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WO2025068209A1 - Utilisation d'un ensemble de marqueurs pour déterminer le risque de développer un cancer de la prostate résistant à la castration - Google Patents

Utilisation d'un ensemble de marqueurs pour déterminer le risque de développer un cancer de la prostate résistant à la castration Download PDF

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Publication number
WO2025068209A1
WO2025068209A1 PCT/EP2024/076828 EP2024076828W WO2025068209A1 WO 2025068209 A1 WO2025068209 A1 WO 2025068209A1 EP 2024076828 W EP2024076828 W EP 2024076828W WO 2025068209 A1 WO2025068209 A1 WO 2025068209A1
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Prior art keywords
prostate cancer
castration
resistant prostate
marker set
substances
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PCT/EP2024/076828
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English (en)
Inventor
Johannes EIGLSPERGER
Marouane Kdadra
Eric SCHIFFER
Rudolf JAGDHUBER
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Numares AG
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Numares AG
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    • G01N33/57555—
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis

Definitions

  • the present invention relates to the in-vitro use of a marker set for distinguishing castrationresistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer according to the preamble of claim 1 , to the further medical use of such a marker set according to the preamble of claim 8 as well as to an analysis method for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer according to the preamble of claim 9.
  • Prostate cancer affects 1 out of 6 to 8 men. 15 to 35 % of newly diagnosed prostate cancers are locally advanced and/or metastatic.
  • the currently applied standard for diagnosing prostate cancer is determining the concentration of prostate-specific antigen (PSA).
  • PSA prostate-specific antigen
  • PSA has low specificity so that there is a high number of patients who obtain a misdiagnosis and an overtreatment.
  • PCa PCa and its distinction from other prostate conditions is based on prostate biopsy results. This assessment has low detection sensitivity and is therefore prone to misclassify the cancer. The invasive nature of the biopsy is associated with a risk of infection.
  • Such a marker set comprises at least four (e.g., 4, 5, 6, 7, 8, 9, 10, 11 , or 12) substances chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarboxylic acid (Sumiki’s acid), phenylacetylglutamine, N-acetylglutamine, L-tyrosine, dimethylamine, L- leucine, mannitol, sucrose, cis-aconitic acid, alanine, and scyllo-inositol.
  • this marker set is used for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer.
  • the concentration of the substances contained in the marker set is determined in a body fluid obtained from a patient.
  • This concentration determination can be carried out by any appropriate measuring or analysis method, such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and infrared spectroscopy such as Fourier-transform infrared (FT-IR) spectroscopy.
  • NMR nuclear magnetic resonance
  • mass spectrometry mass spectrometry
  • infrared spectroscopy such as Fourier-transform infrared (FT-IR) spectroscopy.
  • An alteration of concentration of at least four substances of the marker set with respect to the concentration in a control group or an alteration of a concentration ratio between at least four substances with respect to the concentration ratio of the same substances in a control group was correlated in a statistically significant way with the presence of castration-resistant prostate cancer at the time of analysis (i.e., enabling a distinction between castration-resistant prostate cancer and non-castration resistant prostate cancer) or the onset of castrationresistant prostate cancer at a time point after analysis (i.e., enabling a determination of the risk of an individual to develop castration-resistant prostate cancer).
  • urine (as representative body fluid) of patients having prostate cancer with clinical signs of tumor progression was used. These patients showed a testosterone concentration in blood of less than 0.5 ng/mL and a confirmed PSA increase by at least 100% with respect to the blood PSA concentration in the last three months prior to the sample collection. Furthermore, the patients were newly diagnosed with bone metastases and/or progression of existing metastases.
  • the control group consisted of patients having prostate cancer that remained in stable remission after treatment. These patients showed a testosterone concentration in blood of less than 0.5 ng/mL and a blood PSA concentration of less than 1 ng/mL. Furthermore, they showed no clinical signs of tumor progression.
  • two biomarkers of this marker set at the same time, or even three biomarkers of this marker set at the same time no significant results could be obtained for distinguishing the two groups (castration-resistant prostate cancer versus non-castration resistant prostate cancer). Rather, the area under the curve (AUC) values of receiver operating characteristic (ROC) plots showed values mainly lying in a range of from 0.5 to 0.65.
