Methods for treating cancer
The present invention relates to methods and materials for treating an individual with KRAS-mutated cancer or a cancer in which ROCK is inhibited independently of mutated KRAS. The invention is based on the prevention or disruption of the binding of TRAIL-Receptor to its ligand, TRAIL, in vivo, for example by use of an agent that neutralizes TRAIL and/or a the TRAIL-Receptor (such TRAIL-R2) and/or diminishes TRAIL/TRAIL-Receptor activity, thereby reducing cancer cell transformation, migration and metastasis, prolonging survival of patients.
1. A method for treating an individual with a Kirsten rat sarcoma viral oncogene homologue (KRAS)-mutated cancer, or a cancer in which Rho Associated Coiled-Coil Containing Protein Kinase (ROCK) is inhibited independently of KRAS mutation, the method comprising administering to the individual a therapeutically-effective amount of an agent selected from the group consisting of:
(i) an agent that binds to and neutralises TNF-related apoptosis-inducing ligand (TRAIL), and
(ii) an agent that binds to and neutralises TRAIL-receptor 2 (TRAIL-R2).
2. The method of claim 1 , wherein the agent is a compound that prevents or inhibits TRAIL from binding to TRAIL-R2 or disrupts a TRAIL/TRAIL-R2 complex resulting from such binding.
3. The method of claim 1 , wherein the agent is a compound that binds to and neutralises TRAIL-R2.
4. The method according to claim 3 , wherein the compound is an antibody or fragment thereof that binds to and neutralises TRAIL-R2.
5. The method of claim 1 , wherein the agent is a compound that binds to and neutralises TRAIL.
6. The method of claim 5 , wherein the compound is an antibody or fragment thereof that binds to and neutralises TRAIL.
7. The method of claim 5 , wherein the agent is a fusion protein comprising an amino acid sequence selected from the list consisting of:
(i) the amino acid sequence of SEQ ID NO: 15;
(ii) the amino acid sequence of SEQ ID NO: 15 lacking the leader peptide:
MEQRGQNAPAASGARKRHGPGPREARGARPGPRVPKTLVLVVAAVLLLVSAESAL (amino acids 1-55); and
(iii) the amino acid sequence of SEQ ID NO: 15 lacking the leader peptide:
MEQRGQNAPAASGARKRHGPGPREARGARPGPRVPKTLVLVVAAVLLLVSAESAL (amino acids 1-55) and further lacking up to 5 amino acids from the N-terminus.
8. The method of claim 1 , wherein said method inhibits or results in inhibition of Rac1 activity.
9. The method of claim 1 , wherein said method inhibits or prevents activation of Rac1 by TRAIL and/or TRAIL-R2 in the KRAS-mutated cancer or cancer in which ROCK is inhibited independently of KRAS mutation.
10. The method of claim 1 , the method comprising the steps of
(i) selecting the individual by identifying the presence of at least one mutation in the KRAS gene in a sample from the individual, and
(ii) administering a therapeutically effective amount of the agent.
11. The method of claim 10 , wherein the individual suffers from a KRAS-mutated cancer, wherein a KRAS gene in the individual is mutated, wherein the mutation in the KRAS gene is selected from Gly12Asp, Gly12Val, Gly13Asp, Gly12Cys, Gly12Ser, Gly12Ala and Gly12Arg, or selected from 12D, 12V, 12C, 12A, 12S, 12R, 12F, 13D, 13C, 13R, 13S, 13A, 13V, 131, 61H, 61L, 61R, 61K, 61E and 61P.
12. The method of claim 1 , wherein said cancer is a human cancer selected from the list consisting of: pancreatic cancer, colorectal cancer, lung cancer, breast cancer, endometrial cancer, cervical cancer, liver cancer, myeloid leukemia, cholangiocarcinoma and bladder cancer.
13. The method of claim 1 , wherein the agent is administered in combination with a second therapeutic agent.
14. The method of claim 1 , wherein the cancer in which ROCK is inhibited independently of KRAS mutation is one which is associated with aberrant signalling in a pathway selected from: Src, FAK, BRAF, Raf-1, Notch3.