Dual function markers for diagnostics and therapeutics for upper gastrointestinal tract precancer
OwnerWa Xian, Frank McKeon +2inventors
InventorsWa Xian, Frank McKeon, Matthew Vincent, Khek Yu Ho
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Abstract
The invention described herein relates to the detection, diagnosis, and treatment of intestinal metaplasias that develop to esophageal, gastric, and pancreatic adenocarcinoma. The stem cells and differentiated cells of these intestinal metaplasias show high expression of CDH17 as well as other proteins. The invention also includes a clonal population of Barrett's esophagus stem cells as well as the stem cells of the surrounding normal epithelia and methods of using them for the detection, diagnosis, and treatment of Barrett's esophagus.
Claims101
A composition comprising a clonal population of stem cells isolated from an esophagus of a subject with Barrett's esophagus, wherein the stem cells differentiate into Barrett's epithelium, wherein the stem cells are characterized as having an mRNA profile wherein the amount of one or more of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4 mRNA are each in the range of 5 to 50 percent of the amount of actin mRNA in the stem cell.
A purified cell preparation comprising Barrett's esophagus (BE) stem cells, wherein the BE stem cells differentiate into columnar epithelial cells and are characterized as having an mRNA profile wherein the amount of one or more of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4 mRNA are each in the range of 5 to 50 percent of the amount of actin mRNA in the stem cell.
An isolated Barrett's esophagus (BE) stem cell capable of producing columnar epithelial cells, which BE stem cell is characterized as having an mRNA profile wherein the amount of one or more of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4 mRNA are each in the range of 5 to 50 percent of the amount of actin mRNA in the stem cell.
A method of screening for an agent which may be used to treat or prevent the occurrence of Barrett's esophagus, comprising
- a) providing BE stem cells;
- b) contacting the BE stem cells with the test agent;
- c) detecting the ability of the test agent to reduce viability, growth or differentiation of the BE stem cells;
- wherein if the test agent reduces the viability, growth or differentiation of the BE stem cells than the test agent may be effective in the treatment or prevention of Barrett's esophagus and wherein the test agent specifically binds to or reduces the expression of one or more of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4.
A method of screening for an agent effective in the detection of Barrett's esophagus comprising
- a) providing a BE stem cells;
- b) contacting the BE stem cells with the test agent;
- c) detecting the ability of the test agent to bind to the BE stem cells;
- wherein if the test agent binds to the BE stem cells, the test agent may be an agent effective in the detection of Barrett's esophagus wherein the test agent specifically binds to one or more of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4.
A method of detecting the presence of esophageal metaplasia, such as associated with Barrett's esophagus, in a patient comprising
- a) providing a detection agent that specifically binds to a BE stem cell relative to normal tissue of the esophagus and (optionally) stomach;
- b) administering the detection agent to a patient or contacting the detection agent with a biopsy therefrom;
- and
- c) detecting whether the detection agent binds to BE stem cells in the esophagus of the patient,
- wherein the detection agent specifically binds to one or more of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4.
A method for treating or preventing Barrett's esophagus and/or esophageal metaplasia in a subject in need thereof comprising administering to the subject an effective amount of an therapeutic agent that is cytotoxic or cytostatic for Barrett's Esophagus (BE) stem cells in the esophagus of the subject, or inhibits differentiation of the BE stem cells to columnar epithelium, wherein the therapeutic agent specifically binds to or reduces the expression of one or more of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4.
A method of detecting the presence of Barrett's esophagus (BE) stem cells, in a patient comprising
- a) providing a detection agent that specifically binds to a BE stem cell relative to normal tissue of the esophagus and (optionally) stomach;
- b) administering the detection agent to a patient or contacting the detection agent with a biopsy therefrom;
- and
- c) detecting whether the detection agent binds to BE stem cells in the esophagus of the patient,
- wherein the detection agent specifically binds to one or more of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4.
A method of detecting the likelihood of the presence of intestinal metaplasia (IM), in a patient comprising
- a) providing a detection agent that specifically binds to CDH17;
- b) administering the detection agent to a patient or contacting the detection agent with a biopsy therefrom;
- and
- c) detecting whether the detection agent binds to the cells in the biopsy of the patient,
- wherein if the detection agent binds to the cells in the biopsy of the patient the IM is more likely to be present in the patient.
A composition comprising a binding agent that specifically binds to a protein selected from the group consisting of CDH17, CLRN3, TM4SF4, FAM3B, NMUR2, MUC17, CEACAM7, ANXA13, SLC16A4, CD44, NPNT, PLBD1, TFF3 and REG4 attached to an imaging agent.
A method of screening for an agent which may be used to treat or prevent the occurrence of Barrett's esophagus, comprising
- a) providing BE stem cells;
- b) providing one or more of esophageal and gastric cardia stem cells;
- c) contacting the BE stem cells and one or more of esophageal and gastric cardia stem cells with the test agent;
- and
- d) detecting the ability of the test agent to reduce viability, growth or differentiation of the BE stem cells relative to one or more of esophageal and gastric cardia stem cells;
- wherein if the test agent reduces the viability, growth or differentiation of the BE stem cells relative to one or more of esophageal and gastric cardia stem cells than the test agent may be effective in the treatment or prevention of Barrett's esophagus.
A method of screening for an agent effective in the detection of Barrett's esophagus comprising
- a) providing a BE stem cells;
- b) providing one or more of esophageal and gastric cardia stem cells;
- c) contacting the BE stem cells and one or more of esophageal and gastric cardia stem cells with the test agent;
- and
- d) detecting the ability of the test agent to bind to the BE stem cells and one or more of esophageal and gastric cardia stem cells;
- wherein if the test agent binds to the BE stem cells with greater affinity than it binds to one or more of esophageal and gastric cardia stem cells, the test agent may be an agent effective in the detection of Barrett's esophagus.
Dependencies are inferred from the claim text.