  • the AUC value of ROC plots is an aggregated metric that evaluates how well a logistic regression model classifies positive and negative outcomes at all possible cut-offs. It can range from 0 to 1 .0.
  • An AUC value of 0 represents a prediction of the opposite of the trained correlation.
  • An AUC value of 0.5 represents a random prediction.
  • An AUC value of higher than 0.5 represents a classification of an event as fulfilling the trained correlation wherein higher values represent better classification.
  • the marker sets were tested against training datasets and test datasets and iteratively crossvalidated.
  • Cross-validation was performed by splitting the training dataset into, e.g., five parts and by using four parts for training (training subset) and the fifth part for testing (testing subset).
  • the individual parts were iteratively removed from and returned to the training set so that each of the five parts belonged - in different training rounds - to the training subset and to the testing subset.
  • acetone, 5-hydroxymethyl-2-furancarboxylic acid (Sumiki’s acid), phenylacetylglutamine, N-acetylglutamine, L-tyrosine, dimethylamine, L- leucine, mannitol, sucrose, cis-aconitic acid, alanine, and scyllo-inositol turned out to be valid biomarkers for the underlying question (i.e., distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or determining the risk of an individual to develop castration-resistant prostate cancer), provided that the concentration of at least four of these biomarkers was determined at the same time (i.e., in one or more body fluid samples from the same patient obtained at the same time point).
  • the concentration determination can be made with a method being able to determine the concentration of the substances by a single measurement or by a method requiring more than one measurement for such determination.
  • NMR spectroscopy is particularly appropriate for such a concentration determination since it enables a highly accurate concentration determination in a body fluid by a single measurement in a very short measuring time.
  • the concentration of the substances is standardized to the concentration of creatinine in the same sample or, alternatively, to the concentration of another substance that is naturally present in the sample.
  • the group of substances comprises either phenylacetylglutamine or N- acetylglutamine. Both substances show NMR signals in a very similar spectral region so that their NMR signals cannot always be easily distinguished from each other.
  • the marker set comprises or consists of at least five substances, wherein two of the substances are phenylacetylglutamine and N-acetylglutamine.
  • phenylacetylglutamine or N-acetylglutamine are not chosen at the same time as substances for the marker set.
  • the marker set comprises or consists of alanine, 5-hydroxymethyl-2- furancarboxylic acid, cis-aconitic acid, and sucrose.
  • a marker set showed an AUC value of 0.677 in the test dataset and an AUC value of even 0.788 in the training dataset (cf. Figure 1)-
  • the marker set comprises or consists of L-leucine, L-tyrosine, 5- hydroxymethyl-2-furancarboxylic acid, and mannitol.
  • Such a marker set showed an AUC value of 0.661 in the test dataset and an AUC value of even 0.758 in the training dataset (cf. Figure 3).
  • the marker set comprises or consists of sucrose, L-tyrosine, 5- hydroxymethyl-2-furancarboxylic acid, and cis-aconitic acid.
  • sucrose L-tyrosine
  • 5- hydroxymethyl-2-furancarboxylic acid 5- hydroxymethyl-2-furancarboxylic acid
  • cis-aconitic acid Such a marker set showed an AUC value of 0.655 in the test dataset and an AUC value of even 0.788 in the training dataset (cf. Figure 4).
  • 5-hydroxymethyl-2-furancarboxylic acid is present in the marker set (i.e., is one of the at least four substances in the marker set).
  • cis-aconitic acid is present in the marker set (i.e., is one of the at least four substances in the marker set).
  • L-tyrosine is present in the marker set (i.e., is one of the at least four substances in the marker set).
  • At least one of sucrose and mannitol is present in the marker set.
  • the marker set comprises at least four (e.g., 4, 5, 6, 7, or 8) substances chosen from the group consisting of alanine, 5-hydroxymethyl-2-furancarboxylic acid, cisaconitic acid, sucrose, scyllo-inositol, L-tyrosine, L-leucine, and mannitol.
  • the inventors Upon analyzing a plurality of NMR spectra for identifying appropriate biomarkers for the underlying question, the inventors were able to identify NMR signals in bin A232 that appeared to be highly appropriate for distinguishing castration-resistant prostate cancer from noncastration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer.
