RARE DISEASE
Familial adenomatous polyposis
Familial adenomatous polyposis
Familial adenomatous polyposis
Synonyms: Colorectal adenomatous polyposis, FAP, Familial polyposis coli
Synonyms: Colorectal adenomatous polyposis, FAP, Familial polyposis coli
Synonyms: Colorectal adenomatous polyposis, FAP, Familial polyposis coli
Drug discovery
25
drugs
With orphan designations
Overview
Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by APC gene mutations, characterized by hundreds to thousands of colorectal adenomas developing by adolescence. Left untreated, it carries a near 100% risk of colorectal cancer by age 40–50. Extracolonic manifestations include duodenal/ampullary polyps, desmoid tumors (10–20%), and thyroid/central nervous system cancers. Attenuated FAP (AFAP) presents with fewer polyps and later cancer onset. Genetic testing guides diagnosis and family screening [1][4][7][12].
Burden
Therapies
Prophylactic colectomy: Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is standard to prevent CRC, typically recommended by late teens [3][5][12].
Surveillance: Annual colonoscopy pre-surgery; upper endoscopy every 1–4 years for duodenal polyps [3][11][18].
Adjunctive therapies: NSAIDs (sulindac) or COX-2 inhibitors (celecoxib) for polyp regression; targeted therapy trials (e.g., EGFR inhibitors) [4][8][13].
Categories: rare gastroenterological diseases, rare genetic diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
2,546 drug discovery papers about Familial adenomatous polyposis, with 4 first-in-class and 18 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,546 drug discovery papers about Familial adenomatous polyposis, with 4 first-in-class and 18 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-04-20 | Identify CCL20 as the key immune microenvironment regulator in APC-mutation colon cancer by sc-RNA data analysis.
The inactivation of the APC gene is strongly associated with the initiation and progression of Colorectal Cancer (CRC). However, the specific role of Adenomatous Polyposis Coli (APC) inactivation in CRC development and its regulation of the Tumor Microenvironment (TME) remains poorly understood. In this study, we identified a distinctive feature of the APCm+ CRC-specific TME, characterized by an enrichment of T helper 17 (Th17) cells, T follicular helper (Tfh) cells, Germinal Center (GC) B cells, and dendritic cells (DCs), by utilizing single-cell RNA (sc-RNA) sequencing data. Notably, we discovered that a key immune regulatory gene CCL20, is upregulated in APCm+ CRC through the APC inactivation/WNT/MYC signaling pathway. The increased expression and secretion of CCL20 by APCm+ CRC epithelial cells further facilitate the recruitment of CCR6+ Th17 cells to the TME, thereby promoting the shaping of the distinct APCm+ CRC-specific TME. This work provides a comprehensive understanding of the APCm+ specific TME, and the identified key immune regulator CCL20 may present a potential immunotherapeutic strategy for the treatment of APCm+ CRC.
2025-10-01 | S6203 Regression of Duodenal Adenomatous Polyposis in Response to Combination FOLFOX/Nivolumab for the Treatment of Gastric Adenocarcinoma in a Patient With Familial Adenomatous Polyposis Syndrome
Introduction: Duodenal adenomas (DA) in Familial Adenomatous Polyposis (FAP) patients carry a lifetime cancer risk of 2%-18%. Current management involves endoscopic surveillance with Spiegelman staging and selective polypectomy. Studies have failed to identify effective preventative treatments, with scarce evidence supporting underlying mechanisms governing their development. The unique immunological microenvironment of the duodenum may hold key insights into pathogenesis and potential therapeutic targets, however immune mechanisms are largely unexplored as therapeutic targets despite emerging immunomodulatory treatments. We present a case of DA regression in an FAP patient receiving FOLFOX-nivolumab combination therapy for metastatic gastric adenocarcinoma. Case Description/Methods: A 43-year-old woman with Hashimoto thyroiditis and FAP underwent annual surveillance since 2009. History includes colectomy with ileoanal J-pouch reconstruction and ampullectomy for large ampullary adenoma. Endoscopy revealed high burden fundal gland polyps (10-50 mm) and extensive DA (5-25 mm) with low burden jejunal polyps. During 2024 surveillance, gastric ulcer biopsy confirmed moderate to poorly differentiated adenocarcinoma. Testing showed intact expression of mismatch repair proteins, PD-L1 positive, with metastases to liver and lymph nodes on PET-computed tomography. She received FOLFOX-nivolumab for 8 cycles then 5-FU-nivolumab maintenance, she has currently achieved stable disease. After 27 cycles, endoscopy showed complete gastric ulcer resolution and remarkable DA improvement (size ≤5 mm). Discussion: We observed significant DA improvement following FOLFOX-nivolumab therapy. Whether regression is attributable to FOLFOX, nivolumab, or synergistic interaction remains unclear. We identified only 2 case reports documenting DA regression with FOLFOX alone; our patient showed a more dramatic response. Additionally, reported complete colorectal adenoma regression following FOLFOX-durvalumab supports our hypothesis that immunotherapy may enhance adenoma regression. The duodenum possesses rich immunological microenvironment with abundant gut-associated lymphoid tissue, regulatory T-cells, and antigen-presenting cells, creating unique milieu where immunotherapy might exert effects. Nivolumab's PD-1 blockade may mediate local cytotoxic T-cell activity against neoplastic cells. This synergistic hypothesis is compelling given immunosurveillance's hypothesized role in preventing adenoma-to-carcinoma progression.
2024-12-10 | METTL3-VISTA axis-based combination immunotherapy for APC truncation colorectal cancer.
Although immune checkpoint blockade (ICB) therapy represents a bright spot in antitumor immunotherapy, its clinical benefits in colorectal cancer (CRC) are limited. Therefore, a new target for mediating CRC immunosuppression is urgently needed. Adenomatous polyposis coli (APC) mutations have been reported as early-stage characteristic events in CRC, but the role of truncated APC in the CRC immune microenvironment remains unclear and its clinical significance has yet to be explored. Adenocarcinoma formation in the colon of the APCMin/+ mouse model, which displays features associated with the translation of truncated APC proteins, was induced by azoxymethane/dextran sodium sulfate. Multiplexed immunohistochemical consecutive staining on single slides and flow cytometry were used to explore the activation of immune cells and the expression of the immune checkpoint V-domain immunoglobulin suppressor of T-cell activation (VISTA) in the CRC tissues of APCWT and APCMin/+ mice. The construction of truncated APC vectors and an initial subserosal graft tumor mouse model was employed to mimic the tumor microenvironment (TME) during APC mutation. Methylated RNA immunoprecipitation-quantitative PCR assays were performed to investigate the N6-methyladenosine (m6A)-dependent transcriptional regulation of hypoxia-inducible factor-1 alpha (HIF1α) by methyltransferase-like protein 3 (METTL3). Mettl3fl/fl vil1-cre+/- mice were used to demonstrate that targeting METTL3 is a mediator that mitigates the deleterious effects of the APC978∆-HIF1α axis on antitumor immunity. A chimeric VISTA humanized mouse model was used to evaluate the drug efficacy of the VISTA-targeted compound onvatilimab. We showed that APC978∆, a truncated APC protein, mediated overexpression of METTL3, resulting in m6A methylation of HIF1α messenger RNA and high expression of HIF1α. Furthermore, HIF1α promotes the migration of myeloid-derived suppressor cells to the TME by binding to the promoters of MCP-1 and MIF. In addition, HIF1α enhances the expression of the immune checkpoint VISTA on CRC cells, weakening tumor immune monitoring. We elucidate that an underappreciated function of truncated APC in CRC is its ability to drive an immunosuppressive program that boosts tumor progression. Our work could provide a new perspective for the clinical application of immunotherapy in patients with CRC resistant to ICB therapy.
2024-11-21 | Chronic pouchitis: what every gastroenterologists need to know
Background Chronic pouchitis is a complication after restorative proctocolectomy with ileal pouch-anal anastomosis in ulcerative colitis (UC) and patients with familial adenomatous polyposis. Despite medical advances, many patients develop chronic inflammation in the ileal pouch, affecting their quality of life. Objective This narrative review provides an overview of chronic pouchitis, focusing on pathogenesis, clinical presentation, diagnostics and management, highlighting the need for a multidisciplinary approach. Methods A comprehensive literature review was conducted, analysing studies on chronic pouchitis incidence, pathogenesis, diagnosis and treatment, with an emphasis on emerging therapies and personalised medicine. Results The pathogenesis of chronic pouchitis involves genetic, immunological, microbial and environmental factors. Symptoms include increased stool frequency, urgency and abdominal pain. Diagnosis relies on clinical evaluation, endoscopy and histology. Management includes antibiotics, probiotics, immunomodulators, biologics and dietary interventions. Emerging therapies like anti-TNFα monoclonal antibodies, vedolizumab, ustekinumab and small molecules show promise for refractory cases. Conclusion Effective chronic pouchitis management requires a personalised approach. Treatment aims to alleviate symptoms and prevent recurrence. Chronic pouchitis can severely impact on a patient’s quality of life, and therefore surgical options remain a valuable alternative for those not responding to medical therapy. Ongoing research and interdisciplinary collaboration are essential to improve patient outcomes.
2024-05-25 | Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D.
