Human Notch Receptor Mutations and Their Use
AssigneeOncoMed Pharmaceuticals, Inc.
InventorsJennifer Anne Cain, Min Wang, Ann M. Kapoun, Timothy C. Hoey
Life of this patent
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Abstract
The present invention provides the identification and characterization of NOTCH mutations associated with enhanced receptor signaling. The present invention provides methods and kits for using the same. The present invention further provides methods of treating cancer in a patient having a solid tumor, wherein the solid tumor cells comprise an elevated level of NOTCH ICD.
Claims31
A method of identifying solid tumor cells that exhibit increased NOTCH receptor signaling, comprising identifying whether said cells contain a mutation in the proline, glutamate, serine, threonine-rich (PEST) domain of a human NOTCH receptor or in the TAD domain of human NOTCH1, wherein said solid tumor cells are selected from the group consisting of:
- a lung tumor, a glioma, a gastrointestinal tumor, a renal tumor, an ovarian tumor, a liver tumor, a colorectal tumor, an endometrial tumor, kidney tumor, prostate tumor, thyroid tumor, neuroblastoma, pancreatic tumor, glioblastoma multiforme, cervical tumor, stomach tumor, bladder tumor, hepatoma, breast tumor, colon tumor, melanoma, biliary tract tumor, and head and neck tumor.
A method for determining whether a patient diagnosed with cancer should be administered a NOTCH inhibitor, comprising:
- (a) determining whether tumor cells from said patient contain an activating mutation of the PEST domain or the TAD domain of a human NOTCH receptor, wherein the presence of the mutation is predictive of said patient having a favorable response to treatment with a NOTCH inhibitor;
- and/or
- (b) determining the level of NOTCH ICD in solid tumor cells from said patient, wherein a level of NOTCH ICD above a reference level is predictive of said patient having a favorable response to treatment with a NOTCH inhibitor.
5-6. (canceled)
A method of treating cancer in a patient having a solid tumor comprising administering to said patient a therapeutically effective amount of a NOTCH inhibitor, wherein:
- (a) at least one of the solid tumor cells in said patient comprises an activating mutation in the human NOTCH1 or NOTCH3 gene;
- and/or
- (b) the solid tumor cells in said patient comprise NOTCH ICD at a level above a reference level.
9-10. (canceled)
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22-25. (canceled)
(canceled)
An isolated polynucleotide encoding a mutant human NOTCH1 or NOTCH3 receptor, wherein said polynucleotide comprises
- a) a deletion at nucleotide 7279 of the human NOTCH1 gene;
- b) a guanine (G) deletion at nucleotide 7279 of the human NOTCH1 gene;
- c) an insertion at position 6622 of the human NOTCH3 gene;
- d) a cytosine (C) insertion at position 6622 of the human NOTCH3 gene;
- e) an insertion at position 6096 of the human NOTCH3 gene;
- f) a cytosine (C) insertion at position 6096 of the human NOTCH3 gene;
- g) a substitution at position 6733 of the human NOTCH1 gene;
- h) an adenine (A) or cytosine (C) at position 6733 of the human NOTCH1 gene;
- i) a substitution at position 6788 of the human NOTCH1 gene;
- and/or
- j) an adenine (A) at position 6788 of the human NOTCH1 gene.
(canceled)
Dependencies are inferred from the claim text.