Method and compositions for inhibiting tumorigenesis
First Claim
1. A method of inducing a tumor cell to undergo apoptosis comprising administering an antagonist to the SHH/GLI signaling pathway in the cell, wherein said administering results in tumor cell death and prevention from metastasis.
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Abstract
The present invention relates to compounds, small interfering RNAs and compositions and methods of inhibiting tumorigenesis using agents that inhibit the sonic hedgehog and GLI signaling pathway, including agents that inhibit GLI expression, synthesis and/or function. The present invention also relates to particular biomarkers that can be used in the diagnosis and prognosis of cancer. Methods of treating cancer, including glioblastomas, medulloblastomas, basal cell carcinomas, prostate cancer and small cell and non-small cell lung cancer are also provided using small organic compounds, siRNAs and blocking antibodies that inhibit or block the SHH/GLI pathway.
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Citations
52 Claims
- 1. A method of inducing a tumor cell to undergo apoptosis comprising administering an antagonist to the SHH/GLI signaling pathway in the cell, wherein said administering results in tumor cell death and prevention from metastasis.
- 3. A method of screening for apoptotic resistant tumor cells, comprising measuring the level of expression of a GLI protein or a nucleic acid encoding said GLI protein in said tumor cells, wherein enhanced expression of said GLI protein or nucleic acid encoding said GLI protein correlates with apoptosis resistance in said tumor cells.
- 4. A method of treating apoptotic resistant tumor cells in vivo or in vitro comprising administering an antagonist of the SHH/GLI signaling pathway to said tumor cells.
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5. A method of treating a subject suffering from a cancerous condition, wherein said condition is characterized by the presence of apoptotic resistant tumor cells, comprising administering an antagonist of the SHH/GLI signaling pathway to said subject.
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7. A method of predicting resistance of a tumor cell to chemotherapeutic agents, said method comprising measuring the level of expression of at least one GLI protein or nucleic acid encoding said at least one GLI protein in said tumor cell, whereby an increased level of expression of at least one GLI protein or nucleic acid encoding said at least one GLI protein in said tumor cell is predictive of resistance of said tumor cell to chemotherapeutic agents.
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9. A method of overcoming resistance to chemotherapeutic agents in tumor cells, comprising administering an antagonist to the SHH/GLI signaling pathway to the cell, wherein said administering results in increased sensitivity of the tumor cell to said chemotherapeutic agent and results in subsequent tumor cell death and prevention from metastasis.
- 15. A method of treating a tumor in an animal subject, said method comprising administering an antagonist of the SHH/GLI signaling pathway, wherein said administering results in induction of apoptosis in said tumor, in increased sensitivity to chemotherapeutic agents, and in prevention of metastasis of said tumor.
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20. A method of identifying a subject that is likely to have an aggressive and highly invasive form of cancer comprising:
determining the level of GLI in a tissue specimen from said subject;
wherein when the level of GLI determined is significantly elevated in tumor cells relative to that determined in benign cells of the same specimen, the animal subject is identified as being likely to have an aggressive form of cancer.- View Dependent Claims (21, 22, 23, 24)
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25. A method of identifying an animal subject that is likely to have a slow growing form of cancer comprising detecting low GLI levels in a tumor obtained from a tumor tissue sample from the subject;
- wherein when the GLI is barely detectable in the tumor tissue sample from the subject, and is comparable to the levels detected in the benign cells of the same specimen, the subject is identified as being likely to have a slow growing and non-invasive cancer.
- View Dependent Claims (28, 29, 30)
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26. A method of identifying an animal subject that is likely to have a slow growing form of lung cancer comprising detecting low GLI levels in a sample of tumorous lung tissue obtained from the subject;
- wherein when the GLI is barely detectable in the sample of tumorous lung tissue from the subject and is comparable to the levels detected in a sample obtained from non-cancerous lung tissue from a normal subject known to be free of lung cancer, the subject is identified as being likely to have a slow growing and non-invasive lung cancer.
- View Dependent Claims (27)
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31. An isolated siRNA molecule selected from the group consisting of SEQ ID NOs:
- 29, 31 and 32, wherein said siRNA molecule inhibits the proliferation of tumor cells.
- View Dependent Claims (32)
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33. An isolated nucleic acid probe specific for GLI;
- wherein said probe is used to identify GLI in a tumor sample, and wherein said probe can differentiate between highly invasive and aggressive tumors and benign tumors in a patient sample.
- View Dependent Claims (34, 35)
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36. A recombinant DNA molecule that is operatively linked to an expression control sequence;
- wherein the recombinant DNA molecule comprises a nucleic acid that encodes human GLI.
- View Dependent Claims (37, 38, 39, 40, 41, 42, 43)
Specification