0140] As mentioned above, computer implementation methods also make it possible to monitor pancreatic cancer-related proteins across multiple time points to support more effective treatment planning. A non-limiting example of such a process is shown in Figure 1. The method involves obtaining a biological sample (e.g., a serum sample) at time point 1 (T1). The sample is subjected to proteolysis 10A to produce hydrolyzed proteins, which are then subjected to mass spectrometry 20A to measure pancreatic cancer-related proteins 30A. The concentrations are compared to a pancreatic cancer-negative sample 40A to determine whether the concentration of protein(s) is increased or decreased compared to a standard 50A. In this non-limiting example, the pancreatic cancer-related proteins are at least one of L-selectin, tetranectin, phospholipid transporter proteins, and / or fibronectin. In this example of the disclosure, at least one of L-selectin, tetranectin, and / or phospholipid transporter proteins is elevated compared to baseline (e.g., a pancreatic-negative sample). In this case, the subject is determined to have or be at risk of developing pancreatic cancer (yes). If the concentrations of L-selectin, tetranectin, phospholipid transporter proteins, and / or fibronectin differ significantly from the normal range, the subject is considered to have a low risk of pancreatic cancer.60 (No). The greater the elevation between the measured pancreatic cancer-related proteins and those in pancreatitis-negative samples, the "worse off" the likelihood of having or developing pancreatic cancer. To maximize any benefit from slowing or offsetting pancreatic cancer progression, it is desirable to obtain this information earlier in the individual's life (e.g., under 40, under 35, under 30, or under 25).

[0141] In other embodiments, a small increase between the measured pancreatic cancer-associated protein and the pancreatic cancer-associated protein from a pancreatic-negative sample reflects a low probability that the individual has or has developed pancreatic cancer up to that point in time, but there is no guarantee that the increase will remain small at later points in time. Therefore, it is recommended that these individuals be regularly and continuously monitored for their risk of having or developing pancreatic cancer. For example, if a subject is determined to have or be at risk of developing pancreatic cancer (yes), a second biological sample (e.g., a serum sample) is taken at time point 2 (T2) after T1. In some embodiments, the risk of an individual having or developing pancreatic cancer is measured over the individual's lifetime (or at least for a long period, e.g., at least 2 months, at least 4 months, at least 6 months, at least 1 year, at least 2 years, at least 5 years, at least 10 years, at least 20 years, or at least 30 years). The sample is subjected to proteolysis 10B to produce hydrolyzed proteins, which are then subjected to mass spectrometry 20B to measure pancreatic cancer-associated proteins 30B. The concentration is compared to T2 40B, and it is determined whether the protein(s) are increased or decreased compared to the T2 concentration level 50B. If at least one of the pancreatic cancer-related proteins selected from L-selectin, tetranectin, phospholipid transporter proteins, and / or fibronectin is elevated by a threshold (e.g., at least 10%, at least 20%, at least 30%) compared to T1, the subject is identified as having pancreatic cancer or at high risk of developing the disease.70 (Yes). Typically, after a biopsy is taken and the presence of cancer cells is analyzed (e.g., using microscopy), the subject is identified as having pancreatic cancer. If the concentrations of L-selectin, tetranectin, phospholipid transporter proteins, and / or fibronectin differ significantly from T1, the subject is judged to be at low risk of pancreatic cancer.60 (No). If necessary, pancreatic cancer-related proteins may be measured at a third time point after T2, time point 3 (T3).By comparing the concentration of pancreatic cancer-associated proteins in T3 to the levels in T2 and / or T1, it is possible to identify whether a subject is at high or low risk of having pancreatic cancer or developing the disease. As a result, the method described herein makes it possible to monitor changes in the state of pancreatic cancer or changes in the risk of developing (or recurring) pancreatic cancer over time, particularly after any treatment plan. Treatment plans typically include surgery, but may also include, additionally or alternatively, the administration of chemotherapy and / or radiation therapy.

