Two Breakthrough Studies Advance Personalized Therapies for Familial Adenomatous Polyposis
SCRM supported research: Personalized Therapies for Familial Adenomatous Polyposis
In two pioneering studies published in Cancer Gene Therapy in July 2025, researchers Aline Habib, Rose Mamistvalov, Mira Malcov, and principal investigator Prof. Dalit Ben-Yosef from Tel Aviv Sourasky Medical Center and Tel Aviv University have advanced the understanding of familial adenomatous polyposis (FAP) and identified new avenues for personalized treatment of this hereditary colorectal cancer syndrome.
Prof. Dalit Ben-Yosef
In the first study, the team used human embryonic stem cell–derived colon organoids from FAP patients with distinct APC gene mutations to explore mutation-specific disease mechanisms. They discovered that certain truncating mutations (FAP1) led to overactivation of the mTOR pathway, which impaired normal organoid differentiation. Treatment with the mTOR inhibitor rapamycin successfully restored mature organoid formation in these cases, but not in mutations lacking mTOR activation—highlighting a precision medicine opportunity for a subset of patients.
In the second study, the same group applied CRISPR/Cas9 gene editing to correct APC mutations in patient-derived organoids. Editing two severe mutations (FAP1 and FAP2) fully restored the organoids’ ability to develop into complex, healthy colon tissue. Using AlphaFold2 structural modeling, the researchers revealed that truncated APC proteins from these mutations form abnormal, highly stable heterodimers with the normal APC protein, disrupting its tumor-suppressive function through a dominant-negative effect.
Together, these findings strengthen the genotype–phenotype correlation in FAP and demonstrate how patient-specific organoid models can serve as powerful platforms for both drug testing and gene therapy. By integrating pharmacological and genetic correction strategies, the research opens new possibilities for preventing colorectal cancer in genetically predisposed individuals.
Read the full studies:
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