The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options.
gene therapies
2026-09-11 | In vitro and in vivo studies on the impact of the familial adenomatous polyposis heterogeneous mutation MUC20-S671C on colorectal carcinogenesis and progression.
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer (CRC). We performed genetic testing on nine FAP patients and identified a recurrent mutation at the 671st site of the MUC20 gene-MUC20-S671C. This mutation has a detection frequency of zero in the 1000 Genomes Project database. Previous studies have demonstrated that MUC20 can promote CRC progression through epithelial-mesenchymal transition (EMT). We conducted a series of experiments to analyze the impact of this mutation on CRC cells, aiming to infer its potential role and significance in CRC patients. We introduced the MUC20-S671C mutation into the CRC SW480 cell line using the CRISPR-Cas9 technique and established a stable cell line carrying this mutation. We then conducted various experiments to assess the effects of this mutation. The Transwell assay was used to evaluate cell invasion and migration. We also examined cell proliferation, cell cycle progression, and apoptosis rate. Furthermore, we tested the tumorigenic ability of these cells in NOD-scid IL2Rγ[null] (NSG) mice. Additionally, transcriptome sequencing was performed on both cell lines and mouse tumor tissues to obtain molecular regulatory network data, and key molecules were further validated. The results of Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assays indicated that the proliferation ability of mutant cells was significantly reduced. The Transwell assay demonstrated a marked decline in the invasion and migration capabilities of mutant cells. Flow cytometry analysis revealed that the mutation increased the apoptosis rate of CRC cells and might have caused S-phase arrest. The tumor formation assay in nude mice showed that the tumorigenic ability of mutant cells was weakened. Transcriptome sequencing of both the cells and tumor tissues suggested that the mutation altered the expression of apoptosis- and cell cycle-related molecules and also affected EMT. Further experiments confirmed that key molecules involved in the EMT process, such as E-cadherin, were upregulated, while Vimentin, MMP9, and MMP14 were significantly downregulated, indicating that the mutation weakened the EMT capability of CRC cells. We have identified a novel mutation, MUC20-S671C, in patients with FAP. Our study demonstrates that this mutation exerts its tumor-suppressive effect by reversing the EMT process.
2025-12-04 | Advances in research on congenital and hereditary intestinal diseases: From molecular mechanisms to precision medicine.
Congenital and hereditary intestinal diseases are a group of major disorders caused by gene mutations or embryonic developmental anomalies and are characterized by diverse clinical manifestations and complex management. This review systematically explores the molecular genetic basis and pathogenic mechanisms of common intestinal diseases, including familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), Lynch syndrome (LS), Hirschsprung disease (HSCR), congenital short bowel syndrome (SBS), and cystic fibrosis (CF). It focuses on cross-disease commonalities in translational research frontiers such as gene-environment interactions, organoid-based precision medicine, the immune microenvironment, and metabolic and microbiome remodeling. The review also forecasts future directions, including gene therapy, targeted drugs, and other cutting-edge research advances.
2025-07-23 | Predicting colorectal cancer risk in FAP patients using patient-specific organoids.
Colorectal cancer (CRC), a prevalent global cancer, is mostly sporadic. Familial adenomatous polyposis (FAP), arises from APC germline mutations. We established FAP-human embryonic stem cell lines (FAP1,2,3) with distinct APC mutations and differentiated them into colon organoids to study cancer development. While normal expressing APC lines and FAP3 formed complex organoids, FAP1,2 failed to differentiate. By utilizing CRISPR editing to correct APC mutations in FAP1,2, we succeeded in restoring their ability to form complex organoids expressing colon gene (CDX2). To elucidate the truncated APC proteins' mechanism of action, we used AlphaFold2 algorithm to model their secondary structures. Structural analysis of the normal phenotype organoids (normal and FAP3) revealed 5-6 salt bridges only at the N-terminal oligomerization domain. In contrast, analysis of disease organoids-phenotype (FAP1,2) revealed a production of novel salt bridges, likely act in a dominant-negative manner on full-length APC, disrupting APC function and promoting tumorigenesis. Our study underscores the critical role of germline APC mutations in colon cancer initiation, revealing how specific mutations influence disease severity. By deciphering APC structure-function relationships, we illuminate potential therapies and the molecular underpinnings of APC mutations that precede clinical presentation.
2023-05-03 | LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice.
Amino acid transporters play an important role in supplying nutrition to cells and are associated with cell proliferation. L-type amino acid transporter 1 (LAT1) is highly expressed in many types of cancers and promotes tumor growth; however, how LAT1 affects tumor development is not fully understood. To investigate the role of LAT1 in intestinal tumorigenesis, mice carrying LAT1 floxed alleles that also expressed Cre recombinase from the promoter of gene encoding Villin were crossed to an ApcMin/+ background (LAT1fl/fl; vil-cre; ApcMin/+), which were subject to analysis; organoids derived from those mice were also analyzed. This study showed that LAT1 was constitutively expressed in normal crypt base cells, and its conditional deletion in the intestinal epithelium resulted in fewer Paneth cells. LAT1 deletion reduced tumor size and number in the small intestine of ApcMin/+ mice. Organoids derived from LAT1-deleted ApcMin/+ intestinal crypts displayed fewer spherical organoids with reduced Wnt/β-catenin target gene expression, suggesting a low tumor-initiation capacity. Wnt3 expression was decreased in the absence of LAT1 in the intestinal epithelium, suggesting that loss of Paneth cells due to LAT1 deficiency reduced the risk of tumor initiation by decreasing Wnt3 production. LAT1 affects intestinal tumor development in a cell-extrinsic manner through reduced Wnt3 expression in Paneth cells. Our findings may partly explain how nutrient availability can affect the risk of tumor development in the intestines.
2021-12-13 | A truncated protein product of the germline variant of the DUOX2 gene leads to adenomatous polyposis.
In some patients with adenomatous polyposis, an identifiable pathogenic variant of known associated genes cannot be found. Researchers have studied this for decades; however, few new genes have been identified. Adenomatous polyposis coli (APC) negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification. Then, whole-exome sequencing (WES) was used to determine candidate genes harboring pathogenic variants. Functional experiments were performed to explore their effects. Subsequently, using Sanger sequencing, we found other polyposis patients carrying variants of the DUOX2 gene, encoding dual oxidase 2, and analyzed them. From 88 patients with suspected familial adenomatous polyposis, 25 unrelated APC negative polyposis patients were identified. Based on the WES results of 3 patients and 2 healthy relatives from a family, the germline nonsense variant (c.1588A>T; p.K530X) of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis. During functional experiments, we observed that the truncated protein, hDuox2 K530, was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant, causing abnormal cell proliferation through endoplasmic reticulum (ER) retention. In addition, we found two unrelated APC negative patients carrying DUOX2 missense variants (c.3329G>A, p.R1110Q; c.4027C>T, p.L1343F). Given the results of the in silico analysis, these two missense variants might exert a negative influence on the function of hDuox2. To our knowledge, this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis. With an autosomal dominant inheritance, it causes ER retention, inducing an unfolded protein response.
small molecules
2026-09-21 | Defining absolute postoperative desmoid risk in familial adenomatous polyposis according to APC genotype and family history: retrospective cohort study.
Desmoid disease is a major cause of morbidity and mortality in familial adenomatous polyposis (FAP), particularly after prophylactic colorectal surgery. Although APC genotype and family history are recognized risk factors, previous sizeable studies report relative rather than absolute risks. This study aimed to quantify absolute postoperative desmoid risk in FAP patients undergoing risk-reducing colectomy, stratified by APC genotype, and to assess the modifying effect of family history. This retrospective observational study used records from a prospectively maintained registry. Patients with an APC pathogenic variant (PV) 3' of codon 1399 were classified as high risk, and those with an APC PV 5' of (or at) codon 1399 were classified as low risk. Patients who had not undergone prophylactic colectomy, with < 5 years of postoperative follow-up, or those with a desmoid diagnosed before or at the time of surgery were excluded. Clinical records were reviewed for details of surgery, desmoid diagnosis, and family history. A positive family history was defined as a first-degree relative with genetically confirmed FAP and a diagnosis of desmoid disease (clinical and/or radiological). Among 48 high-risk patients, 30 (63%) developed desmoid, with no significant difference between colectomy and proctocolectomy (54% versus 70%, respectively; χ2 = 1.42; P = 0.233). Family history was present in 35 of the 48 patients (73%) and increased desmoid risk relative to no family history (80% versus 15%, respectively; P < 0.01). Among the 1213 low-risk patients, 154 (12.7%) developed desmoids, with no significant effect of surgical procedure (13.9% versus 12.1% for proctocolectomy and total/partial colectomy, respectively; χ² = 0.77; P = 0.380). Family history increased desmoid risk relative to no family history (30% versus 10%, respectively; P < 0.01). A family history of desmoid disease appears to be an important determinant of postoperative desmoid risk in FAP. Although APC PV 3' of codon 1399 does confer a high overall risk, this is largely confined to individuals with first-degree relatives with desmoid. In the absence of a family history, postoperative desmoid risk appeared relatively low regardless of genotype. This supports a more individualized approach to perioperative counselling and surgical decision-making in patients with FAP. In addition, these data highlight that patients with both a 3' APC PV and a positive family history are a particularly high-risk subgroup who may represent an appropriate target population for future chemoprevention trials.