  • This bin comprises a doublet signal around 5.60 ppm, wherein a first line of the doublet lies under exemplary measuring conditions at approximately 5.620 ppm and a second line of the doublet lies under the same measuring conditions at approximately 5.607 ppm. So far, the inventors were not yet successful in assigning a specific metabolite to these signals observed in bin A232. Therefore, the metabolite being responsible for the signals in bin A232 will be referred to in the following as substance Y.
  • the present invention relates to uses of a marker set comprising the substances listed above and additionally comprising substance Y, as well as to related methods. It turned out that it is fully sufficient to use three substances as biomarkers for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer, as long as substance Y is one of these three substances.
  • the present invention relates to the in-vitro use of a marker set comprising at least three (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13) substances chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarboxylic acid (Sumiki’s acid), phenylacetylglutamine, N-acetylglutamine, L-tyrosine, dimethylamine, L- leucine, mannitol, sucrose, cis-aconitic acid, alanine, scyllo-inositol, and substance Y for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer, with the proviso that substance Y is one of the at least three substances.
  • substance Y is one of the at least three substances.
  • the marker set comprises or consists of acetone, L-tyrosine, 5- hydroxymethyl-2-furancarboxylic acid, and substance Y.
  • Such a marker set showed an AUC value of 0.688 in the test dataset and an AUC value of even 0.776 in the training dataset (cf. Figure 5).
  • the marker set comprises or consists of substance Y, L-tyrosine, and 5- hydroxymethyl-2-furancarboxylic acid.
  • substance Y substance Y
  • L-tyrosine substance Y
  • 5- hydroxymethyl-2-furancarboxylic acid substance Y
  • Such a marker set showed an AUC value of 0.681 in the test dataset and an AUC value of even 0.743 in the training dataset (cf. Figure 6).
  • the marker set comprises or consists of dimethylamine, L-tyrosine, 5- hydroxymethyl-2-furancarboxylic acid, and substance Y.
  • Such a marker set showed an AUC value of 0.659 in the test dataset and an AUC value of even 0.767 in the training dataset (cf. Figure 7).
  • the marker set comprises or consists of acetone, 5-hydroxymethyl-2- furancarboxylic acid, substance Y, and at least one of phenylacetylglutamine and N- acetylglutamine.
  • Such a marker set showed an AUC value of 0.655 in the test dataset and an AUC value of even 0.757 in the training dataset (cf. Figure 8).
  • the marker set comprises or consists of acetone, 5-hydroxymethyl-2- furancarboxylic acid, alanine, and substance Y.
  • the marker set comprises or consists of L-tyrosine, 5-hydroxymethyl-2- furancarboxylic acid, sucrose, and substance Y.
  • acetone is present in the marker set (i.e., is one of the at least three substances in the marker set).
  • L-tyrosine is present in the marker set (i.e., is one of the at least three substances in the marker set).
  • dimethylamine is present in the marker set (i.e., is one of the at least three substances in the marker set). In an embodiment, at least one of phenylacetylglutamine and N-acetylglutamine is present in the marker set.
  • the marker set comprises at least three (e.g., 3, 4, 5, 6, or 7) substances chosen from the group consisting of substance Y, acetone, L-tyrosine, 5-hydroxymethyl-2- furancarboxylic acid, dimethylamine, and at least one of phenylacetylglutamine and N- acetylglutamine, with the proviso that substance Y is one of the at least three substances.
  • the present invention relates to the further medical use of a marker set comprising at least four (e.g., 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12) substances chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarboxylic acid, phenylacetylglutamine, N- acetylglutamine, L-tyrosine, dimethylamine, L-leucine, mannitol, sucrose, cis-aconitic acid, alanine, and scyllo-inositol for in-vivo diagnostics of castration-resistant prostate cancer and/or for the prediction of the risk of an individual to develop castration-resistant prostate cancer.
  • four e.g., 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12
  • substances chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarboxylic acid, phenylacetylglutamine, N- acetylglutamine, L-tyrosine,
  • the present invention relates to the further medical use of a marker set comprising at least three (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, or 13) substances chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarboxylic acid, phenylacetylglutamine, n- acetylglutamine, L-tyrosine, dimethylamine, L-leucine, mannitol, sucrose, cis-aconitic acid, alanine, scyllo-inositol, and substance Y, with the proviso that substance Y is one of the at least three substances, for in-vivo diagnostics of castration-resistant prostate cancer and/or for the prediction of the risk of an individual to develop castration-resistant prostate cancer.