[0142] The following embodiments describe several exemplary ways of carrying out the specific methods described herein. It should be understood that the embodiments are for illustrative purposes only and do not limit the scope of the systems and methods described herein. [Examples]

[0143] Example 1: Diagnosis and treatment of stage 1 pancreatic cancer patients determined by monitoring changes in pancreas-related protein concentrations over time. As part of a multi-omics health assessment provided by the applicant, patients' proteome profiles were monitored over a three-year period from 2019 to 2022. Each protein, as shown in Table 1 below, was found to show significant changes in blood concentrations (nM) measured over the three years. Surprisingly, certain proteins (L-selectin, tetranectin, and phospholipid transporter proteins) also showed significant increases in concentration at time 2 (T2) compared to time 1 (T1). Fibronectin, on the other hand, decreased by 323.98% from time 3 (T3) to time 2 (T2). [Table 1-1] [Table 1-2]

[0144] L-selectin, tetranectin, and phospholipid transport proteins were elevated at T2 (time point 2) and identified as early indicators of pancreatic cancer. The concentrations of each of these proteins also increased at T3 (time point 3). Furthermore, fibronectin levels were low at time points T1 (242.0 nM) and T3 (295.7 nM), but high at T2 (1254.2 nM). A change of -323.98% in fibronectin was observed between T2 and T3.

[0145] This result is surprising because previous studies have shown that tetranectin levels decrease in pancreatic cancer (Caputo et al., 2022, Cancers (Basel), 14(19):4658; and Felix et al., 2013, PloS ONE, 8e82755). However, the inventors discovered that this protein increased during the measurement period.

[0146] The patient was examined by a physician and diagnosed with stage 1 pancreatic cancer. A biopsy was taken from the patient and examined under a microscope to confirm the diagnosis. The patient underwent surgery to remove the tumor. To the best of the inventors' knowledge, this is the first early diagnosis and treatment of pancreatic cancer using the novel proteomic profile identified herein.

[0147] Measuring changes in the blood concentration of one or a combination of specific proteins associated with pancreatic cancer over time provides a tool for the early detection of pancreatic cancer that was unavailable with known diagnostic approaches. Monitoring protein combinations identified as elevated in patients represents a significant advance in this field for diagnosing and treating pancreatic cancer.

[0148] Examples of other embodiments will become apparent upon consideration of the teachings herein.

[0149] Please note that titles or subtitles may be used throughout this specification for the convenience of the reader, but these do not limit the scope of this disclosure. Furthermore, certain theories may be proposed and disclosed in this specification, but such theories do not limit the scope of the invention.

[0150] Elements of the methods and / or systems of this disclosure described in relation to the examples are also applicable to other aspects of this disclosure. Therefore, it is understood that the methods and / or systems of this disclosure encompass any methods and / or systems that include any of the steps and / or components referenced herein in any embodiment in which each such step or component exists independently as defined herein. Many other methods and / or systems may be included besides those specifically described herein.

[0151] The dimensions and values ​​disclosed herein should not be understood as being strictly limited to the exact numerical values ​​stated. Instead, unless otherwise specified, each dimension shall mean both the stated value and a functionally equivalent range around that value. For example, a dimension disclosed as "40mm" shall mean "approximately 40mm."

[0152] All documents referenced herein, including any cross-references or related patents or applications and any patent applications or patents to which this application claims priority or interest, are incorporated herein by reference in their entirety unless expressly excluded or limited. No document reference constitutes prior art with respect to any disclosure disclosed or claimed herein, nor does it teach, suggest or disclose any such disclosure, either alone or in any combination with any other reference(s). Furthermore, in the event of any conflict between the meaning or definition of a term in this document and the meaning or definition of the same term in any document incorporated by reference, the meaning or definition assigned to that term in this document shall prevail.

[0153] While specific embodiments of this disclosure are illustrated and described, it will be apparent to those skilled in the art that various other changes and modifications are possible without departing from the scope of this disclosure. Accordingly, all such changes and modifications within the scope of this disclosure are intended to be covered by the appended claims. [Brief explanation of the drawing]

[0154] [Figure 1] This shows a non-exclusive example of the process.

Claims

1. A method for treating pancreatic cancer in a subject, wherein the method is (i) Receiving a proteome profile from the subject, wherein the proteome profile is obtained in advance by: (a) To provide biological samples obtained from the subject; (b) From the obtained sample, measure the concentration levels of one or a combination of at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or their peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; (c) Comparing the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample with the concentration level of the reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative reference value and / or from a sample obtained earlier from the subject; (ii) If the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample differs from the pancreatic cancer-negative reference value and / or the reference pancreatic cancer-related protein or its peptide fragment from a sample obtained from the subject at an earlier time, the subject is identified as being at risk of having pancreatic cancer; (iii) Optionally, biopsy a sample is taken from the subject identified in step (ii) as being at risk of having pancreatic cancer; (iv) to analyze the biopsy to determine whether cancer cells are present; (v) If the subject is identified as being at risk of having pancreatic cancer based on the proteome profile of step (ii) and cancer cells are present during the biopsy, then the subject is identified as having pancreatic cancer; (vi) A method comprising, if the subject is identified as having pancreatic cancer, optionally removing cancerous tissue from the pancreas and / or bile duct(s) of the subject.