2026-08-03 | Data from Phase II Trial of Encapsulated Rapamycin to Reduce Polyp Burden Associated with Familial Adenomatous Polyposis
<div>Abstract Purpose:<p>Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies.</p> Patients and Methods:<p>Thirty patients with FAP enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1—every other day, cohort 2—daily every other week, or cohort 3—daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 months. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden and change in International Society for Gastrointestinal Hereditary Tumors stage and Spigelman score at 6 and 12 months.</p> Results:<p>Twenty nine of thirty patients (97%) completed the 12-month study with predictable bioavailability. Low-grade adverse events were frequent but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 months: −39.4 % (IQR, 108.9; <i>P</i> = 0.28), −33.33 % (IQR, 90; <i>P</i> = 0.04), and −38.6 % (IQR, 88.5; <i>P</i> = 0.26), respectively. At 12 months, cohort 2 had the largest decrease median PCFB CPB and TPB: −29.3 % (IQR, 67.6; <i>P</i> = 0.37) and −26.3 % (IQR, 49.5; <i>P</i> = 0.29), respectively. Intermittent dosing cohorts (1 and 2) reduced DPB at 6 months (<i>P</i> = 0.04) and improved TPB at 12 months (<i>P</i> = 0.05) compared with daily dosing.</p> Conclusions:<p>eRapa was safe, tolerable, and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.</p></div>
2026-07-14 | DCAF13: a positive regulator of colon cancer cell proliferation via the AMER2/ Wnt/β-catenin pathway.
The Wnt/β-catenin pathway plays a critical role in colorectal cancer (CRC) development. The significance of Wnt/β-catenin in maintaining the stability of adult tissues and challenges in identifying suitable molecular targets have limited the application of targeting the Wnt/β-catenin pathway. As one of the Cullin RING Ligase 4 adapters, DNA damage-binding protein 1 (DDB1) - and CUL4 correlation factor 13 (DCAF13) appears strongly expressed in different tumors. Our findings confirm enhanced expression of DCAF13 in tissues of CRC origin and related cell. In colon cancer cells, DCAF13 regulated adenomatous polyposis coli membrane recruitment 2 (AMER2) through ubiquitination, DCAF13 deletion increased AMER2 expression, which inhibited Wnt/β-catenin activity, suppressing cell proliferation. This effect was further validated in mice with gut-specific DCAF13 knockout. The ubiquitin-proteasome system is a potential target for drug development and cancer treatment. Beta-propeller proteins, such as CRL4 adapter DCAFs, are easily targeted by drugs. DCAF-proteolysis-targeting chimeras (PROTACs) can overcome drug resistance and selectively target tumor drivers by leveraging the unique substrate specificity of the DCAF subunits. DCAF13 emerges as a promising target for CRC, acting via the DCAF13-AMER2-Wnt /β-catenin axis.
2026-07-10 | Progressive intestinal tumor cell plasticity, Myc activation, and loss of Lgr5+ tumor stem cell lineage commitment upon Wnt depletion.
Plasticity, the capability of tumor cells to go through phenotypic transitions, promotes colorectal cancer (CRC) progression and treatment resistance. Although plasticity is evident in advanced CRCs, little is known about plasticity in early-stage tumors and tumor stem cells. Here, we demonstrate that a plastic cell state (PCS) is present already in polyps from patients with familial adenomatous polyposis and in mouse intestinal adenomas, in which PCS is associated with PROX1+ tumor stem cells. We furthermore analyzed progressive plasticity upon loss of the canonical wingless-related integration site (Wnt) effector Tcf7 or Lef1 in Apc mutant mice. Deletion of either gene led to emergence of new plastic tumor cell populations, failure of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) tumor stem cell differentiation into enterocyte-like cells, enhanced Myc pathway activation, and increased tumor cell proliferation and tumorigenesis. Together, we demonstrate that PCS is associated with early CRC development and identify multiple potentially druggable mechanisms activated during progressive tumor cell plasticity.
2026-06-30 | Pelvic desmoid fibromatosis: a diagnostic and therapeutic challenge.
Pelvic desmoid fibromatosis is a rare locally aggressive benign neoplasm, typically presenting in the reproductive age group with lower abdominal pain. Extra-abdominal occurrence being predominant, the pelvic origin of the tumour makes the clinical management a multidisciplinary challenge. Previous surgeries, current or previous pregnancies, and familial adenomatous polyposis have been documented as associated risk factors. Our patient was a young woman with three previous caesarean sections, admitted with a large infiltrative lesion extending into the left pelvic sidewall up to the pelvic bone, causing ipsilateral severe hydroureteronephrosis. Malignancy was suspected due to the infiltrating nature of the lesion on imaging. Due to its proximity to the pelvic veins, preoperative embolisation of the feeding vessel was done. An exploratory laparotomy was performed by a multidisciplinary team. For this deep-seated disease, mass excision was performed along with total hysterectomy, left salpingo-oophorectomy and left ureteroneocystostomy. A part of the lesion infiltrating the presacral fascia was not removed during the primary surgery. Within 24 hours of surgery, she developed critical limb ischaemia in the left limb due to thrombosis in the ipsilateral external iliac artery. An emergency thrombo-embolectomy was performed by the vascular surgeons and thromboprophylaxis continued. Final histopathology confirmed desmoid fibromatosis. For the residual disease, the patient has been under close follow-up and is receiving targeted therapy with oral sorafenib to prevent local progression. Her follow-up imaging showed a decrease in the size of the residual disease and she is asymptomatic currently.
cell therapies
2026-06-22 | Intestinal transplantation for tumors.
Transplantation of the intestine is a vital component in the treatment of many intrabdominal tumors. This is a comprehensive review of current practice and outcome of intestinal transplantation for tumors. Most commonly described for the intrabdominal desmoid tumor, excellent survival outcomes can be attained, particularly for the more aggressive desmoid tumors associated with familial adenomatous polyposis syndrome and early referral is critical in order to avoid diffuse tumor spread which would necessitate a more complex multivisceral transplant. Currently, consensus within the intestinal transplant community lists invasive intrabdominal desmoid tumor as a primary indication for intestinal transplantation. Rare tumors such as metastatic neuroendocrine tumors confined to the abdomen, and pseudomyxoma peritonei have been associated with acceptable survival and recurrence outcomes with intestinal transplantation in carefully selected patients who would otherwise have a dismal prognosis. In addition, intestinal transplantation is an option for patients with a history of abdominal malignancy who have been rendered with intestinal failure due to surgical complications from resection of a primary tumor. Intestinal transplantation is a therapeutic option with excellent results in selected patients with intrabdominal desmoid tumors, neuroendocrine tumors and pseudomyxoma peritonei. Careful patient selection, technical expertise, and posttransplant oncologic surveillance is critical for successful long-term outcomes.
2026-06-01 | The role of endoscopic treatment for advanced duodenal adenomas in patients with familial adenomatous polyposis: a long-term single-center experience
Aims Patients with familial adenomatous polyposis (FAP) develop duodenal adenomatous polyps, whose risk of malignant progression increases with advancing Spigelman stage. However, prophylactic duodenal surgery carries substantial morbidity and mortality. This study aimed to evaluate the efficacy and safety of endoscopic treatment in FAP patients classified as Spigelman stages III-IV. Methods A retrospective analysis was conducted on patients who underwent endoscopic duodenal surveillance and treatment at a tertiary referral center between 2013 and 2025. Cold-snare polypectomy (CSP) and endoscopic mucosal resection (EMR) were the resection techniques employed. Data were collected on patient characteristics, polyp features, endoscopic procedures, histological findings, and Spigelman stage and score. Results Between 2013 and 2025, 1035 EGDs were performed in 247 patients (55% male, median age 47 years, IQR 33-57) at out center, with a median follow-up of 84 months (IQR 49-115). Duodenal non-ampullary adenomas were detected in 130 patients (52.6%). Their Spigelman stage distribution was: 31 (23.8%) stage I, 44 (33.9%) stage II, 22 (16.9%) stage III, and 33 (25.4%) stage IV. Among patients with advanced Spigelman stages, thirty-five (74% male, median age 53 years, IQR 40-60), 17 classified as stage IV and 18 as stage III, underwent endoscopic treatment for duodenal polyps. During a median follow-up of 32 months (IQR 17–90), 268 polyps were resected in 122 endoscopic procedures (57% CSP). The median polyp size was 10 mm (IQR 7-10.5), 76.5% of resected polyps were located in the descending duodenum, and 17.5% harbored high-grade dysplasia. After therapeutic work-up, 69% of patients achieved downstaging of baseline Spigelman stage (p<0.001). The median Spigelman score decreased from 8 (IQR 8–9) to 6 (IQR 5–8) (p<0.001), while the proportion of patients with high-grade dysplasia declined from 74.3% to 5.7% (p<0.001). Kaplan-Meier analysis showed median times to re-progression and re-treatment after the first endoscopic treatment of 42 and 45 months, respectively. No major adverse events occured. One patient required surgery for multiple high-grade dysplasia adenomas not amenable to endoscopic resection, and no duodenal cancer were observed during the study period. Conclusions Endoscopic treatment proved to be safe and effective in downstaging both Spigelman score/stage and histological dysplasia severity, thereby reducing the need for prophylactic surgery in FAP patients with advanced duodenal disease. Given the risk of re-progression in this setting, multiple endoscopic resections are often required to achieve long-term disease control. Publication History Article published online: 05 June 2026 © 2026. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-02-25 | Cold snare polypectomy for 10-19 mm colorectal adenomas in familial adenomatous polyposis: a prospective randomized controlled trial.
