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1. WO2006102111 - BIOMARKER FOR SENSITIVITY TO MTOR INHIBITOR THERAPY IN KIDNEY CANCER

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[ EN ]
What is claimed is:

1. A method for identifying a mammalian tumor cell that is likely to respond, or is responsive to an mTOR polypeptide inhibitor, the method comprising examining the mammalian tumor cell for:
an at least 50% decrease in the expression of the Von Hippel Undau (FHL) tumor suppressor protein (SEQ ID NO: 1) in the mammalian tumor cell as compared to a control cell of the same cellular lineage as the mammalian tumor cell;
wherein an at least 50% decrease in the expression of the Von Hippel Undau (VHLJ) tumor suppressor protein identifies the mammalian tumor cell as likely to respond or responsive to an mTOR polypeptide inhibitor.

2. The method of claim 1, wherein the mammalian tumor cell is a kidney cell.

3. The method of claim 1, wherein the expression of Von Hippel Undau (VHU) tumor suppressor protein (SEQ ID NO: 1) is examined using an antibody that binds the Hippel Undau (VHLJ) tumor suppressor protein.

4. The method of claim 1, wherein a decrease in the expression of the Von Hippel Undau (FHL) tumor suppressor protein (SEQ ID NO: 1) is examined by a method comprising using F-18 fluorodeoxyglucose-positron emission tomography.

5. The method of claim 1, wherein a decrease in the expression of the Von Hippel Undau (VHL) tumor suppressor protein is examined by a method comprising observing an at least 10% increase in the level of HIF-lα (SEQ ID NO: 2) or HIF-2 α (SEQ ID NO: 3) polypeptide in the mammalian tumor cell as compared to a control cell of the same cellular lineage as the mammalian tumor cell.

6. The method of claim 1, wherein a decrease in the expression of the Von Hippel Undau (VHL) tumor suppressor protein (SEQ ID NO: 1) is examined by a method comprising observing an at least 50% decrease in the expression of mRNA encoding the Von HippelJJndau (FHL) tumor suppressor protein (SEQ ID NO: 1).

7. The method of claim 6, wherein the method uses a polynucleotide that hybridizes to mRNA encoding the Von Hippel Undau (P7HL) tumor suppressor protein (SEQ ID

NO: 1).

8. The method of claim 7, wherein the method comprises polymerase chain reaction (PCR) method or a Northern blot method.

9. The method of claim 1, wherein the mTOR inhibitor is rapamycin, SDZ-RAD, CCI-779, RAD 001, or AP23573.

10. A method for identifying a mammalian tumor cell that is likely to respond, or is responsive to an mTOR polypeptide inhibitor, the method comprising examining the mammalian tumor cell for:
expression of a Von Hippel Undau (VHL) tumor suppressor protein (SEQ ID NO: 1) having a deletion, substitution or insertion mutation;
wherein a deletion, substitution or insertion mutation in the Von Hippel Undau (VHD) tumor suppressor protein identifies the mammalian tumor cell as likely to respond or responsive to an mTOR inhibitor.

11. The method of claim 10, wherein the mammalian tumor cell is a kidney cell.

12. The method of claim 10, wherein the method comprises using a polynucleotide that hybridizes to mRNA encoding the Von Hippel Undau (VHU) tumor suppressor protein (SEQ ID NO: 1).

13. The method of claim 12, wherein the method comprises polymerase chain reaction (PCR) method.

14. The method of claim 10, wherein a deletion, substitution or insertion mutation in the Von Hippel Undau (FHL) tumor suppressor protein (SEQ ID NO: 1) is examined by a method comprising observing an at least 10% increase in the level of HIF-I α (SEQ ID NO: 2) or HIF-2 α (SEQ ID NO: 3) polypeptide in the mammalian tumor cell as compared to a control cell of the same cellular lineage as the mammalian tumor cell.

15. The method of claim 10, wherein the mTOR inhibitor is rapamycin, SDZ-RAD, CCI-779, RAD 001, or AP23573.

16. A method of monitoring the efficacy of an mTOR polypeptide inhibitor in the treatment of a mammalian tumor having a decrease in the expression of the Von Hippel Undau (VtIQ tumor suppressor protein (SEQ ID NO: 1), the method comprising examining cells in a biological sample for:
an at least 10% amount decrease in HIF-I α (SEQ ID NO: 2) and/or HIF-2 α

(SEQ ID NO: 3) polypeptide levels in a test cell from the mammalian tumor that has been exposed to the mTOR polypeptide inhibitor as compared to a cell from the mammalian tumor that has not been exposed to the mTOR polypeptide inhibitor;
wherein an at least 10% amount decrease in HIF- lα (SEQ ID NO: 2) and/ or HIF-2 α (SEQ ID NO: 3) polypeptide levels in the test cell provides evidence that the mTOR polypeptide inhibitor is efficacious in the treatment of the mammalian tumor.

17. The method of claim 16, wherein the mammalian tumor cell is a kidney cell.

18. The method of claim 16, wherein the method comprises using F-18 fluorodeoxyglucose-positron emission tomography.

19. The method of claim 16, wherein the method comprises using an antibody that binds a HIF-lα (SEQ ID NO: 2) or HIF-2 α (SEQ ID NO: 3) polypeptide.

20. The method of claim 16, wherein the mTOR inhibitor is rapamycin, SDZ-RAD, CCI-779, RAD 001, or AP23573.