2. A method for diagnosing and treating pancreatic cancer in a subject, wherein the method is: (a) To provide biological samples obtained from the subject; (b) From the obtained sample, measure the concentration level of one or more of at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; (c) Comparing the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample with the concentration level of the reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative reference value and / or from a sample obtained from the subject at an earlier time; (d) If the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample differs from the pancreatic cancer-negative reference value and / or the reference pancreatic cancer-related protein or its peptide fragment from a sample obtained from the subject at an earlier time, the subject is identified as having pancreatic cancer or being at risk of having pancreatic cancer; (e) A method comprising, optionally, treating or having a subject identified as having pancreatic cancer treated with a pancreatic cancer treatment plan which optionally includes surgery and / or administration of chemotherapeutic agents or radiotherapy.

3. A method for diagnosing and treating pancreatic cancer in a subject, wherein the method is: (a) To provide biological samples obtained from the subject; (b) From the obtained sample, measure or have measured the concentration levels of pancreatic cancer-related proteins or combinations of peptide fragments selected from apolipoprotein A1; apolipoprotein A-II; plasma protease C1 inhibitor; L-selectin; tetranectin; phospholipid transport protein; apolipoprotein M; gelzolin; adipocyte membrane-related protein; C1s complement factor; C4b complement factor; C6 complement factor; and fibronectin using a spectroscopic unit: (c) Comparing or allowing a comparison of the concentration level of the pancreatic cancer-related protein or its peptide fragment measured by the spectroscopic unit with the concentration level of a reference pancreatic cancer-negative reference value and / or a reference pancreatic cancer-related protein or its peptide fragment from a sample obtained at an earlier time from the subject; (d) If the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample differs from the concentration level of the reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative sample and / or a sample obtained from the subject at an earlier time, the subject is identified as having pancreatic cancer or being at risk of having pancreatic cancer; (e) A method comprising, optionally, treating or having a subject identified as having pancreatic cancer treated with a pancreatic cancer treatment plan which optionally includes surgery and / or administration of chemotherapeutic agents or radiotherapy.

4. The method according to claim 1, 2, or 3, wherein the treatment of pancreatic cancer comprises reducing the blood levels of one or more pancreatic cancer-related proteins or peptide fragments in the subject diagnosed with pancreatic cancer.

5. The method according to claim 4, wherein the adjustment of the blood levels of one or more pancreatic cancer-related proteins or peptide fragments in the subject is carried out until the levels of pancreatic cancer-related proteins or peptide fragments in the subject are reduced to a predetermined level.

6. The method according to any one of claims 1 to 5, wherein the identifying step is performed when it is determined that the concentration levels of at least one, at least two, at least three, at least four, or at least five of the pancreatic cancer-related proteins or their peptide fragments from the obtained sample are increased by about 10% or more, 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, or about 70% or more compared to the concentration level of the reference pancreatic cancer-related proteins or their peptide fragments from the pancreatic cancer-negative reference value and / or compared to the concentration level in a sample previously obtained from the subject.

7. The method according to any one of claims 1 to 6, wherein measuring the concentration level of the pancreatic cancer-related protein or peptide fragment comprises measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

8. The method according to any one of claims 1 to 7, wherein at least the concentration level of tetranectin is measured.

9. The method according to any one of claims 1 to 8, wherein the obtained sample is blood or urine.

10. The method according to any one of claims 1 to 8, wherein the obtained sample is serum or plasma.

11. The method according to claim 9, wherein the obtained sample is urine.

12. The method according to any one of claims 1 to 8, wherein the pancreatic cancer-related protein or its peptide fragment is measured by a spectroscopic technique, the spectroscopic technique being selected from the group consisting of liquid chromatography, gas chromatography, liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, high-performance liquid chromatography-mass spectrometry, capillary electrophoresis-mass spectrometry, nuclear magnetic resonance spectroscopy (NMR), Raman spectroscopy, and infrared spectroscopy.

13. The method according to claim 12, wherein the spectroscopic technique includes mass spectrometry.

14. The method according to any one of claims 1 to 8, wherein the comparison of the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample with the concentration level of the reference value is performed using multivariate statistical analysis.