Evidence for cold snare polypectomy (CSP) in treating 10-19 mm colorectal adenomas in patients with familial adenomatous polyposis (FAP) is limited. This study compared the efficacy and safety of CSP vs. hot snare polypectomy (HSP). This prospective non-inferiority randomized controlled trial predefined a non-inferiority margin of 4%. A total of 452 colorectal adenomas (10-19 mm) from 41 FAP patients were enrolled between May 2024 and May 2025 and randomized 1:1 to CSP (n = 220) or HSP (n = 232). The primary endpoint was histological complete resection (R0). Subgroup analyses were performed by lesion size (10-15 mm vs. 16-19 mm). R0 resection rates were similar between CSP and HSP (92.3% vs. 92.7%, p = 0.76). CSP was associated with shorter procedure time (4.53 ± 1.18 vs. 6.53 ± 1.46 min, p < 0.01) and lower hospitalization costs (p < 0.01). Intra-procedural bleeding was more frequent with CSP, whereas delayed bleeding and post-polypectomy electrocoagulation syndrome were more common with HSP. At 6 months, recurrence was rare (one lesion in each group). No significant interaction by lesion size was observed. CSP is non-inferior to HSP for R0 resection of 10-19 mm colorectal adenomas in FAP patients and offers advantages in efficiency, safety and cost.
2025-12-15 | Autologous Adipose Tissue Injection as Treatment for Ileoanal Pouch-Related Fistulae.
Ileal pouch-anal anastomosis (IPAA) is a standard surgical procedure for ulcerative colitis (UC) and familial adenomatous polyposis. However, pouch-related fistulae (PRF) are a significant complication. There is no consensus on the optimal treatment for PRF. This study evaluated the effectiveness of autologous adipose tissue injection (AATI) as a treatment for PRF. Twenty-one patients with IPAA and a total of 29 PRF were treated with AATI. Patients who did not achieve healing after the first treatment were offered repeated injections. Patients were followed for a median of 16 months after AATI. Outcomes including clinical healing, treatment complications, and recurrence of PRF were registered. After a single treatment with AATI, 48% of the fistulae were clinically healed. Repeated treatments increased the healing rate to 69%. An additional 14% responded to AATI by reduced secretion from PRF. The procedure was well tolerated with minimal complications. AATI appears to be a safe, minimally invasive, and sphincter-saving treatment for PRF with promising healing rates. Further studies with larger cohorts are necessary to validate these findings.
2025-10-07 | Low‐Power Pure‐Cut Hot Snare Polypectomy for Intensive Downstaging in Familial Adenomatous Polyposis: Promise, Practicality, and Evidence Still Needed
The author declares no conflicts of interest.
other
2026-09-06 | Inhibitory effects of c-MYC degrading rLON protease on intestinal polyps in PIRC rat, a familial adenomatous polyposis model.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, accounting for approximately 10% of all cases, and is the second leading cause of cancer-related deaths in the United States. In patients with Familial Adenomatous Polyposis (FAP), APC mutations drive c-MYC overexpression, promoting metabolic and immune dysregulation that contributes to CRC development, making c-MYC a potential target for FAP-associated chemoprevention. Although no c-MYC inhibitors are currently available, recent evidence indicates that a uropathogenic E. coli protease can degrade c-MYC protein. This study evaluated recombinant LON protease (rLONP) for chemopreventive efficacy in PIRC rats, a model of FAP. Rat pups were genotyped, baseline polyp burden was established by colonoscopy, and animals were randomized to receive saline or rLONP twice daily (2.5 mg/kg, p.o.) for 2 or 4 weeks. Serum analyses showed no significant changes in liver or kidney function markers in rLONP-treated rats compared with controls. rLONP-treated male rats exhibited a ∼40% reduction in colonic polyps at both time points, and small intestinal polyp counts were also lower in treated males and females. Combined analysis demonstrated a ≥60% reduction in total intestinal polyp multiplicity after 2-4 weeks of treatment (p<0.001). Protein expression analyses of colonic polyps revealed decreased c-MYC protein levels following rLONP treatment. Immunohistochemistry further showed reduced Ki-67, Cyclin D1, and c-MYC expression in treated polyps compared with controls. Overall, rLONP was well tolerated and significantly reduced intestinal polyp burden in PIRC rats in this short-term study, supporting further long-term efficacy evaluation.
2026-06-22 | Identification, design, and in vivo proof of concept of a shared APC neoantigen delivered via a self-amplifying RNA containing virus-like nanoparticle for cancer vaccination.
Colorectal Cancer (CRC) accounts for the second highest number of cancer-related mortalities rate worldwide, and its incidence and mortality is expected to continue to increase in the coming years. Over 80% of CRC cases are caused by mutation in the Adenomatous Polyposis Coli (APC) gene, a tumor suppressor gene involved in the Wnt signaling pathway that prevents uncontrolled cell growth. Familial Adenomatous Polyposis (FAP) is a rare, inherited, pediatric disorder characterized by the development of countless adenomatous (benign) polyps in the colon and/or rectum, and over the patient's lifetime there is an almost 100% likelihood that the disorder will progress into CRC. In this study, we utilized bioinformatics to identify shared neoantigen epitopes present at the mutational cluster region (MCR) of the APC gene of multiple CRC patients, where FAP-associated mutation is typically observed. We then developed and optimized a chimeric virus-like particle (VLP) to encapsulate an saRNA replicon encoding a neoantigen construct featuring the identified mutated APC sequences inserted into a WT APC backbone. T-cell specific activation and restimulation against neoantigen peptide fragments were observed in vitro, indicating the capacity for a T-cell mediated response in vivo. Serum samples from intramuscularly-dosed BALB/c mice exhibited significant neoantigen-specific IgG titers compared against vehicle control and WT APC control mice, confirming VLP-expression of neoantigens and indicating neoantigen-specific in vivo immune activity. The significant response observed against the nanoparticle-expressed APC neoantigen serves as proof-of-concept for a saRNA-expressed cancer vaccine against APC-associated CRC.
2026-01-05 | Targeting PTPN13 with 11-amino-acid peptides of C-terminal APC prevents immune evasion of colorectal cancer.
Colorectal cancer (CRC) remains largely refractory to immune-checkpoint blockade, with adenomatous polyposis coli (APC) mutations present in 80%-90% of cases. Loss of APC was previously thought to promote tumor progression mainly through deregulated Wnt/β-catenin signaling. Here, we report that APC loss leads to inhibition of CD8+ T cell infiltration and CRC immune evasion through the dephosphorylation of signal transducers and activators of transcription 1 (STAT1) by protein tyrosine phosphatase non-receptor type 13 (PTPN13), independently of β-catenin. Peptides containing the last 11 C-terminal amino acid (aa) residues of APC (APC11) bind directly to PTPN13 to block PTPN13-STAT1 interactions and facilitate STAT1 phosphorylation, interferon regulatory factor-1 (IRF1) expression, major histocompatibility complex (MHC) class I antigen presentation, and T cell intratumoral infiltration, all of which eventually inhibit tumor progression and enhance the effects of programmed cell death 1 (PD1) blockade. Thus, we have identified a previously unknown APC/PTPN13/STAT1-dependent tumor immune-suppressive mechanism. The potent tumor-suppressing effect of combining anti-PD1 antibodies with APC11 peptides provides a compelling target and rationale for future development of anti-tumor drugs for patients with CRC.
2025-06-23 | Nuclear adenomatous polyposis coli elevates STAT1 and reduces CXCL1,2, and 3 expression and inhibits neutrophil recruitment.
Adenomatous polyposis coli (APC) mutations and chronic inflammation can each promote colon cancer. Though both mice and humans with germline APC mutations show reduced tumorigenesis if treated with anti-inflammatory agents, direct links between APC and inflammation remain incomplete. In the current study, we examine a novel role for APC in intestinal inflammation via inhibition of neutrophil-recruiting chemokines CXCL1, 2, and 3. Patients with colorectal adenocarcinoma, the majority of whom would be expected to harbor APC mutations, showed upregulated CXCL1, 2, and 3 expression at early stages of disease. APC induction in cultured human colon cells reduced levels of CXCL1 and CXCL2 proteins and CXCL1, CXCL2, and CXCL3 RNAs and increased expression of signal transducer and activator of transcription 1 (STAT1), a potential negative regulator of CXCL1 transcription. By mining published Chromatin-immunoprecipitation sequencing (ChIP-Seq) data, we found regions of the STAT1 promoter and upstream CpG island as APC-bound. Methylation-specific PCR and bisulfite sequencing each revealed decreased methylation of the STAT1 CpG island upon APC induction. Intestinal tissue explants from mice compromised for nuclear Apc (ApcmNLS/mNLS) secreted more CXCL1 and CXCL2 than wild-type explants. Conditioned media from APC-expressing cells recruited fewer neutrophils in a trans-well migration assay. In vivo, colon and ileal tissues from ApcmNLS/mNLS mice displayed more neutrophils than Apc+/+ mice. Experimental evidence from in vitro and in vivo systems validates that nuclear APC can inhibit inflammation by suppressing neutrophil-recruiting chemokines CXCL1, 2, and 3, potentially via epigenetic regulation of STAT1. These findings offer a new target for managing inflammation in inflammatory bowel disease and reveal a new mechanism by which APC loss enables cancer progression.