  • a marker set comprising at least three (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, or 13) substances chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarbox
  • the present invention relates to a method for analyzing an isolated body fluid sample in vitro, comprising the steps explained in the following. This method is carried out on an isolated body fluid sample originating from an individual.
  • the concentration of at least four (e.g., 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12) substances in the body fluid sample is determined by analyzing the body fluid sample with a suited measuring technique.
  • the at least four substances are chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarboxylic acid, phenylacetylglutamine, N-acetylglutamine, L-tyrosine, dimethylamine, L-leucine, mannitol, sucrose, cis-aconitic acid, alanine, and scyllo- inositol.
  • a very well suited measuring technique for determining the concentration of the individual substances is nuclear magnetic resonance spectroscopy (NMR spectroscopy).
  • a score is calculated from the determined concentrations, wherein the score is indicative for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of the individual to develop castration-resistant prostate cancer.
  • the score can be calculated by taking into consideration the concentrations measured or expected in a body fluid sample from a control group.
  • the score can be the median of the concentration ratios of the at least four substances between the body fluid test sample of the patient and corresponding control values of a body fluid control sample that have been measured in the past. If the score is above a predetermined threshold value, a significant increase of the marker substances is present in the body fluid test sample that is indicative for castration-resistant prostate cancer. It should be noted that other calculation methods as well as a weighting of individual marker concentrations with respect to other marker concentrations can also be performed in an embodiment.
  • Parameter “I” can be, e.g., the signal intensity or signal integral of an according signal observed in the evaluated measuring result.
  • “I” can be the signal intensity or signal integral of an NMR signal in an NMR spectrum if NMR spectroscopy is used as measuring technique.
  • “I” is a ratio between two signal intensities or two signal integrals. In such a case, it is, e.g., possible to standardize the concentration of a first substance (or a plurality of substances) by the concentration of a second substance such as, e.g., creatinine.
  • the score is a (semi-)quantitative measure for the likelihood that a prostate cancer is castration-resistant prostate cancer or non-castration resistant prostate cancer.
  • the score serves for (semi-)quantitatively distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer.
  • the score is a (semi-) quantitative measure for the risk of an individual to develop castration-resistant prostate cancer.
  • Calculating the score comprises multiplying each of the concentrations of the substances by a substance-specific weighting factor to provide a plurality of weighted values and combining the weighted values into a risk equation. Afterwards, an output of the risk equation is compared to a predefined threshold. If the score is above the threshold, there is a likelihood that a prostate cancer is castration-resistant prostate cancer and/or that there is a risk of an individual to develop castration-resistant prostate cancer. In an embodiment, the likelihood and/or the risk is higher, the higher the score is (i.e., the likelihood and/or the risk increases with increasing distance of the score from the threshold).
  • the calculated score is output and presented to the individual and/or to a third person such as a physician or medical staff.
  • the output can be performed on a display (i.e., in an electronic way) or in printed form.
  • a report indicating the score, optionally in combination with a comparative scale of possible scores and their meaning with respect to distinguishing castration-resistant prostate cancer from noncastration resistant prostate cancer and/or with respect to determining the risk of an individual to develop castration-resistant prostate cancer.
  • the method is a computer-implemented method.
  • all steps of spectral analysis and concentration determination as well as of score calculation are performed on a computer.
  • Such steps are far too complex to be done in a manual way.
  • the computer- implemented concentration determination is, in an embodiment, based on a spectral analysis, such as an analysis of NMR spectra.
  • the spectral analysis and the further required steps until the score can be output can be done on the same computer that is used for controlling a spectrometer performing the spectral analysis or on a different computer.
  • the body fluid sample is a urine sample or a blood sample.
  • the blood sample is a whole blood sample, a blood serum sample, a blood plasma sample, or any other blood preparation derivable from whole blood or from other blood preparations.
  • the body fluid sample (and therewith the patient from whom the body fluid sample originates) is grouped into one of at least two predefined groups based on the calculated score.
