Joshua Nedelisky

Introduction. Familial adenomatous polyposis (FAP) is an autosomal dominant disease resulting from a germline mutation within the adenomatous polyposis coli (APC) gene.^1,2 APC loss results in dysregulated cell proliferation via constitutive activation of the WNT/β-catenin signaling, causing prolific intestinal polyp expression and a definitive lifetime risk of colorectal cancer.^2,3,4 Intestinal stem cell (ISC) crypts have long been implicated as the primary zone of mutant tumorigenesis, but clinical therapeutics have lagged due to an incomplete understanding of mutant ISC’s mechanistic dominance within intestinal crypts.^5,6 However, a recent study demonstrated that mutant cells achieve crypt dominance regardless of environmental variables; thus mutant fixation must be obtained via paracrine signaling. While no exact mechanism was identified, this effort initiated a whirlwind of resulting trials as other researchers focused on clarifying this pathway as well as potential therapeutic targets.⁷ Methods. Paralleling organoid and mouse models co-cultures of wildtype and APC-mutants with fluorescent labels were tracked longitudinally while measuring WNT inhibition.⁸ Co-cultures were then used to identify if downstream targets could be reactivated to restore WNT pathway regulation and reduce APC-null tumorigenesis.⁹ A novel inhibitor of Phosphodiesterase-10A was then screened for potential tumorigenic suppression.¹⁰ Lastly, the TCF/LEF1 complex, a key tumorigenic initiation factor, served as the focus of a knockout experiment to identify alternative tumor suppression possibilities.¹¹ Results. APC-mutant populations demonstrated exponentially higher WNT-inhibitor secretion. When the leading WNT-inhibitor—NOTUM—was genetically nullified from consequent trials, the resulting tumorigenesis was drastically reduced.⁸ Lithium chloride exhibited WNT-inhibition reversal by preventing GSK3β’s downstream inhibition within the WNT path. When introduced to APC-null mice, the rate of tumorigenesis was reduced by over two-thirds with no detectable toxicity.⁹ Selective inhibition of Phosphodiesterase-10A served to reduce tumorigenesis via reduced cyclic-AMP energy production, which is critical for tumor production. When employed in mouse models, the novel agent resulted in a notable decrease of polyp development and no perceivable adverse impact.¹⁰ Lastly, an in-depth analysis of the TCF/LEF1 complex demonstrated that LEF1 possesses an inherent negative feedback loop that may contribute to combatting tumorigenesis.¹¹ Conclusions. While these aforementioned potentials are not yet ready for human trials, the fact remains that none of these were fully recognized just 12 months ago. Clinical application requires extensive time and effort, but recent endeavors have revitalized long-stalled efforts in pursuit of potential FAP treatments. Scientific advance continues to redefine clinical approaches, and these ongoing efforts demonstrate the potential of revolutionary impact within the FAP population.

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