2025-06-13 | Enhancing cyclic peptide functionality with hydrophilic diamino acids for improved APC-Asef interaction inhibition.
Cyclic peptides inherently possess advantages in inhibiting protein-protein interactions (PPIs). However, those constructed using traditional disulfide bonds are susceptible to cleavage by disulfide isomerase or reducing environments, leading to diminished biological activity. To address this challenge, our study employed novel hydrophilic diamino acids with enhanced electronegativity to construct cyclic peptides, effectively resolving issues related to stability and aqueous solubility, thereby overcoming the limitations associated with disulfide bond-based cyclic peptides. Furthermore, we applied this diamino acid strategy to the APC-Asef PPI peptide inhibitor MAI-516. Compared to cyclic peptides constructed using traditional disulfide bonds, those generated using the diamino acid strategy exhibited enhanced aqueous solubility, stability, and inhibitory activity. This study provides an application example for the modification of novel hydrophilic diamino acids in peptide cyclization and offers an effective strategy for the development of therapeutic agents for metastatic colorectal cancer.
antibodies
2026-04-20 | Identify CCL20 as the key immune microenvironment regulator in APC-mutation colon cancer by sc-RNA data analysis.
The inactivation of the APC gene is strongly associated with the initiation and progression of Colorectal Cancer (CRC). However, the specific role of Adenomatous Polyposis Coli (APC) inactivation in CRC development and its regulation of the Tumor Microenvironment (TME) remains poorly understood. In this study, we identified a distinctive feature of the APCm+ CRC-specific TME, characterized by an enrichment of T helper 17 (Th17) cells, T follicular helper (Tfh) cells, Germinal Center (GC) B cells, and dendritic cells (DCs), by utilizing single-cell RNA (sc-RNA) sequencing data. Notably, we discovered that a key immune regulatory gene CCL20, is upregulated in APCm+ CRC through the APC inactivation/WNT/MYC signaling pathway. The increased expression and secretion of CCL20 by APCm+ CRC epithelial cells further facilitate the recruitment of CCR6+ Th17 cells to the TME, thereby promoting the shaping of the distinct APCm+ CRC-specific TME. This work provides a comprehensive understanding of the APCm+ specific TME, and the identified key immune regulator CCL20 may present a potential immunotherapeutic strategy for the treatment of APCm+ CRC.
2025-10-01 | S6203 Regression of Duodenal Adenomatous Polyposis in Response to Combination FOLFOX/Nivolumab for the Treatment of Gastric Adenocarcinoma in a Patient With Familial Adenomatous Polyposis Syndrome
Introduction: Duodenal adenomas (DA) in Familial Adenomatous Polyposis (FAP) patients carry a lifetime cancer risk of 2%-18%. Current management involves endoscopic surveillance with Spiegelman staging and selective polypectomy. Studies have failed to identify effective preventative treatments, with scarce evidence supporting underlying mechanisms governing their development. The unique immunological microenvironment of the duodenum may hold key insights into pathogenesis and potential therapeutic targets, however immune mechanisms are largely unexplored as therapeutic targets despite emerging immunomodulatory treatments. We present a case of DA regression in an FAP patient receiving FOLFOX-nivolumab combination therapy for metastatic gastric adenocarcinoma. Case Description/Methods: A 43-year-old woman with Hashimoto thyroiditis and FAP underwent annual surveillance since 2009. History includes colectomy with ileoanal J-pouch reconstruction and ampullectomy for large ampullary adenoma. Endoscopy revealed high burden fundal gland polyps (10-50 mm) and extensive DA (5-25 mm) with low burden jejunal polyps. During 2024 surveillance, gastric ulcer biopsy confirmed moderate to poorly differentiated adenocarcinoma. Testing showed intact expression of mismatch repair proteins, PD-L1 positive, with metastases to liver and lymph nodes on PET-computed tomography. She received FOLFOX-nivolumab for 8 cycles then 5-FU-nivolumab maintenance, she has currently achieved stable disease. After 27 cycles, endoscopy showed complete gastric ulcer resolution and remarkable DA improvement (size ≤5 mm). Discussion: We observed significant DA improvement following FOLFOX-nivolumab therapy. Whether regression is attributable to FOLFOX, nivolumab, or synergistic interaction remains unclear. We identified only 2 case reports documenting DA regression with FOLFOX alone; our patient showed a more dramatic response. Additionally, reported complete colorectal adenoma regression following FOLFOX-durvalumab supports our hypothesis that immunotherapy may enhance adenoma regression. The duodenum possesses rich immunological microenvironment with abundant gut-associated lymphoid tissue, regulatory T-cells, and antigen-presenting cells, creating unique milieu where immunotherapy might exert effects. Nivolumab's PD-1 blockade may mediate local cytotoxic T-cell activity against neoplastic cells. This synergistic hypothesis is compelling given immunosurveillance's hypothesized role in preventing adenoma-to-carcinoma progression.
2024-12-10 | METTL3-VISTA axis-based combination immunotherapy for APC truncation colorectal cancer.
Although immune checkpoint blockade (ICB) therapy represents a bright spot in antitumor immunotherapy, its clinical benefits in colorectal cancer (CRC) are limited. Therefore, a new target for mediating CRC immunosuppression is urgently needed. Adenomatous polyposis coli (APC) mutations have been reported as early-stage characteristic events in CRC, but the role of truncated APC in the CRC immune microenvironment remains unclear and its clinical significance has yet to be explored. Adenocarcinoma formation in the colon of the APCMin/+ mouse model, which displays features associated with the translation of truncated APC proteins, was induced by azoxymethane/dextran sodium sulfate. Multiplexed immunohistochemical consecutive staining on single slides and flow cytometry were used to explore the activation of immune cells and the expression of the immune checkpoint V-domain immunoglobulin suppressor of T-cell activation (VISTA) in the CRC tissues of APCWT and APCMin/+ mice. The construction of truncated APC vectors and an initial subserosal graft tumor mouse model was employed to mimic the tumor microenvironment (TME) during APC mutation. Methylated RNA immunoprecipitation-quantitative PCR assays were performed to investigate the N6-methyladenosine (m6A)-dependent transcriptional regulation of hypoxia-inducible factor-1 alpha (HIF1α) by methyltransferase-like protein 3 (METTL3). Mettl3fl/fl vil1-cre+/- mice were used to demonstrate that targeting METTL3 is a mediator that mitigates the deleterious effects of the APC978∆-HIF1α axis on antitumor immunity. A chimeric VISTA humanized mouse model was used to evaluate the drug efficacy of the VISTA-targeted compound onvatilimab. We showed that APC978∆, a truncated APC protein, mediated overexpression of METTL3, resulting in m6A methylation of HIF1α messenger RNA and high expression of HIF1α. Furthermore, HIF1α promotes the migration of myeloid-derived suppressor cells to the TME by binding to the promoters of MCP-1 and MIF. In addition, HIF1α enhances the expression of the immune checkpoint VISTA on CRC cells, weakening tumor immune monitoring. We elucidate that an underappreciated function of truncated APC in CRC is its ability to drive an immunosuppressive program that boosts tumor progression. Our work could provide a new perspective for the clinical application of immunotherapy in patients with CRC resistant to ICB therapy.
2024-11-21 | Chronic pouchitis: what every gastroenterologists need to know
Background Chronic pouchitis is a complication after restorative proctocolectomy with ileal pouch-anal anastomosis in ulcerative colitis (UC) and patients with familial adenomatous polyposis. Despite medical advances, many patients develop chronic inflammation in the ileal pouch, affecting their quality of life. Objective This narrative review provides an overview of chronic pouchitis, focusing on pathogenesis, clinical presentation, diagnostics and management, highlighting the need for a multidisciplinary approach. Methods A comprehensive literature review was conducted, analysing studies on chronic pouchitis incidence, pathogenesis, diagnosis and treatment, with an emphasis on emerging therapies and personalised medicine. Results The pathogenesis of chronic pouchitis involves genetic, immunological, microbial and environmental factors. Symptoms include increased stool frequency, urgency and abdominal pain. Diagnosis relies on clinical evaluation, endoscopy and histology. Management includes antibiotics, probiotics, immunomodulators, biologics and dietary interventions. Emerging therapies like anti-TNFα monoclonal antibodies, vedolizumab, ustekinumab and small molecules show promise for refractory cases. Conclusion Effective chronic pouchitis management requires a personalised approach. Treatment aims to alleviate symptoms and prevent recurrence. Chronic pouchitis can severely impact on a patient’s quality of life, and therefore surgical options remain a valuable alternative for those not responding to medical therapy. Ongoing research and interdisciplinary collaboration are essential to improve patient outcomes.
