Compositions and methods for altering Wnt autocrine signaling
View Patent ↗The present invention relates to compounds and methods for treating cancers in which the autocrine Wnt canonical signaling pathway is activated. In particular, there is provided a method for inhibiting growth of a tumor cell or sensitizing a cancer cell to treatment by contacting such a tumor cell with a compound that alters Wnt signaling. The compound that alters Wnt signaling can be a Wnt antagonist, a Wnt receptor antagonist, or a combination thereof.
1. A method for inhibiting growth of a tumor cell, which tumor cell has active autocrine Wnt signaling and is selected from the group consisting of breast cancer cell, ovarian cancer cell, and Non-Small Cell Lung Carcinoma (NSCLC) cell, comprising contacting said tumor cell with a Wnt receptor antagonist, wherein the Wnt receptor antagonist inhibits said autocrine Wnt signaling.
2. The method of claim 1 , wherein the Wnt receptor antagonist is an antisense RNA or an siRNA.
3. The method of claim 1 , wherein the Wnt receptor antagonist is Dickkopf-1 (DKKI).
4. The method of claim 2 , wherein the Wnt receptor antagonist is an siRNA specific for low density lipoprotein receptor-related protein 5 (LRP5) or lipoprotein receptor-related protein 6 (LRP6).
5. The method according to any one of claim 1 , 2 , 3 , or 4 wherein the Wnt receptor antagonist induces or enhances apoptosis in said tumor cell.
6. The method of claim 1 wherein the tumor cell is an ovarian cancer cell.
7. The method of claim 1 , wherein the tumor cell is a breast cancer cell.
8. The method of claim 1 , further comprising contacting the tumor cell with a chemotherapeutic agent.
9. The method of claim 1 , further comprising contacting the tumor cell with radiation.
10. The method of claim 1 wherein the inhibited Wnt signaling is detected as a reduction in uncomplexed β-catenin levels.
11. A method for sensitizing a tumor cell to a treatment, which tumor cell has active autocrine Wnt signaling and is selected from the group consisting of breast cancer cell, ovarian cancer cell, and Non-Small Cell Lung Carcinoma (NSCLC) cell, comprising contacting said tumor cell with a Wnt receptor antagonist, wherein the Wnt receptor antagonist inhibits said autocrine Wnt signaling.
12. The method of claim 11 wherein the Wnt receptor antagonist is an antisense RNA or an siRNA.
13. The method of claim 11 wherein the Wnt receptor antagonist is Dickkopf-1 (DKKI).
14. The method of claim 12 , wherein the Wnt receptor antagonist is an siRNA specific for low density lipoprotein receptor-related protein 5 (LRP5) or lipoprotein receptor-related protein 6 (LRP6).
15. The method according to anyone of claims 11 , 12 , 13 , or 14 wherein the Wnt receptor antagonist induces or enhances apoptosis in said tumor cell.
16. The method of claim 11 wherein the tumor cell is an ovarian cancer cell.
17. The method of claim 11 wherein the tumor cell is a breast cancer cell.
18. The method of claim 11 , wherein the treatment is a chemotherapy.
19. The method of claim 11 , wherein the treatment is a radiation therapy.
20. The method of claim 11 , wherein the inhibited Wnt signaling is detected as a reduction in uncomplexed β-catenin levels.
21. The method of claim 1 or claim 11 wherein the Wnt receptor antagonist is formulated as a pharmaceutical composition, comprising the Wnt receptor antagonist and a pharmaceutically acceptable carrier or excipient.