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Combined Treatment with a WNT Inhibitor and the NSAID Sulindac Reduces Colon Adenoma Burden in Mice with Truncated
Maree C Faux1,2,3, Janet Weinstock1,2,4, Sophia Gogos1,2
1Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Abstract:
Adenomatous polyposis coli (APC) truncations occur in many colorectal cancers and are often associated with immune infiltration. The aim of this study was to determine whether a combination of Wnt inhibition with anti-inflammatory (sulindac) and/or proapototic (ABT263) drugs can reduce colon adenomas. Apc min/+ and doublecortin-like kinase 1 (Dclk1)Cre/+ ;Apc fl/fl mice were exposed to dextran sulphate sodium (DSS) in their drinking water to promote the formation of colon adenomas. Mice were then treated with either a Wnt-signaling antagonist pyrvinium pamoate (PP), an anti-inflammatory agent sulindac or proapoptotic compound ABT263 or a combination of PP+ABT263, or PP+sulindac. Colon adenoma frequency, size, and T-cell abundance were measured. DSS treatment resulted in significant increases in colon adenoma number (P < 0.001, n > 5) and burden in Apc min/+ (P < 0.01, n > 5) and Dclk1 Cre/+ ;Apc fl/fl (P < 0.02, n > 5) mice. There was no effect on adenomas following treatment with PP in combination with ABT263. Adenoma number and burden were reduced with PP+sulindac treatment in Dclk1 Cre/+;Apc fl/fl mice (P < 0.01, n > 17) and in Apc min/+ mice (P < 0.001, n > 7) treated with sulindac or PP+sulindac with no detectable toxicity. PP treatment of Apc min/+ mice increased the frequency of CD3+ cells in the adenomas. The combination of Wnt pathway inhibition with sulindac was more effective in Dclk1 Cre/+;Apc fl/fl mice and provides an opportunity for killing Apc-mutant colon adenoma cells, indicating a strategy for both colorectal cancer prevention and potential new treatments for patients with advanced colorectal cancer. Outcomes from the results of this study may be translatable to the clinic for management of FAP and other patients with a high risk of developing colorectal cancer.
Significance:
Colorectal cancer is one of the most common cancers worldwide with limited therapeutic options. APC and other Wnt signaling mutations occur in the majority of colorectal cancers but there are currently no Wnt inhibitors in the clinic. The combination of Wnt pathway inhibition with sulindac provides an opportunity for killing Apc-mutant colon adenoma cells and suggests a strategy for colorectal cancer prevention and new treatments for patients with advanced colorectal cancer.
Insights
Combining Wnt pathway inhibition with sulindac effectively reduced colon adenomas in mouse models of colorectal cancer. This strategy shows promise for colorectal cancer prevention and treatment in patients with Apc mutations.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Adenomatous polyposis coli (APC) truncations are common in colorectal cancer, often linked to immune infiltration.
- Wnt signaling pathway mutations, including APC, are prevalent in colorectal cancers.
- Current therapeutic options for colorectal cancer are limited, with no Wnt inhibitors approved for clinical use.
Purpose of the Study:
- To investigate the efficacy of combining Wnt inhibition with anti-inflammatory (sulindac) and/or pro-apoptotic (ABT263) drugs in reducing colon adenomas.
- To evaluate the impact of these drug combinations on adenoma frequency, size, and T-cell infiltration in mouse models.
Main Methods:
- Utilized mouse models: Apcmin/+ and Dclk1Cre/+;Apcfl/fl mice, induced for adenoma formation with dextran sulphate sodium (DSS).
- Administered treatments including Wnt antagonist pyrvinium pamoate (PP), sulindac, ABT263, and combinations (PP+ABT263, PP+sulindac).
- Assessed colon adenoma number, size, and CD3+ T-cell abundance post-treatment.
Main Results:
- DSS treatment significantly increased colon adenoma number and burden in both mouse models.
- PP combined with ABT263 showed no effect on adenomas.
- PP+sulindac significantly reduced adenoma number and burden in both Apcmin/+ and Dclk1Cre/+;Apcfl/fl mice without detectable toxicity.
- PP treatment alone increased CD3+ T-cell frequency in adenomas of Apcmin/+ mice.
Conclusions:
- The combination of Wnt pathway inhibition with sulindac is effective in reducing colon adenomas in Apc-mutant mice.
- This combination strategy demonstrates potential for colorectal cancer prevention and treatment of advanced colorectal cancer.
- Results suggest clinical translatability for managing Familial Adenomatous Polyposis (FAP) and high-risk individuals.
