WO2021138611A2 - Biomarqueurs de métabolites fiables pour de multiples cancers urologiques - Google Patents

Biomarqueurs de métabolites fiables pour de multiples cancers urologiques Download PDF

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Publication number
WO2021138611A2
WO2021138611A2 PCT/US2020/067743 US2020067743W WO2021138611A2 WO 2021138611 A2 WO2021138611 A2 WO 2021138611A2 US 2020067743 W US2020067743 W US 2020067743W WO 2021138611 A2 WO2021138611 A2 WO 2021138611A2
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cancer
biomarker
compound
doi
cancers
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PCT/US2020/067743
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English (en)
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WO2021138611A3 (fr
Inventor
Guohua Xiong
Qun Wang
Robin Carter
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Femtera Laboratories
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Publication of WO2021138611A3 publication Critical patent/WO2021138611A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers

Definitions

  • the present disclosure relates to a set of reliable metabolite biomarkers for three types of urological cancers namely bladder cancer, kidney cancer and prostate cancer. It also illustrates these cancers’ cellular metabolism, including the associated metabolites and metabolic pathways, the difference in metabolic behavior between cancer patients’ body fluids and cancer cell cultures for each type of the cancers, and the difference in metabolic behavior between these cancers. It shows that the comprehensive and integrated technical solution (CITS) and the double-ensuring approach (DEA) are suitable for effective capture of reliable metabolite biomarkers for these solid-tumor cancers.
  • the CITS and DEA were first presented in U.S. provisional applications number 62946728 and number 62957102 and then U.S. non-provisional application number 17118836 and international application PCT/US20/65203.
  • LDT laboratory-developed test
  • Metabolomics emerged and dramatically advanced over the past two decades as a large-scale study of biochemical processes involving metabolites (i.e. the small molecule substrates, intermediates and products of metabolism) [1-9].
  • metabolomics i.e. the small molecule substrates, intermediates and products of metabolism
  • untargeted metabolomics intends to comprehensively scan all the measurable metabolites including unknowns to obtain metabolomic profiles, while targeted metabolomics determines defined groups of chemically characterized and biochemically annotated metabolites.
  • genomics, transcriptomics and proteomics Unlike the earlier primary -omics approaches (i.e. genomics, transcriptomics and proteomics), metabolomics best represents the molecular phenotype because metabolites are the downstream products of cellular regulatory processes and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes [1-4,10]. So far, 114,008 metabolite entries have been collected in the Human Metabolome Database by the Metabolomics Innovation Center in Canada [11,12], and
  • urological cancers are a group of severe diseases occurring within the human body’s urinary system.
  • Other less popular urological cancers include cancers of ureter, urethra, penile and testicles. Determined by the urinary system, cancers of prostate, penile and testicles are for men only.
  • prostate cancer is the most common cancer among men in the U.S., except for skin cancer.
  • Kidney cancer is the 6th most common cancer for men and the 8th most common cancer for women.
  • Bladder cancer is the 4th most common cancer for men, and the chances for men to be diagnosed with this disease are 4 times more likely than women [47].
  • Prostate-specific antigen has been known for a long time as a molecular biomarker to play a significant role in prostate cancer screening in order to help reduce the mortality. However, it is subject to cause false positive results and so leads to overdiagnosis and overtreatment of this disease [48].
  • PSMA prostate-specific membrane antigen
  • HRAM high-resolution accurate mass spectrometry
  • CITS A comprehensive and integrated technical solution (CITS) is used to ensure an omnibus detection of different types of metabolites as well as accurate omics data analysis/interpretation, resulting in dramatically increased number of detectable cancer-specific metabolites, improved representativity of the selected metabolite biomarkers as well as better detection sensitivity.
  • the CITS covers the following elements:
  • DEA double-ensuring approach
  • a set of de-identified cancer patient samples are tested against a set of de-identified healthy controls to find a group of significantly altered metabolites specific to the cancer patients;
  • B). the corresponding cancer cell cultures are tested against the media control to find a group of metabolites associated with the cancer’s cellular activities;
  • C). a final comparison between these two groups of discovered specific metabolites is undergone to “lock” the events overlapping in both the cancer patients and the cancer cell cultures. This forms a double-ensuring process of capturing reliable metabolite biomarker candidates.
  • the “locked” compounds will be used for our clinical testing method development and validation. Since we do not only perform untargeted scans to find the specific metabolites but also conduct confirmatory targeted detection of these compounds, it is actually a “double-double-ensuring” mechanism for metabolite biomarker discovery.
  • Cancer Marker Panel [0021] Although not every metabolite biomarker can be confirmed with DEA due to the apparent difference between human bodies and cell cultures, the “locked” metabolites will become a part of highly representative and reliable biomarkers.
  • a comprehensive panel of urological biomarkers is formed based on the double-ensured metabolites and other representative. This comprehensive panel comprises individual signature biomarker panels for each of the urological cancers.
  • the comprehensive panel of urological cancer biomarkers comprises two parts: one contains metabolite biomarkers suitable for GC-MS/MS analysis, and the other contains metabolite biomarkers suitable for LC-MS/MS analysis.
  • a reference to a compound or component includes the compound or component by itself, as well as in combination with other compounds or components, such as mixtures of compounds.
  • Fig. 1 is a schematic representing the applicant’s comprehensive and integrated technical solution.
  • Fig. 2 is a scheme representing experimental design of double- ensuring approach.
  • Fig. 3a is an overlay of total ion chromatogram of GC-Q-TOF-MS/MS analysis with urine lipid phase of all samples.
  • Fig. 3b is a cloud plot of significant figures of bladder cancer patients.
  • Fig. 4a is an overlay of total ion chromatogram of GC-Q-TOF-MS/MS analysis with urine lipid phase of cell cultures.
  • Fig. 4b is a cloud plot of significant figures of bladder cancer cell lines.
  • Fig. 5 is a Venn Diagram from GC-MS/MS analysis of shared metabolites which are significantly altered within each two-group comparison.
  • Fig. 3a shows the GC-Q-TOF chromatograms of a set of lipid-fraction samples from the urine specimens of 7 bladder cancer patients vs. 7 healthy controls.
  • Fig. 3b shows the 326 significant events observed by comparing the patient sample set to the healthy control set (p ⁇ 0.05, fold change>1.5). The green bubbles represent the events in patient samples with signal intensities at least 1.5-fold as high as in the healthy controls, while the red bubbles display the opposite.
  • Fig. 4a shows the GC-Q-TOF chromatograms of a set of lipid-fraction samples from three cell culture batches of a bladder cancer cell line HT-1197 vs. culture medium controls.
  • Fig. 3b shows the 326 significant events observed by comparing the patient sample set to the healthy control set (p ⁇ 0.05, fold change>1.5). The green bubbles represent the events in patient samples with signal intensities at least 1.5-fold as high as in the healthy controls, while the red bubbles display the opposite.
  • Fig. 4a shows the
  • FIG. 5 further summarizes the numbers of detected significant events and the “locked” metabolites with the double-ensuring approach based on GC-Q-TOF MS/MS scans of the lipid fraction for each of bladder cancer, kidney cancer and prostate cancer.
  • Bingol K Recent advances in targeted and untargeted metabolomics by NMR and MS/NMR methods. High Throughput. 2018;7(2):9. pii: E9. doi: 10.3390/ht7020009
  • Vermeersch KA Styczynski MR. Applications of metabolomics in cancer research. J. Carcinog. 2013; 12:9
  • Attard JA Dunn WB, Mergental H, Mirza DF, Afford SC, Perera MTPR.
  • Cuperlovic-Culf M Barnett DA, Gulf AS, Chute I. Cell culture metabolomics: applications and future directions. Drug Discov Today. 2010 Aug; 15(15-16):610-21. doi: 10.1016/j.drudis.2010.06.012.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

