Method and compositions for inhibiting tumorigenesis
First Claim
1. A method for inhibiting the synthesis and/or expression and/or activity of a GLI protein in a cell in vitro or in vivo comprising, contacting said cell with or introducing into said cell an inhibitor or antagonist of GLI synthesis and/or expression and/or activity, said inhibitor or antagonist selected from the group consisting of a small molecule inhibitor or antagonist of GLI synthesis and/or expression and/or activity, an antisense molecule or a siRNA molecule that is complementary to at least a part of the sequence of a nucleic acid encoding the GLI protein, antibodies to GLI, and agents that exhibit mimicry to GLI or antagonism to it or control over its production, said contacting or introducing resulting in inhibition of synthesis and/or expression and/or activity of the GLI protein in said cell.
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Abstract
The present invention relates to compounds, small interfering RNAs and compositions and methods of inhibiting tumorigenesis and methods of inhibiting tumor cell growth and proliferation using agents that inhibit the hedgehog and Gli signaling pathway, including agents that inhibit GLI synthesis and/or function. The present invention also relates to particular biomarkers that can be used in the diagnosis and prognosis of prostate cancer. Methods of treating cancer, including prostate 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
82 Claims
- 1. A method for inhibiting the synthesis and/or expression and/or activity of a GLI protein in a cell in vitro or in vivo comprising, contacting said cell with or introducing into said cell an inhibitor or antagonist of GLI synthesis and/or expression and/or activity, said inhibitor or antagonist selected from the group consisting of a small molecule inhibitor or antagonist of GLI synthesis and/or expression and/or activity, an antisense molecule or a siRNA molecule that is complementary to at least a part of the sequence of a nucleic acid encoding the GLI protein, antibodies to GLI, and agents that exhibit mimicry to GLI or antagonism to it or control over its production, said contacting or introducing resulting in inhibition of synthesis and/or expression and/or activity of the GLI protein in said cell.
- 24. A method of preventing and/or treating cellular debilitations, derangements and/or dysfunctions and/or hyperplastic/hyperproliferative and/or cancerous disease states in a mammal characterized by the presence and/or expression of a GLI gene or gene product, comprising administering to a mammal a therapeutically effective amount of an agent that inhibits or antagonizes the synthesis and/or expression and/or activity of a GLI molecule.
- 46. A method of inducing a tumor cell to undergo apoptosis comprising administering an inhibitor or antagonist to the SHH/GLI signaling pathway in the cell.
- 51. A method of overcoming resistance to chemotherapeutic agents in tumor cells, comprising administering an antagonist or inhibitor 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, and wherein said antagonist or inhibitor is selected from the group consisting of a small molecule inhibitor or antagonist of GLI synthesis and/or expression and/or activity, an antisense molecule or a siRNA molecule that is complementary to at least a part of the sequence of a nucleic acid encoding the GLI protein, antibodies to GLI, and agents that exhibit mimicry to GLI or antagonism to it or control over its.
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54. The method of claim 51, wherein said siRNA molecule is selected from the group consisting of the nucleic acid sequences of SEQ ID NO:
- 29, SEQ ID NO;
31 and SEQ ID NO;
32.
- 29, SEQ ID NO;
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54-1. A method for inhibiting and/or attenuating the expression of a gli gene in a mammalian cell, said method comprising:
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a) introducing into the cell an RNA having a nucleotide sequence which is substantially identical to or complementary to at least a part of the gli gene in an amount sufficient to inhibit and/or attenuate expression of a gli gene;
b) verifying inhibition and/or attenuation of expression of the gli gene; and
wherein the mammalian cell is a tumor cell or a cell obtained from tissue exhibiting hyperplasia that is characterized by the expression of at least one gli gene or gene product.
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57. The method of claim 56, wherein said gli gene is selected from the group consisting of gli1, gli2 and gli3.
- 58. The method of claim 56, wherein said RNA is a single stranded RNA (SS-RNA) or a double stranded RNA (DS-RNA) molecule.
- 64. A double stranded siRNA for inhibiting expression of a gli gene, comprising a first nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of a gli gene and a second nucleotide sequence that is complementary to said first nucleotide sequence.
- 69. A pharmaceutical composition comprising at least one inhibitor or antagonist of GLI synthesis and/or expression and/or activity and a pharmaceutically acceptable carrier.
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74. A method of identifying a subject that is likely to be suffering from a hyperproliferative condition or a cancerous condition comprising:
determining the level of at least one GLI protein or a nucleic acid encoding at least one GLI protein in a tissue specimen or in a specimen of bodily fluid from said subject;
wherein when the level of GLI protein or a nucleic acid encoding said GLI protein determined is significantly elevated in cells obtained from said tissue or bodily fluid compared to a predetermined range of normal values established from screening individuals known to be free of a hyperproliferative or cancerous condition, the animal subject is identified as being likely to have a hyperproliferative condition or a cancerous condition.- View Dependent Claims (75, 76, 77)
- 78. A method of predicting resistance of a tumor cell to chemotherapeutic agents comprising measuring the level of expression of GLI in said tumor cell, whereby an increased level of expression of GLI in said tumor cell is predictive of resistance of said tumor cell to chemotherapeutic agents.
- 81. A method of screening for apoptotic resistant tumor cells, comprising measuring the level of expression of GLI in said tumor cells, wherein enhanced expression of GLI correlates with apoptosis resistance in said tumor cells.
Specification