15. The method according to claim 14, wherein the multivariate statistical analysis is selected from principal component analysis (PCA) or partial least squares latent structure discriminant analysis (PLS-DA).

16. A method for monitoring proteins or peptide fragments in a subject and treating pancreatic cancer in that subject, (a) to provide a first biological sample obtained from the subject at a first time point; (b) Evaluating a first pancreatic cancer-related proteome profile by measuring the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin; (c) Comparing the first pancreatic cancer-associated proteome profile with a reference pancreatic cancer-associated proteome profile from a pancreatic cancer-negative sample; (d) Determining that there is a first difference between the first pancreatic cancer-associated proteome profile and the reference pancreatic cancer-associated proteome profile from the pancreatic cancer-negative sample, and that the first difference indicates pancreatic cancer; (e) to provide a second biological sample obtained from the subject at a second time point after the first time point; (f) Evaluating a second pancreatic cancer-related proteome profile by measuring the concentration level of the pancreatic cancer-related protein or its peptide fragment from the second biological sample; (g) Comparing the second pancreatic cancer-associated proteome profile with the reference pancreatic cancer-associated proteome profile from the pancreatic cancer-negative sample; (h) Determining that there is a second difference between the first pancreatic cancer-associated proteome profile and the reference pancreatic cancer-associated proteome profile from the pancreatic cancer-negative sample, and that the second difference indicates pancreatic cancer; (i) Determining whether there is a risk of progression of pancreatic cancer or having pancreatic cancer based on at least some of the differences between the first and second; (j) A method comprising, if identified as having pancreatic cancer, optionally treating or having such treatment performed on the subject with a pancreatic cancer treatment plan that optionally includes surgery and / or administration of anticancer agents or radiation therapy.

17. The method according to claim 16, wherein the period between the first time point and the second time point is at least one month, at least two months, at least three months, or at least six months.

18. The method according to claim 16 or 17, wherein measuring the concentration levels of the pancreatic cancer-related protein or its peptide fragment from the first and / or second biological sample comprises measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

19. The method according to claim 16, 17, or 18, wherein at least the concentration level of tetranectin is measured.

20. The method according to claim 17, wherein the first sample, the second sample, or both are blood or urine, or both samples are of the same specimen type and are selected from serum, plasma, or urine.

21. A diagnostic kit for pancreatic cancer, (a) A detector configured to detect the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments, selected from a biological sample, including apolipoprotein A1; apolipoprotein A-II; plasma protease C1 inhibitor; L-selectin; tetranectin; phospholipid transport protein; apolipoprotein M; gelzolin; adipocyte membrane-related protein; C1s complement factor; C4b complement factor; C6 complement factor; and fibronectin; (b) A composition comprising apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin, at a control level corresponding to a control group of pancreatic cancer-negative subjects; (c) A multivariate analysis system configured to analyze the difference between the concentration level of the pancreatic cancer-related protein or its peptide fragment and the control level; (d) Optionally, providing instructions for a method for diagnosing pancreatic cancer, the method comprising: measuring the level of the pancreatic cancer-related protein or a peptide fragment thereof from a obtained biological sample using the detector; and comparing the obtained level of the pancreatic cancer-related protein or a peptide fragment thereof to a control level of the pancreatic cancer-related protein or a peptide fragment thereof obtained from a pancreatic cancer-negative subject and / or from a sample obtained from the subject at an earlier time.

22. The kit according to claim 21, wherein the detector comprises a multiproteome detector configured to measure the levels of the pancreatic cancer-related protein or its peptide fragments, comprising apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin.

23. The kit according to claim 21 or 22, wherein the detector is configured to measure the concentration level of the pancreatic cancer-related protein or peptide fragment, comprising at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

