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US-12618844-B2 - Cancer

US12618844B2US 12618844 B2US12618844 B2US 12618844B2US-12618844-B2

Abstract

The invention relates to biomarkers, and to novel biological markers for diagnosing cancer. In particular, the invention relates to the use of these compounds as diagnostic and prognostic markers in assays for detecting cancer, such as oesophagogastric cancer, and corresponding methods of detection. The invention also relates to methods of determining the efficacy of treating these diseases with a therapeutic agent. The assays are qualitative and/or quantitative, and are adaptable to large-scale screening and clinical trials.

Inventors

  • George Hanna
  • Sophie Doran

Assignees

  • IMPERIAL COLLEGE INNOVATIONS LIMITED

Dates

Publication Date
20260505
Application Date
20210118
Priority Date
20200117

Claims (10)

  1. 1 . A method of treating an individual suffering from oesophagogastric cancer, said method comprising the steps of: a) detecting the level of at least one signature compound in a bodily sample from a test subject using gas chromatography, mass spectrometry, and/or GCMS, wherein the bodily sample is a breath sample from the test subject, wherein the at least one signature compound is elected from group (i) consisting of methyl 2,3,5,6-tetra-O-methyl-α-D-galactofuranoside; 1-tetradecanol; N-butyl-benzenesulfonamide; hexadecanoic acid; tetradec-5-yl ester 3,5,5-trimethyl-hexanoic acid; tetradecyl ester undec-10-ynoic acid; 1-dotriacontanol; 1-chloro-tetradecane; 4-methyloctan-1-ol; carbon monoxide; nickel; 2-ethyl-cyclohexylamine; 3-ethyl-1-octene; ethyl lactate; tetramethyl succinimide; 6-methyl-2-heptanone; (E)-ethen-2-d-ol; 4-anilino-4-keto-2-phenyl-butyric acid; diisobutyl (oxybis(ethane-2,1-diyl)) dicarbonate; nickel tetracarbonyl; (E)-2-ethylene-4-methylene-5-hexenal; 3-methyl-1-butyne; (R)-5-methyl-2-(1-methylethylidene)-cyclohexanone; α-propyl-benzeneethanol; 4-methyl-1-pentene; 1,3,3-trimethyl-2-oxabicyclo[2.2.2]oct-5-ene; 2,2′-(ethene-1,2-diylbis(sulfanediyl))diethanol; 3-methyl-thiophene; tert-butyl alcohol; and 2-methoxysuccinonitrile, compared to the reference, in the bodily sample from the test subject, or group (ii) consisting of 4-hydroximino-2,2,6,6-tetramethyl-1-piperidinyl ester 4-amino-benzoic acid; 4,4-dimethyl-octane; benzyl 3-deuterio-α-diazopropionate; and 1-methylethyl ester formic acid; and b) treating the test subject with a therapeutic agent and/or radiotherapy, if there is an increase in the level of the at least one signature compound selected from group (i) or a decrease in the level of the at least one signature compound selected from group (ii) in the bodily sample from the test subject, compared to a reference, wherein the reference level is the level of the at least one signature compound in an individual, or the average level for a group of individuals, wherein the individual or group of individuals do not suffer from oesophagogastric cancer, wherein the treatment reduces or delays progression of cancer and/or treats cancer.
