Compositions and methods for treating colorectal cancer
The present invention relates to methods of treating a patient who has colorectal cancer and to methods of reducing the likelihood that a patient will develop or experience a recurrence of colorectal cancer. The methods comprise a step of introducing, to the patient, an effective amount of an agent that targets an intestinal H + -coupled di/tripeptide transporter (PepT1). Useful compositions including, for example, the tripeptide KPV, vectors encoding such peptides, and cells (e.g., bacterial cells) including them, are also within the scope of the present invention, as are kits including such compositions.
1. A method of treating a patient who has colorectal cancer with up-regulated intestinal H + -coupled di/tripeptide transporter (PepT1) expression in colon tumors relative to normal tissue, or of reducing the likelihood that a patient will develop colorectal cancer or experience a recurrence of colorectal cancer, the method comprising administering to the patient an amount of an anti-inflammatory tri-peptide effective to reduce tumor number, tumor size, or tumor burden in the patient relative to a control subject not treated by the method, reduce the likelihood that a patient will develop colorectal cancer, or experience a recurrence of the cancer,
wherein the anti-inflammatory tri-peptide is selected from the group consisting of Lys-Pro-Val (KPV), KPV stereochemical analogues, and post-translationally modified KPV at the C- and/or N-terminal, that targets PepT1,
wherein the colorectal cancer has up-regulated PepT1 expression in colon tumors relative to normal tissue.
2. The method of claim 1 , wherein the tri-peptide is the tri-peptide Lys-Pro-Val (KPV).
3. The method of claim 1 , wherein the tri-peptide is formulated for oral administration.
4. The method of claim 1 , wherein the tri-peptide is formulated for parenteral administration.
5. The method of claim 1 , further comprising a step of identifying a patient in need of treatment for colorectal cancer or a patient who has an increased risk of developing colorectal cancer or experiencing a recurrence thereof.
6. The method of claim 5 , wherein the method further comprises determining whether the level of PepT1 mRNA or protein is elevated in a biological sample from the patient.
7. The method of claim 1 , wherein the patient has colorectal cancer and the method further comprises a radiation treatment, a surgical intervention, or administering a second chemotherapeutic agent.
8. The method of claim 1 , wherein the patient has an inflammatory bowel disease (IBD) and the method further comprises administering a second agent that treats the IBD, the second agent being optionally fused or conjugated to the tri-peptide that targets the PepT1.
9. The method of claim 8 , wherein the second agent is diphenoxylate, an antibiotic, bestatin, sulfasalazine, or a corticosteroid.
10. The method of claim 1 , wherein the colorectal cancer is colitis-associated cancer.
11. The method of claim 1 , wherein the colorectal cancer is not sporadic colorectal cancer.
12. The method of claim 1 , wherein the tri-peptide affects a PepT1-dependent and nuclear factor-κB (NF-κB)-independent pathway.