  • one group encompasses patients suffering from castrationresistant prostate cancer, wherein the other group encompasses patients suffering from noncastration resistant prostate cancer.
  • the resulting grouping can also be indicated on an according report.
  • the present invention relates to another method for analyzing an isolated body fluid sample in vitro, comprising the steps explained in the following. This method is done on an isolated body fluid sample originating from an individual.
  • the concentration of at least three (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, or 13) substances in the body fluid sample is determined by analyzing the body fluid sample with a suited measuring technique.
  • the at least three substances are chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarboxylic acid, phenylacetylglutamine, n- acetylglutamine, L-tyrosine, dimethylamine, L-leucine, mannitol, sucrose, cis-aconitic acid, alanine, scyllo-inositol, and substance Y, with the proviso that substance Y is one of the at least three substances.
  • a score is calculated from the determined concentrations, wherein the score is indicative for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of the individual to develop castration-resistant prostate cancer.
  • the present invention relates to a medical method for making a differential diagnosis between castration-resistant prostate cancer and non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer. This method comprises the steps explained in the following.
  • a score is calculated from the determined concentrations, wherein the score is indicative for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of the individual to develop castration-resistant prostate cancer.
  • a differential diagnosis between castration-resistant prostate cancer and non-castration resistant prostate cancer is made on the basis of the previously calculated score.
  • the risk of the patient to develop castration-resistant prostate cancer is determined on the basis of the previously calculated score.
  • the respective result is then output to the patient or to a third person like a physician or medical staff.
  • the present invention relates to another medical method for making a differential diagnosis between castration-resistant prostate cancer and non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer.
  • This method comprises the steps explained in the following.
  • a body fluid sample is gathered from a patient.
  • the concentration of at least three (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, or 13) substances in the body fluid sample is determined by analyzing the body fluid sample with a suited measuring technique.
  • the at least three substances are chosen from the group consisting of acetone, 5- hydroxymethyl-2-furancarboxylic acid, phenylacetylglutamine, n-acetylglutamine, L-tyrosine, dimethylamine, L-leucine, mannitol, sucrose, cis-aconitic acid, alanine, scyllo-inositol, and substance Y, with the proviso that substance Y is one of the at least three substances.
  • a score is calculated from the determined concentrations, wherein the score is indicative for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of the individual to develop castration-resistant prostate cancer.
  • a differential diagnosis between castration-resistant prostate cancer and non-castration resistant prostate cancer is made on the basis of previously calculated score.
  • the risk of the patient to develop castration-resistant prostate cancer is determined on the basis of the previously calculated score.
  • the respective result is then output to the patient or to a third person like a physician or medical staff.
  • the present invention relates to a decision support system for analyzing an isolated body fluid sample in vitro, the decision support system comprising: a) a unit for providing a body fluid sample from an individual; b) a unit for determining the concentration of at least four substances chosen from the group consisting of acetone, 5-hydroxymethyl-2-furancarboxylic acid, phenylacetylglutamine, N- acetylglutamine, L-tyrosine, dimethylamine, L-leucine, mannitol, sucrose, cis-aconitic acid, alanine, and scyllo-inositol in the body fluid sample by analyzing the body fluid sample with a suited measuring technique; and c) a unit for calculating a score from the determined concentrations, the score being indicative for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of the individual to develop castration-resistant prostate cancer.
  • the unit for determining the concentration of the at least four substances is configured to determine the concentration of any substance combination of the embodiments explained above.
  • All embodiments of the use of the marker set can be combined in any desired way and can be transferred either individually or in any arbitrary combination to the further medical use of the marker set as well as to the different methods and to the decision support system.
  • all embodiments of the further medical use of the marker set can be combined in any desired way and can be transferred either individually or in any arbitrary combination to the use of the marker set, to the different methods, and to the decision support system.
  • all embodiments of the different methods can be combined in any desired way and can be transferred either individually or in any arbitrary combination to the use of the marker set, to the further medical use of the marker set, to any other of the described methods, and to the decision support system.