2024-05-25 | Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D.
The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options.
gene therapies
2026-09-11 | In vitro and in vivo studies on the impact of the familial adenomatous polyposis heterogeneous mutation MUC20-S671C on colorectal carcinogenesis and progression.
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer (CRC). We performed genetic testing on nine FAP patients and identified a recurrent mutation at the 671st site of the MUC20 gene-MUC20-S671C. This mutation has a detection frequency of zero in the 1000 Genomes Project database. Previous studies have demonstrated that MUC20 can promote CRC progression through epithelial-mesenchymal transition (EMT). We conducted a series of experiments to analyze the impact of this mutation on CRC cells, aiming to infer its potential role and significance in CRC patients. We introduced the MUC20-S671C mutation into the CRC SW480 cell line using the CRISPR-Cas9 technique and established a stable cell line carrying this mutation. We then conducted various experiments to assess the effects of this mutation. The Transwell assay was used to evaluate cell invasion and migration. We also examined cell proliferation, cell cycle progression, and apoptosis rate. Furthermore, we tested the tumorigenic ability of these cells in NOD-scid IL2Rγ[null] (NSG) mice. Additionally, transcriptome sequencing was performed on both cell lines and mouse tumor tissues to obtain molecular regulatory network data, and key molecules were further validated. The results of Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assays indicated that the proliferation ability of mutant cells was significantly reduced. The Transwell assay demonstrated a marked decline in the invasion and migration capabilities of mutant cells. Flow cytometry analysis revealed that the mutation increased the apoptosis rate of CRC cells and might have caused S-phase arrest. The tumor formation assay in nude mice showed that the tumorigenic ability of mutant cells was weakened. Transcriptome sequencing of both the cells and tumor tissues suggested that the mutation altered the expression of apoptosis- and cell cycle-related molecules and also affected EMT. Further experiments confirmed that key molecules involved in the EMT process, such as E-cadherin, were upregulated, while Vimentin, MMP9, and MMP14 were significantly downregulated, indicating that the mutation weakened the EMT capability of CRC cells. We have identified a novel mutation, MUC20-S671C, in patients with FAP. Our study demonstrates that this mutation exerts its tumor-suppressive effect by reversing the EMT process.
2025-12-04 | Advances in research on congenital and hereditary intestinal diseases: From molecular mechanisms to precision medicine.
Congenital and hereditary intestinal diseases are a group of major disorders caused by gene mutations or embryonic developmental anomalies and are characterized by diverse clinical manifestations and complex management. This review systematically explores the molecular genetic basis and pathogenic mechanisms of common intestinal diseases, including familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), Lynch syndrome (LS), Hirschsprung disease (HSCR), congenital short bowel syndrome (SBS), and cystic fibrosis (CF). It focuses on cross-disease commonalities in translational research frontiers such as gene-environment interactions, organoid-based precision medicine, the immune microenvironment, and metabolic and microbiome remodeling. The review also forecasts future directions, including gene therapy, targeted drugs, and other cutting-edge research advances.
2025-07-23 | Predicting colorectal cancer risk in FAP patients using patient-specific organoids.
Colorectal cancer (CRC), a prevalent global cancer, is mostly sporadic. Familial adenomatous polyposis (FAP), arises from APC germline mutations. We established FAP-human embryonic stem cell lines (FAP1,2,3) with distinct APC mutations and differentiated them into colon organoids to study cancer development. While normal expressing APC lines and FAP3 formed complex organoids, FAP1,2 failed to differentiate. By utilizing CRISPR editing to correct APC mutations in FAP1,2, we succeeded in restoring their ability to form complex organoids expressing colon gene (CDX2). To elucidate the truncated APC proteins' mechanism of action, we used AlphaFold2 algorithm to model their secondary structures. Structural analysis of the normal phenotype organoids (normal and FAP3) revealed 5-6 salt bridges only at the N-terminal oligomerization domain. In contrast, analysis of disease organoids-phenotype (FAP1,2) revealed a production of novel salt bridges, likely act in a dominant-negative manner on full-length APC, disrupting APC function and promoting tumorigenesis. Our study underscores the critical role of germline APC mutations in colon cancer initiation, revealing how specific mutations influence disease severity. By deciphering APC structure-function relationships, we illuminate potential therapies and the molecular underpinnings of APC mutations that precede clinical presentation.
2023-05-03 | LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice.
Amino acid transporters play an important role in supplying nutrition to cells and are associated with cell proliferation. L-type amino acid transporter 1 (LAT1) is highly expressed in many types of cancers and promotes tumor growth; however, how LAT1 affects tumor development is not fully understood. To investigate the role of LAT1 in intestinal tumorigenesis, mice carrying LAT1 floxed alleles that also expressed Cre recombinase from the promoter of gene encoding Villin were crossed to an ApcMin/+ background (LAT1fl/fl; vil-cre; ApcMin/+), which were subject to analysis; organoids derived from those mice were also analyzed. This study showed that LAT1 was constitutively expressed in normal crypt base cells, and its conditional deletion in the intestinal epithelium resulted in fewer Paneth cells. LAT1 deletion reduced tumor size and number in the small intestine of ApcMin/+ mice. Organoids derived from LAT1-deleted ApcMin/+ intestinal crypts displayed fewer spherical organoids with reduced Wnt/β-catenin target gene expression, suggesting a low tumor-initiation capacity. Wnt3 expression was decreased in the absence of LAT1 in the intestinal epithelium, suggesting that loss of Paneth cells due to LAT1 deficiency reduced the risk of tumor initiation by decreasing Wnt3 production. LAT1 affects intestinal tumor development in a cell-extrinsic manner through reduced Wnt3 expression in Paneth cells. Our findings may partly explain how nutrient availability can affect the risk of tumor development in the intestines.
2021-12-13 | A truncated protein product of the germline variant of the DUOX2 gene leads to adenomatous polyposis.
In some patients with adenomatous polyposis, an identifiable pathogenic variant of known associated genes cannot be found. Researchers have studied this for decades; however, few new genes have been identified. Adenomatous polyposis coli (APC) negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification. Then, whole-exome sequencing (WES) was used to determine candidate genes harboring pathogenic variants. Functional experiments were performed to explore their effects. Subsequently, using Sanger sequencing, we found other polyposis patients carrying variants of the DUOX2 gene, encoding dual oxidase 2, and analyzed them. From 88 patients with suspected familial adenomatous polyposis, 25 unrelated APC negative polyposis patients were identified. Based on the WES results of 3 patients and 2 healthy relatives from a family, the germline nonsense variant (c.1588A>T; p.K530X) of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis. During functional experiments, we observed that the truncated protein, hDuox2 K530, was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant, causing abnormal cell proliferation through endoplasmic reticulum (ER) retention. In addition, we found two unrelated APC negative patients carrying DUOX2 missense variants (c.3329G>A, p.R1110Q; c.4027C>T, p.L1343F). Given the results of the in silico analysis, these two missense variants might exert a negative influence on the function of hDuox2. To our knowledge, this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis. With an autosomal dominant inheritance, it causes ER retention, inducing an unfolded protein response.
small molecules
2026-09-21 | Defining absolute postoperative desmoid risk in familial adenomatous polyposis according to APC genotype and family history: retrospective cohort study.
Desmoid disease is a major cause of morbidity and mortality in familial adenomatous polyposis (FAP), particularly after prophylactic colorectal surgery. Although APC genotype and family history are recognized risk factors, previous sizeable studies report relative rather than absolute risks. This study aimed to quantify absolute postoperative desmoid risk in FAP patients undergoing risk-reducing colectomy, stratified by APC genotype, and to assess the modifying effect of family history. This retrospective observational study used records from a prospectively maintained registry. Patients with an APC pathogenic variant (PV) 3' of codon 1399 were classified as high risk, and those with an APC PV 5' of (or at) codon 1399 were classified as low risk. Patients who had not undergone prophylactic colectomy, with < 5 years of postoperative follow-up, or those with a desmoid diagnosed before or at the time of surgery were excluded. Clinical records were reviewed for details of surgery, desmoid diagnosis, and family history. A positive family history was defined as a first-degree relative with genetically confirmed FAP and a diagnosis of desmoid disease (clinical and/or radiological). Among 48 high-risk patients, 30 (63%) developed desmoid, with no significant difference between colectomy and proctocolectomy (54% versus 70%, respectively; χ2 = 1.42; P = 0.233). Family history was present in 35 of the 48 patients (73%) and increased desmoid risk relative to no family history (80% versus 15%, respectively; P < 0.01). Among the 1213 low-risk patients, 154 (12.7%) developed desmoids, with no significant effect of surgical procedure (13.9% versus 12.1% for proctocolectomy and total/partial colectomy, respectively; χ² = 0.77; P = 0.380). Family history increased desmoid risk relative to no family history (30% versus 10%, respectively; P < 0.01). A family history of desmoid disease appears to be an important determinant of postoperative desmoid risk in FAP. Although APC PV 3' of codon 1399 does confer a high overall risk, this is largely confined to individuals with first-degree relatives with desmoid. In the absence of a family history, postoperative desmoid risk appeared relatively low regardless of genotype. This supports a more individualized approach to perioperative counselling and surgical decision-making in patients with FAP. In addition, these data highlight that patients with both a 3' APC PV and a positive family history are a particularly high-risk subgroup who may represent an appropriate target population for future chemoprevention trials.