  2. 2 . A method according to claim 1 , wherein the at least one signature compound is selected from the group consisting of methyl 2,3,5,6-tetra-O-methyl-α-D-galactofuranoside; 4-hydroximino-2,2,6,6-tetramethyl-1-piperidinyl ester 4-amino-benzoic acid; 1-tetradecanol; N-butyl-benzenesulfonamide; hexadecanoic acid; tetradec-5-yl ester 3,5,5-trimethyl-hexanoic acid; 4,4-dimethyl-octane; tetradecyl ester undec-10-ynoic acid; 1-dotriacontanol; benzyl 3-deuterio-α-diazopropionate; 1-methylethyl ester formic acid; 1-chloro-tetradecane; 4-methyloctan-1-ol; carbon monoxide; nickel; and 2-ethyl-cyclohexylamine.
  3. 3 . A method according to claim 2 , wherein the at least one signature compound is selected from the group consisting of methyl 2,3,5,6-tetra-O-methyl-α-D-galactofuranoside; 4-hydroximino-2,2,6,6-tetramethyl-1-piperidinyl ester 4-amino-benzoic acid; 1-tetradecanol; N-butyl-benzenesulfonamide; hexadecanoic acid; tetradec-5-yl ester 3,5,5-trimethyl-hexanoic acid; 4,4-dimethyl-octane; tetradecyl ester undec-10-ynoic acid; 1-dotriacontanol; and benzyl 3-deuterio-α-diazopropionate.
  4. 4 . A method according to claim 3 , wherein the at least one signature compound is selected from the group consisting of methyl 2,3,5,6-tetra-O-methyl-α-D-galactofuranoside; 4-hydroximino-2,2,6,6-tetramethyl-1-piperidinyl ester 4-amino-benzoic acid; 1-tetradecanol; N-butyl-benzenesulfonamide; and hexadecanoic acid.
  5. 5 . A method according to claim 1 , wherein the at least one signature compound is selected from the group consisting of 3-ethyl-1-octene; ethyl lactate; tetramethyl succinimide; 6-methyl-2-heptanone; (E)-ethen-2-d-ol; 4-anilino-4-keto-2-phenyl-butyric acid; diisobutyl (oxybis(ethane-2,1-diyl)) dicarbonate; nickel tetracarbonyl; (E)-2-ethylene-4-methylene-5-hexenal; 3-methyl-1-butyne; (R)-5-methyl-2-(1-methylethylidene)-cyclohexanone; α-propyl-benzeneethanol; 4-methyl-1-pentene; 1,3,3-trimethyl-2-oxabicyclo[2.2.2]oct-5-ene; 2,2′-(ethene-1,2-diylbis(sulfanediyl))diethanol; 3-methyl-thiophene; tert-butyl alcohol; and 2-methoxysuccinonitrile.
  6. 6 . A method according to claim 5 , wherein the at least one signature compound is selected from the group consisting of 3-ethyl-1-octene; ethyl lactate; tetramethyl succinimide; 6-methyl-2-heptanone; (E)-ethen-2-d-ol; 4-anilino-4-keto-2-phenyl-butyric acid; diisobutyl (oxybis(ethane-2,1-diyl)) dicarbonate; nickel tetracarbonyl; (E)-2-ethylene-4-methylene-5-hexenal; 3-methyl-1-butyne; (R)-5-methyl-2-(1-methylethylidene)-cyclohexanone; α-propyl-benzeneethanol; 4-methyl-1-pentene; and 1,3,3-trimethyl-2-oxabicyclo[2.2.2]oct-5-ene.
  7. 7 . A method according to claim 6 , wherein the at least one signature compound is selected from the group consisting of 3-ethyl-1-octene; ethyl lactate; tetramethyl succinimide; 6-methyl-2-heptanone; (E)-ethen-2-d-ol; 4-anilino-4-keto-2-phenyl-butyric acid; diisobutyl (oxybis(ethane-2,1-diyl)) dicarbonate; and nickel tetracarbonyl.
  8. 8 . A method according to claim 7 , wherein the at least one signature compound is selected from the group consisting of 3-ethyl-1-octene; and ethyl lactate.
  9. 9 . A method according to claim 1 , wherein the mass spectrometry comprises TOF.
  10. 10 . A method according to claim 1 , wherein the at least one signature compound is selected from the group consisting of 1-tetradecanol; 4-methyloctan-1-ol; 3-ethyl-1-octene; ethyl lactate; 6-methyl-2-heptanone; (E)-ethen-2-d-ol; (E)-2-ethylene-4-methylene-5-hexenal; 3-methyl-1-butyne; 4-methyl-1-pentene; 3-methyl-thiophene; tert-butyl alcohol; and 4,4-dimethyl-octane.

