Compositions and methods for treating colorectal cancer
Inventors
Assignees
Georgia State University Research Foundation Inc • US Department of Veterans Affairs
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Publication Number
US-11040082-B2
Publication Date
2021-06-22
Expiration Date
2035-08-06
Abstract
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.
Core Innovation
The invention relates to methods for treating patients who have colorectal cancer or for reducing the likelihood of development or recurrence of colorectal cancer by administering an effective amount of an agent that targets an intestinal H+-coupled di/tripeptide transporter (PepT1). The invention further includes pharmaceutical compositions comprising a first agent that targets PepT1 and a second agent that treats inflammatory bowel disease or colorectal cancer, which may be administered separately or joined in various formulations. Kits comprising such compositions and instructions for use are also encompassed.
The problem addressed arises from the altered expression of PepT1 in the colon under pathological conditions. While PepT1 is primarily expressed in the small intestine under normal conditions, its expression is upregulated in colonic tissues during chronic inflammation such as inflammatory bowel disease (IBD) and in colorectal cancer. This upregulation can lead to increased transport and interaction with bacterial peptides, triggering pro-inflammatory pathways and exacerbating colitis and tumorigenesis. There is a need for effective therapies that target PepT1 to treat colorectal cancer and to reduce tumor burden and inflammation associated with such disease.
Claims Coverage
The claims include one independent claim focusing on a method of treating colorectal cancer or reducing its recurrence by administering an anti-inflammatory tri-peptide that targets PepT1, detailing various formulation and combination aspects.
Method of treating colorectal cancer with an anti-inflammatory tri-peptide targeting PepT1
Administering to a patient with colorectal cancer exhibiting upregulated PepT1 expression in tumors an amount of an anti-inflammatory tri-peptide effective to reduce tumor number, size, or burden or reduce the risk of cancer development or recurrence. The tri-peptide is selected from Lys-Pro-Val (KPV), its stereochemical analogues, or post-translationally modified KPV at the termini, targeting PepT1.
Formulation and administration routes of the tri-peptide
The tri-peptide can be formulated for oral or parenteral administration to the patient.
Patient identification and diagnostic evaluation
Including a step of identifying a patient in need of treatment or at increased risk for colorectal cancer, optionally by determining elevated PepT1 mRNA or protein levels in a biological sample.
Combination treatments with other therapies
Performing additional treatments such as radiation, surgical intervention, or administering distinct chemotherapeutic agents alongside the tri-peptide. Also, co-administering a second agent for inflammatory bowel disease, optionally fused or conjugated to the tri-peptide.
Applicability to colitis-associated colorectal cancer and related pathways
Targeting colorectal cancers that show colitis association rather than sporadic origins, with the tri-peptide affecting pathways that are PepT1-dependent but nuclear factor-κB (NF-κB)-independent.
The claims collectively cover a therapeutic approach for colorectal cancer involving administering specific PepT1-targeting anti-inflammatory tri-peptides, their formulation, patient selection methods, and combination with other anti-cancer or anti-inflammatory treatments, addressing cancers with upregulated PepT1 expression and associated immune signaling pathways.
Stated Advantages
Targeting PepT1 can reduce tumor number, size, and overall tumor burden in colorectal cancer patients.
The anti-inflammatory tri-peptide KPV can decrease colonic epithelial cell proliferation and reduce inflammation linked to colorectal cancer.
PepT1 upregulation in colon cancer provides a selective target for therapeutic delivery of peptides and drugs.
Using agents that target PepT1 can decrease the risk of colorectal cancer recurrence and may attenuate colitis-associated carcinogenesis.
Documented Applications
Treatment of patients who have colorectal cancer including colitis-associated colorectal cancer through administration of agents targeting PepT1.
Reducing the likelihood that a patient will develop colorectal cancer or experience recurrence by administering PepT1-targeting agents.
Use of anti-inflammatory tri-peptides such as KPV in formulations for oral or parenteral administration to treat colorectal cancer and inflammatory bowel disease.
Combination therapy with PepT1-targeting agents and chemotherapeutic agents, radiation, or surgical intervention for colorectal cancer.
Formulation of kits containing PepT1-targeting agents and instructions for treatment of colorectal cancer or inflammatory bowel disease.
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