2026-08-03 | Data from Phase II Trial of Encapsulated Rapamycin to Reduce Polyp Burden Associated with Familial Adenomatous Polyposis
<div>Abstract Purpose:<p>Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies.</p> Patients and Methods:<p>Thirty patients with FAP enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1—every other day, cohort 2—daily every other week, or cohort 3—daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 months. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden and change in International Society for Gastrointestinal Hereditary Tumors stage and Spigelman score at 6 and 12 months.</p> Results:<p>Twenty nine of thirty patients (97%) completed the 12-month study with predictable bioavailability. Low-grade adverse events were frequent but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 months: −39.4 % (IQR, 108.9; <i>P</i> = 0.28), −33.33 % (IQR, 90; <i>P</i> = 0.04), and −38.6 % (IQR, 88.5; <i>P</i> = 0.26), respectively. At 12 months, cohort 2 had the largest decrease median PCFB CPB and TPB: −29.3 % (IQR, 67.6; <i>P</i> = 0.37) and −26.3 % (IQR, 49.5; <i>P</i> = 0.29), respectively. Intermittent dosing cohorts (1 and 2) reduced DPB at 6 months (<i>P</i> = 0.04) and improved TPB at 12 months (<i>P</i> = 0.05) compared with daily dosing.</p> Conclusions:<p>eRapa was safe, tolerable, and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.</p></div>
2026-07-14 | DCAF13: a positive regulator of colon cancer cell proliferation via the AMER2/ Wnt/β-catenin pathway.
The Wnt/β-catenin pathway plays a critical role in colorectal cancer (CRC) development. The significance of Wnt/β-catenin in maintaining the stability of adult tissues and challenges in identifying suitable molecular targets have limited the application of targeting the Wnt/β-catenin pathway. As one of the Cullin RING Ligase 4 adapters, DNA damage-binding protein 1 (DDB1) - and CUL4 correlation factor 13 (DCAF13) appears strongly expressed in different tumors. Our findings confirm enhanced expression of DCAF13 in tissues of CRC origin and related cell. In colon cancer cells, DCAF13 regulated adenomatous polyposis coli membrane recruitment 2 (AMER2) through ubiquitination, DCAF13 deletion increased AMER2 expression, which inhibited Wnt/β-catenin activity, suppressing cell proliferation. This effect was further validated in mice with gut-specific DCAF13 knockout. The ubiquitin-proteasome system is a potential target for drug development and cancer treatment. Beta-propeller proteins, such as CRL4 adapter DCAFs, are easily targeted by drugs. DCAF-proteolysis-targeting chimeras (PROTACs) can overcome drug resistance and selectively target tumor drivers by leveraging the unique substrate specificity of the DCAF subunits. DCAF13 emerges as a promising target for CRC, acting via the DCAF13-AMER2-Wnt /β-catenin axis.
2026-07-10 | Progressive intestinal tumor cell plasticity, Myc activation, and loss of Lgr5+ tumor stem cell lineage commitment upon Wnt depletion.
Plasticity, the capability of tumor cells to go through phenotypic transitions, promotes colorectal cancer (CRC) progression and treatment resistance. Although plasticity is evident in advanced CRCs, little is known about plasticity in early-stage tumors and tumor stem cells. Here, we demonstrate that a plastic cell state (PCS) is present already in polyps from patients with familial adenomatous polyposis and in mouse intestinal adenomas, in which PCS is associated with PROX1+ tumor stem cells. We furthermore analyzed progressive plasticity upon loss of the canonical wingless-related integration site (Wnt) effector Tcf7 or Lef1 in Apc mutant mice. Deletion of either gene led to emergence of new plastic tumor cell populations, failure of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) tumor stem cell differentiation into enterocyte-like cells, enhanced Myc pathway activation, and increased tumor cell proliferation and tumorigenesis. Together, we demonstrate that PCS is associated with early CRC development and identify multiple potentially druggable mechanisms activated during progressive tumor cell plasticity.
2026-06-30 | Pelvic desmoid fibromatosis: a diagnostic and therapeutic challenge.
Pelvic desmoid fibromatosis is a rare locally aggressive benign neoplasm, typically presenting in the reproductive age group with lower abdominal pain. Extra-abdominal occurrence being predominant, the pelvic origin of the tumour makes the clinical management a multidisciplinary challenge. Previous surgeries, current or previous pregnancies, and familial adenomatous polyposis have been documented as associated risk factors. Our patient was a young woman with three previous caesarean sections, admitted with a large infiltrative lesion extending into the left pelvic sidewall up to the pelvic bone, causing ipsilateral severe hydroureteronephrosis. Malignancy was suspected due to the infiltrating nature of the lesion on imaging. Due to its proximity to the pelvic veins, preoperative embolisation of the feeding vessel was done. An exploratory laparotomy was performed by a multidisciplinary team. For this deep-seated disease, mass excision was performed along with total hysterectomy, left salpingo-oophorectomy and left ureteroneocystostomy. A part of the lesion infiltrating the presacral fascia was not removed during the primary surgery. Within 24 hours of surgery, she developed critical limb ischaemia in the left limb due to thrombosis in the ipsilateral external iliac artery. An emergency thrombo-embolectomy was performed by the vascular surgeons and thromboprophylaxis continued. Final histopathology confirmed desmoid fibromatosis. For the residual disease, the patient has been under close follow-up and is receiving targeted therapy with oral sorafenib to prevent local progression. Her follow-up imaging showed a decrease in the size of the residual disease and she is asymptomatic currently.
cell therapies
2026-06-22 | Intestinal transplantation for tumors.
Transplantation of the intestine is a vital component in the treatment of many intrabdominal tumors. This is a comprehensive review of current practice and outcome of intestinal transplantation for tumors. Most commonly described for the intrabdominal desmoid tumor, excellent survival outcomes can be attained, particularly for the more aggressive desmoid tumors associated with familial adenomatous polyposis syndrome and early referral is critical in order to avoid diffuse tumor spread which would necessitate a more complex multivisceral transplant. Currently, consensus within the intestinal transplant community lists invasive intrabdominal desmoid tumor as a primary indication for intestinal transplantation. Rare tumors such as metastatic neuroendocrine tumors confined to the abdomen, and pseudomyxoma peritonei have been associated with acceptable survival and recurrence outcomes with intestinal transplantation in carefully selected patients who would otherwise have a dismal prognosis. In addition, intestinal transplantation is an option for patients with a history of abdominal malignancy who have been rendered with intestinal failure due to surgical complications from resection of a primary tumor. Intestinal transplantation is a therapeutic option with excellent results in selected patients with intrabdominal desmoid tumors, neuroendocrine tumors and pseudomyxoma peritonei. Careful patient selection, technical expertise, and posttransplant oncologic surveillance is critical for successful long-term outcomes.
2026-06-01 | The role of endoscopic treatment for advanced duodenal adenomas in patients with familial adenomatous polyposis: a long-term single-center experience
Aims Patients with familial adenomatous polyposis (FAP) develop duodenal adenomatous polyps, whose risk of malignant progression increases with advancing Spigelman stage. However, prophylactic duodenal surgery carries substantial morbidity and mortality. This study aimed to evaluate the efficacy and safety of endoscopic treatment in FAP patients classified as Spigelman stages III-IV. Methods A retrospective analysis was conducted on patients who underwent endoscopic duodenal surveillance and treatment at a tertiary referral center between 2013 and 2025. Cold-snare polypectomy (CSP) and endoscopic mucosal resection (EMR) were the resection techniques employed. Data were collected on patient characteristics, polyp features, endoscopic procedures, histological findings, and Spigelman stage and score. Results Between 2013 and 2025, 1035 EGDs were performed in 247 patients (55% male, median age 47 years, IQR 33-57) at out center, with a median follow-up of 84 months (IQR 49-115). Duodenal non-ampullary adenomas were detected in 130 patients (52.6%). Their Spigelman stage distribution was: 31 (23.8%) stage I, 44 (33.9%) stage II, 22 (16.9%) stage III, and 33 (25.4%) stage IV. Among patients with advanced Spigelman stages, thirty-five (74% male, median age 53 years, IQR 40-60), 17 classified as stage IV and 18 as stage III, underwent endoscopic treatment for duodenal polyps. During a median follow-up of 32 months (IQR 17–90), 268 polyps were resected in 122 endoscopic procedures (57% CSP). The median polyp size was 10 mm (IQR 7-10.5), 76.5% of resected polyps were located in the descending duodenum, and 17.5% harbored high-grade dysplasia. After therapeutic work-up, 69% of patients achieved downstaging of baseline Spigelman stage (p<0.001). The median Spigelman score decreased from 8 (IQR 8–9) to 6 (IQR 5–8) (p<0.001), while the proportion of patients with high-grade dysplasia declined from 74.3% to 5.7% (p<0.001). Kaplan-Meier analysis showed median times to re-progression and re-treatment after the first endoscopic treatment of 42 and 45 months, respectively. No major adverse events occured. One patient required surgery for multiple high-grade dysplasia adenomas not amenable to endoscopic resection, and no duodenal cancer were observed during the study period. Conclusions Endoscopic treatment proved to be safe and effective in downstaging both Spigelman score/stage and histological dysplasia severity, thereby reducing the need for prophylactic surgery in FAP patients with advanced duodenal disease. Given the risk of re-progression in this setting, multiple endoscopic resections are often required to achieve long-term disease control. Publication History Article published online: 05 June 2026 © 2026. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-02-25 | Cold snare polypectomy for 10-19 mm colorectal adenomas in familial adenomatous polyposis: a prospective randomized controlled trial.