  • Figure 1 shows an ROC plot of the ability of a first marker set for distinguishing castrationresistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer;
  • Figure 2 shows an ROC plot of the ability of a second marker set for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer;
  • Figure 3 shows an ROC plot of the ability of a third marker set for distinguishing castrationresistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer;
  • Figure 4 shows an ROC plot of the ability of a fourth marker set for distinguishing castrationresistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer;
  • Figure 5 shows an ROC plot of the ability of a fifth marker set for distinguishing castrationresistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer;
  • Figure 6 shows an ROC plot of the ability of a sixth marker set for distinguishing castrationresistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer;
  • Figure 7 shows an ROC plot of the ability of a seventh marker set for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer
  • ROC plots shown in Figures 1 to 8 were obtained by analyzing urine samples of patients having prostate cancer with clinical signs of tumor progression. These patients showed a testosterone concentration in blood of less than 0.5 ng/mL and a confirmed PSA increase by at least 100% with respect to the PSA concentration in the last three months prior to the sample collection. Furthermore, the patients were newly diagnosed with bone metastases and/or progression of existing metastases.
  • the control group consisted of patients having prostate cancer that remained in stable remission. These patients showed a testosterone concentration in blood of less than 0.5 ng/mL and a PSA concentration in blood of less than 1 ng/mL. Furthermore, they showed no clinical signs of tumor progression.
  • Samples were measured in batches of up to 93 samples per run.
  • each run included one Axinon® urine calibrator sample and two Axinon® urine control samples (before and after the analytical urine samples, respectively) in order to assure ideal measurement conditions throughout the run.
  • NMR spectra underwent automatic referencing, phase correction and baseline correction before further analysis.
  • the NMR spectra underwent an automatic standardization and calibration procedure to minimize between-device, between-day and between-run effects.
  • the quality of each of these spectra was assessed by a custom spectrum qualification algorithm that analyzes general spectral properties, e.g., offset and tilt of the baseline in selected spectral regions, and properties of selected indicator signals, e.g., signal position, shape and width. Spectra that did not meet the predefined quality criteria were excluded from further analysis.
  • the remaining spectral regions were subject to an adaptive binning, which divides the spectrum in bins of differing size or extent (typically covering 0.01 to 0.05 ppm, but in extreme cases also covering 0.005 to 0.5 ppm).
  • Typical numbers of bins lie in a range of from 350 to 450.
  • 407 bins resulted from the precedingly explained analytic steps.
  • Quantification of specific signal peaks was done by fitting Pseudo-Voigt functions, which represent a linear combination of a Gaussian and a Lorentzian function, to each peak of interest. The resulting signal fits were checked for goodness of fit in order to reject results of insufficient fit quality.
  • the identified marker substances were tested in different combinations to assess their suitability for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer.
  • the result of the determination based on the marker substances has been checked against clinical signs of castration-resistant prostate cancer in the patient who donated the urine sample, as already explained above.
  • the results are summarized in receiver operating characteristic (ROC) plots.
  • ROC receiver operating characteristic
  • the presented marker sets comprise highly appropriate biomarkers for distinguishing castration-resistant prostate cancer from non-castration resistant prostate cancer and/or for determining the risk of an individual to develop castration-resistant prostate cancer.

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Abstract

La présente invention concerne l'utilisation d'un ensemble de marqueurs comprenant au moins quatre substances choisies dans le groupe comprenant l'acétone, l'acide 5-hydroxyméthyl-2-furanecarboxylique, la phénylacétylglutamine, la N-acétylglutamine, la L-tyrosine, la diméthylamine, la L-leucine, le mannitol, le saccharose, l'acide cis-aconitique, l'alanine et le scyllo-inositol dans un procédé in vitro permettant de faire la distinction entre un cancer de la prostate résistant à la castration et un cancer de la prostate non résistant à la castration et/ou de déterminer le risque qu'un individu développe un cancer de la prostate résistant à la castration.
PCT/EP2024/076828 2023-09-25 2024-09-25 Utilisation d'un ensemble de marqueurs pour déterminer le risque de développer un cancer de la prostate résistant à la castration Pending WO2025068209A1 (fr)

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DE102023125865.6A DE102023125865A1 (de) 2023-09-25 2023-09-25 Verwendung eines Markersets zur Ermittlung des Risikos der Entwicklung von kastrationsresistentem Prostatakrebs
DE102023125865.6 2023-09-25

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