24. The kit according to claim 23, wherein the detector is configured to measure at least tetranectin.

25. A computer implementation method for processing a target biological sample, diagnosing pancreatic cancer, and treating said pancreatic cancer, wherein the computer implementation method is (a) to receive biological samples obtained from the subject; (b) Processing the sample with a spectroscopic unit connected directly or wirelessly to a processing device, wherein the processing device has a memory for storing measurement data from the spectroscopic unit; (c) The spectroscopic unit measures the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin, and stores the measurement data in a processor; (d) The stored measurement data is optionally compared with a reference value in memory representing a pancreatic cancer-negative sample using multivariate statistical analysis; (e) From the obtained sample, the results corresponding to at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from the group consisting of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin are stored in the processing device, wherein if the measurement data representing the level of the pancreatic cancer-related protein or peptide fragment differs from the concentration level of a reference pancreatic cancer-related protein or peptide fragment from a pancreatic cancer-negative sample, the results identify the subject as having pancreatic cancer or being at risk of having pancreatic cancer; (f) For subjects identified as having pancreatic cancer, being at risk of developing pancreatic cancer, or having a predisposition to developing pancreatic cancer, displaying the results on an electronic display directly or wirelessly connected to the processor; (g) A computer implementation method comprising: optionally treating or having a subject identified as having pancreatic cancer treated with a pancreatic cancer plan which optionally includes surgery and / or administration of anticancer agents or radiation therapy.

26. The method according to claim 25, wherein the displayed results are included in a user interface which is a dashboard.

27. The method according to claim 25 or 26, wherein the displayed result is part of the multi-omics information displayed on the user interface.

28. The method according to claim 25, 26, or 27, wherein the spectroscopic unit includes a detector configured to measure the concentration level of the pancreatic cancer-related protein or peptide fragment, or is operably connected to the detector and optionally configured to measure at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

29. The method according to claim 28, wherein the detector is configured to measure at least tetranectin.

30. A method for diagnosing and treating pancreatic cancer in a subject, wherein the method is: (a) To provide biological samples obtained from the subject; (b) Measuring the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin; (c) Comparing the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample with the concentration level of a reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative sample and / or a sample obtained from the subject at an earlier time; (d) If the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample differs from the concentration level of the reference pancreatic cancer-related protein or its peptide fragment from the pancreatic cancer-negative sample and / or a sample obtained from the subject at an earlier time, the subject is identified as having pancreatic cancer or being at risk of having pancreatic cancer; (e) A method comprising, optionally, treating or having the specified subject treated with a pancreatic cancer treatment plan or radiotherapy.

31. The method according to claim 30, wherein measuring the concentration levels of the pancreatic cancer-related protein or its peptide fragment from the first and / or second biological sample comprises measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

32. The method according to claim 30 or 31, wherein at least the concentration level of tetranectin is measured.

33. A method for diagnosing and treating pancreatic cancer in a subject, wherein the method is: (a) to provide a first biological sample obtained from the subject; (b) At a first time point, measure the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, or C6 complement factor, and fibronectin; (c) Comparing the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample with the concentration level of a reference pancreatic cancer-related protein or its peptide fragment from a pancreatic cancer-negative sample and / or a sample obtained from the subject at an earlier time; (d) At a second time point, measure the concentration levels of at least one, at least two, at least three, at least four, or at least five pancreatic cancer-related proteins or peptide fragments selected from apolipoprotein A1; apolipoprotein A-II; plasma protease C1 inhibitor; L-selectin; tetranectin; phospholipid transport protein; apolipoprotein M; gelzolin; adipocyte membrane-related protein; C1s complement factor; C4b complement factor; or C6 complement factor; and fibronectin in a second biological sample obtained from the subject; (e) Comparing the concentration level of the pancreatic cancer-related protein or peptide fragment from the obtained sample at the second time point with the concentration level of the reference pancreatic cancer-related protein or peptide fragment from the pancreatic cancer-negative sample and / or from the sample obtained at the first time point or at an earlier time point from the subject; (f) If the concentration levels of the pancreatic cancer-related protein or its peptide fragment from the first and second obtained samples differ from the concentration levels of the reference pancreatic cancer-related protein or its peptide fragment from the pancreatic cancer-negative sample and / or from the sample obtained at the first time point, the subject is identified as having pancreatic cancer or being at risk of having pancreatic cancer; (g) A method comprising, optionally, treating or having a subject identified as having pancreatic cancer treated using a pancreatic cancer treatment plan.

34. The method according to claim 33, wherein the identifying step (f) is performed when it is determined that the concentration levels of at least one, at least two, at least three, at least four, or at least five of the pancreatic cancer-related proteins or their peptide fragments from the obtained sample are increased by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% or more compared to the concentration levels of the reference pancreatic cancer-related proteins or their peptide fragments from the pancreatic cancer-negative sample.

35. The method according to claim 33, wherein the identifying step (f) is performed when it is determined that the concentration levels of at least three, at least four, or at least five of the pancreatic cancer-related proteins or their peptide fragments from the obtained sample are increased by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% or more compared to the concentration levels of the reference pancreatic cancer-related proteins or their peptide fragments from the pancreatic cancer-negative sample.