Une solution technique intégrée complète (CITS) conjointement avec une approche à double sécurité (DEA) conduit à capturer efficacement des biomarqueurs de métabolites fiables pour la détection simultanée de plusieurs cancers urologiques, à savoir les cancers de la vessie, du rein, de la prostate et de l'uretère. En particulier, la CITS assure une détection polyvalente de différents types de métabolites ainsi que l'analyse/interprétation de données métabolomiques détaillées, ce qui permet d'obtenir un nombre considérablement accru de biomarqueurs de métabolites représentatifs et fiables, et le DEA aide à éliminer ou à réduire au minimum les variations ou biais significatifs associés au profilage métabolomique, garantissant ainsi une découverte efficace de biomarqueurs de métabolites fiables pour chacun des cancers urologiques d'intérêt. De plus, on obtient de nouvelles connaissances concernant le métabolisme cellulaire des cancers urologiques, comprenant les métabolites et les voies métaboliques associés, la différence dans le comportement métabolique entre des fluides corporels du patient cancéreux et des cultures de cellules cancéreuses, et la comparaison du comportement métabolique entre des cancers urologiques individuels. Nombre de ces aspects ne nous apparaissaient pas clairement auparavant. Pour la première fois, un ensemble de métabolites à double sécurité est obtenu en tant que nouveaux biomarqueurs fiables candidats pour les cancers urologiques d'intérêt. Ceci constitue une fondation solide pour le développement ultérieur de méthodes et la validation d'un test de laboratoire clinique précis pour la détection simultanée de plusieurs cancers urologiques, y compris leur identification individuelle et une détection précoce.
PCT/US2020/067743 2020-01-03 2020-12-31 Biomarqueurs de métabolites fiables pour de multiples cancers urologiques WO2021138611A2 (fr)

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US62/957,102 2020-01-03

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WO2021138611A3 WO2021138611A3 (fr) 2021-09-16

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Publication number Priority date Publication date Assignee Title
EP2179292B1 (fr) * 2007-08-16 2012-11-28 The Regents of the University of Michigan Profile metabolomique du cancer de la prostate
US9891224B2 (en) * 2012-01-30 2018-02-13 The Johns Hopkins University Biomarkers for aggressive prostate cancer

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