Description

RELATED APPLICATIONS The present application is a U.S. national phase application under 35 U.S.C. § 371 of International Application No. PCT/GB2021/050104, filed on Jan. 18, 2021, and published as WO 2021/144589 A1 on Jul. 22, 2021; which claims the priority of GB Application No. 2000739.9, filed on Jan. 17, 2020. The content of each of these related applications is incorporated herein by reference in its entirety. The present invention relates to cancer, and particularly although not exclusively, to detecting volatile organic compounds (VOCs) for diagnosis of, and prognostication in, oesophagogastric cancer. The chemical analysis of volatile organic compounds (VOCs) in humans is a rapidly evolving field that has the potential to contribute to the non-invasive detection of multiple disease states. A recent systematic review on the diagnostic accuracy of VOC-based exhaled breath tests showed their potential for non-invasive cancer detection. Previous studies have reported higher concentrations of specific VOCs, within the exhaled breath, gastric content and urine of patients with oesophagogastric cancer. However, whilst several studies have suggested a role for these VOCs in important regulatory processes in oesophagogastric cancer, many of the biochemical pathways relating to their origin in humans are as yet unknown. Nevertheless, it has been postulated that the deregulated production of specific VOCs occurs directly from cancer tissues, and these VOCs may pass in to the systemic circulation with subsequent partition across the alveolar-capillary barrier. Alternatively, VOCs may be released directly by the mucosa within the aerodigestive tract. National studies have shown that about 9% of gastric and oesophageal cancers were missed during endoscopy prior to diagnosis. Accordingly, there is a need for improved techniques for diagnosing oesophagogastric cancer. The present invention arises from the inventor's work in trying to overcome the problems associated with the prior art. In a first aspect of the invention, there is provided a method for diagnosing a subject suffering from cancer, or a pre-disposition thereto, or for providing a prognosis of the subject's condition, the method comprising analysing the level of at least one signature compound in a bodily sample from a test subject and comparing this level with a reference level, wherein the reference level is the level of the at least one signature compound in an individual, or the average level for a group of individuals, wherein the individual or group of individuals do not suffer from cancer, wherein (i) an increase in the level of at least one signature compound selected from the group consisting of methyl 2,3,5,6-tetra-O-methyl-α-D-galactofuranoside; 1-tetradecanol; N-butyl-benzenesulfonamide; hexadecanoic acid; tetradec-5-yl ester 3,5,5-trimethyl-hexanoic acid; tetradecyl ester undec-10-ynoic acid; 1-dotriacontanol; 1-chloro-tetradecane; 4-methyloctan-1-ol; carbon monoxide; nickel; 2-ethyl-cyclohexylamine; 3-ethyl-1-octene; ethyl lactate; tetramethyl succinimide; 6-methyl-2-heptanone; (E)-ethen-2-d-ol; 4-anilino-4-keto-2-phenyl-butyric acid; diisobutyl (oxybis(ethane-2,1-diyl)) dicarbonate; nickel tetracarbonyl; (E)-2-ethylene-4-methylene-5-hexenal; 3-methyl-1-butyne; (R)-5-methyl-2-(1-methylethylidene)-cyclohexanone; α-propyl-benzeneethanol; 4-methyl-1-pentene; 1,3,3-trimethyl-2-oxabicyclo[2.2.2]oct-5-ene; 2,2′-(ethene-1,2-diylbis(sulfanediyl))diethanol; 3-methyl-thiophene; butanal; tert-butyl alcohol; and 2-methoxysuccinonitrile, or an analogue or derivative thereof, in the bodily sample from the test subject, compared to the reference, and/or (ii) a decrease in the level of at least one signature compound selected from the group consisting of 4-hydroximino-2,2,6,6-tetramethyl-1-piperidinyl ester 4-amino-benzoic acid; 4,4-dimethyl-octane; benzyl 3-deuterio-α-diazopropionate; and 1-methylethyl ester formic acid, or an analogue or derivative thereof, in the bodily sample from the test subject, compared to the reference, suggests that the subject is suffering from cancer, or has a pre-disposition thereto, or provides a negative prognosis of the subject's condition. In a second aspect, there is provided a method for determining the efficacy of a treatment a subject suffering from cancer, the method comprising analysing the level of at least one signature compound in a bodily sample from a test subject and comparing this level with a reference level, wherein the reference level is the level of the at least one signature compound in a sample taken from the subject previously, wherein (i) a decrease in the level of at least one signature compound selected from the group consisting of methyl 2,3,5,6-tetra-O-methyl-α-D-galactofuranoside; 1-tetradecanol; N-butyl-benzenesulfonamide; hexadecanoic acid; tetradec-5-yl ester 3,5,5-trimethyl-hexanoic acid; tetradecyl ester undec-10-ynoic acid; 1-dotriacontanol; 1-chloro-tetradecane; 4-methyloctan-1-ol; carbon