36. The method according to claim 33, wherein measuring the concentration levels of the pancreatic cancer-related protein or its peptide fragment from the first and / or second biological sample comprises measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, phospholipid transporter proteins, and fibronectin.

37. The method according to any one of claims 33 to 36, wherein at least the concentration level of tetranectin is measured.

38. The method according to any one of claims 33 to 37, wherein the obtained sample is blood or urine, or serum, plasma or urine.

39. The method according to any one of claims 33 to 38, wherein the pancreatic cancer-related protein or a peptide fragment thereof is measured by a spectroscopic technique, the spectroscopic technique being selected from the group consisting of liquid chromatography, gas chromatography, liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, high-performance liquid chromatography-mass spectrometry, capillary electrophoresis-mass spectrometry, nuclear magnetic resonance spectroscopy (NMR), Raman spectroscopy, and infrared spectroscopy.

40. The method according to any one of claims 33 to 39, wherein the comparison of the concentration level of the pancreatic cancer-related protein or its peptide fragment from the obtained sample with the concentration level of the reference pancreatic cancer-related protein or its peptide fragment from the pancreatic cancer-negative sample includes multivariate statistical analysis.

41. The method according to any one of claims 33 to 40, wherein measuring the concentration level of the pancreatic cancer-related protein or its peptide fragment from the second biological sample comprises measuring at least one, at least two, at least three, or each of L-selectin, tetranectin, and phospholipid transporter proteins, and if the measured levels of L-selectin, tetranectin, and / or phospholipid transporter proteins in the second biological sample are increased by at least 10%, 15%, 20%, or 25% compared to the respective concentration levels measured at the first time point, the subject is identified as having pancreatic cancer or being at risk of having pancreatic cancer.

42. The method according to any one of claims 33 to 41, wherein at least a fibronectin concentration level is measured, and if the measured level of fibronectin in the second biological sample is increased or decreased by at least 10%, 15%, 20%, or 25% compared to the respective concentration levels measured at the first time point, the subject is identified as having pancreatic cancer or being at risk of having pancreatic cancer.

43. A proteolytic sample for use in mass spectrometry to diagnose target pancreatic cancer, comprising one or a combination of peptide fragments of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, L-selectin, tetranectin, phospholipid transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, and fibronectin.

44. A proteolytic sample containing L-selectin, tetranectin, phospholipid transporter proteins, and / or fibronectin peptide fragments for use in mass spectrometry to diagnose target pancreatic cancer.

45. The method according to any one of the prior claims, further comprising obtaining a biopsy sample from a subject identified as being at risk of having pancreatic cancer after measurement of pancreatic cancer proteins or fragments thereof, and, if cancer cells are identified in the sample, surgically removing cancerous tissue from the pancreas and / or bile duct(s) of the subject.

46. The method or kit according to any one of claims 1 to 45, wherein the level of tetranectin, as measured at two or more time points over a period of one month to three years, is increasing over time or higher than the control at a single time point.

47. The method or kit according to any one of claims 1 to 45, further comprising measuring the concentration of at least one L-selectin and phospholipid transporter protein, wherein the level of at least one L-selectin and phospholipid transporter protein is found to be increasing over time or elevated above the control at a single point in time, as measured at two or more time points within a period of one month to three years.

48. The method according to claim 46, further comprising measuring the concentration of at least one L-selectin and phospholipid transporter protein, wherein the levels of at least one L-selectin and phospholipid transporter protein are found to be increasing over time or higher than the control at a single point in time, as measured at two or more points in time within a period of one month to three years.

49. The method or kit according to claim 46, 47, or 48, further comprising measuring the concentrations of L-selectin and phospholipid transporter proteins, wherein the levels of L-selectin and phospholipid transporter proteins are, as measured at two or more time points within a period of one month to three years, increasing over time or elevated above the control at a single time point.

50. The method or kit according to any one of claims 46 to 49, further comprising measuring fibronectin.

51. The method or kit according to any one of claims 46 to 50, further comprising measuring at least one of apolipoprotein A1, apolipoprotein A-II, plasma protease C1 inhibitor, transport protein, apolipoprotein M, gelzolin, adipocyte membrane-related protein, C1s complement factor, C4b complement factor, C6 complement factor, or a combination thereof.

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