Evidence for cold snare polypectomy (CSP) in treating 10-19 mm colorectal adenomas in patients with familial adenomatous polyposis (FAP) is limited. This study compared the efficacy and safety of CSP vs. hot snare polypectomy (HSP). This prospective non-inferiority randomized controlled trial predefined a non-inferiority margin of 4%. A total of 452 colorectal adenomas (10-19 mm) from 41 FAP patients were enrolled between May 2024 and May 2025 and randomized 1:1 to CSP (n = 220) or HSP (n = 232). The primary endpoint was histological complete resection (R0). Subgroup analyses were performed by lesion size (10-15 mm vs. 16-19 mm). R0 resection rates were similar between CSP and HSP (92.3% vs. 92.7%, p = 0.76). CSP was associated with shorter procedure time (4.53 ± 1.18 vs. 6.53 ± 1.46 min, p < 0.01) and lower hospitalization costs (p < 0.01). Intra-procedural bleeding was more frequent with CSP, whereas delayed bleeding and post-polypectomy electrocoagulation syndrome were more common with HSP. At 6 months, recurrence was rare (one lesion in each group). No significant interaction by lesion size was observed. CSP is non-inferior to HSP for R0 resection of 10-19 mm colorectal adenomas in FAP patients and offers advantages in efficiency, safety and cost.
2025-12-15 | Autologous Adipose Tissue Injection as Treatment for Ileoanal Pouch-Related Fistulae.
Ileal pouch-anal anastomosis (IPAA) is a standard surgical procedure for ulcerative colitis (UC) and familial adenomatous polyposis. However, pouch-related fistulae (PRF) are a significant complication. There is no consensus on the optimal treatment for PRF. This study evaluated the effectiveness of autologous adipose tissue injection (AATI) as a treatment for PRF. Twenty-one patients with IPAA and a total of 29 PRF were treated with AATI. Patients who did not achieve healing after the first treatment were offered repeated injections. Patients were followed for a median of 16 months after AATI. Outcomes including clinical healing, treatment complications, and recurrence of PRF were registered. After a single treatment with AATI, 48% of the fistulae were clinically healed. Repeated treatments increased the healing rate to 69%. An additional 14% responded to AATI by reduced secretion from PRF. The procedure was well tolerated with minimal complications. AATI appears to be a safe, minimally invasive, and sphincter-saving treatment for PRF with promising healing rates. Further studies with larger cohorts are necessary to validate these findings.
2025-10-07 | Low‐Power Pure‐Cut Hot Snare Polypectomy for Intensive Downstaging in Familial Adenomatous Polyposis: Promise, Practicality, and Evidence Still Needed
The author declares no conflicts of interest.
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2026-09-06 | Inhibitory effects of c-MYC degrading rLON protease on intestinal polyps in PIRC rat, a familial adenomatous polyposis model.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, accounting for approximately 10% of all cases, and is the second leading cause of cancer-related deaths in the United States. In patients with Familial Adenomatous Polyposis (FAP), APC mutations drive c-MYC overexpression, promoting metabolic and immune dysregulation that contributes to CRC development, making c-MYC a potential target for FAP-associated chemoprevention. Although no c-MYC inhibitors are currently available, recent evidence indicates that a uropathogenic E. coli protease can degrade c-MYC protein. This study evaluated recombinant LON protease (rLONP) for chemopreventive efficacy in PIRC rats, a model of FAP. Rat pups were genotyped, baseline polyp burden was established by colonoscopy, and animals were randomized to receive saline or rLONP twice daily (2.5 mg/kg, p.o.) for 2 or 4 weeks. Serum analyses showed no significant changes in liver or kidney function markers in rLONP-treated rats compared with controls. rLONP-treated male rats exhibited a ∼40% reduction in colonic polyps at both time points, and small intestinal polyp counts were also lower in treated males and females. Combined analysis demonstrated a ≥60% reduction in total intestinal polyp multiplicity after 2-4 weeks of treatment (p<0.001). Protein expression analyses of colonic polyps revealed decreased c-MYC protein levels following rLONP treatment. Immunohistochemistry further showed reduced Ki-67, Cyclin D1, and c-MYC expression in treated polyps compared with controls. Overall, rLONP was well tolerated and significantly reduced intestinal polyp burden in PIRC rats in this short-term study, supporting further long-term efficacy evaluation.
2026-06-22 | Identification, design, and in vivo proof of concept of a shared APC neoantigen delivered via a self-amplifying RNA containing virus-like nanoparticle for cancer vaccination.
Colorectal Cancer (CRC) accounts for the second highest number of cancer-related mortalities rate worldwide, and its incidence and mortality is expected to continue to increase in the coming years. Over 80% of CRC cases are caused by mutation in the Adenomatous Polyposis Coli (APC) gene, a tumor suppressor gene involved in the Wnt signaling pathway that prevents uncontrolled cell growth. Familial Adenomatous Polyposis (FAP) is a rare, inherited, pediatric disorder characterized by the development of countless adenomatous (benign) polyps in the colon and/or rectum, and over the patient's lifetime there is an almost 100% likelihood that the disorder will progress into CRC. In this study, we utilized bioinformatics to identify shared neoantigen epitopes present at the mutational cluster region (MCR) of the APC gene of multiple CRC patients, where FAP-associated mutation is typically observed. We then developed and optimized a chimeric virus-like particle (VLP) to encapsulate an saRNA replicon encoding a neoantigen construct featuring the identified mutated APC sequences inserted into a WT APC backbone. T-cell specific activation and restimulation against neoantigen peptide fragments were observed in vitro, indicating the capacity for a T-cell mediated response in vivo. Serum samples from intramuscularly-dosed BALB/c mice exhibited significant neoantigen-specific IgG titers compared against vehicle control and WT APC control mice, confirming VLP-expression of neoantigens and indicating neoantigen-specific in vivo immune activity. The significant response observed against the nanoparticle-expressed APC neoantigen serves as proof-of-concept for a saRNA-expressed cancer vaccine against APC-associated CRC.
2026-01-05 | Targeting PTPN13 with 11-amino-acid peptides of C-terminal APC prevents immune evasion of colorectal cancer.
Colorectal cancer (CRC) remains largely refractory to immune-checkpoint blockade, with adenomatous polyposis coli (APC) mutations present in 80%-90% of cases. Loss of APC was previously thought to promote tumor progression mainly through deregulated Wnt/β-catenin signaling. Here, we report that APC loss leads to inhibition of CD8+ T cell infiltration and CRC immune evasion through the dephosphorylation of signal transducers and activators of transcription 1 (STAT1) by protein tyrosine phosphatase non-receptor type 13 (PTPN13), independently of β-catenin. Peptides containing the last 11 C-terminal amino acid (aa) residues of APC (APC11) bind directly to PTPN13 to block PTPN13-STAT1 interactions and facilitate STAT1 phosphorylation, interferon regulatory factor-1 (IRF1) expression, major histocompatibility complex (MHC) class I antigen presentation, and T cell intratumoral infiltration, all of which eventually inhibit tumor progression and enhance the effects of programmed cell death 1 (PD1) blockade. Thus, we have identified a previously unknown APC/PTPN13/STAT1-dependent tumor immune-suppressive mechanism. The potent tumor-suppressing effect of combining anti-PD1 antibodies with APC11 peptides provides a compelling target and rationale for future development of anti-tumor drugs for patients with CRC.
2025-06-23 | Nuclear adenomatous polyposis coli elevates STAT1 and reduces CXCL1,2, and 3 expression and inhibits neutrophil recruitment.
Adenomatous polyposis coli (APC) mutations and chronic inflammation can each promote colon cancer. Though both mice and humans with germline APC mutations show reduced tumorigenesis if treated with anti-inflammatory agents, direct links between APC and inflammation remain incomplete. In the current study, we examine a novel role for APC in intestinal inflammation via inhibition of neutrophil-recruiting chemokines CXCL1, 2, and 3. Patients with colorectal adenocarcinoma, the majority of whom would be expected to harbor APC mutations, showed upregulated CXCL1, 2, and 3 expression at early stages of disease. APC induction in cultured human colon cells reduced levels of CXCL1 and CXCL2 proteins and CXCL1, CXCL2, and CXCL3 RNAs and increased expression of signal transducer and activator of transcription 1 (STAT1), a potential negative regulator of CXCL1 transcription. By mining published Chromatin-immunoprecipitation sequencing (ChIP-Seq) data, we found regions of the STAT1 promoter and upstream CpG island as APC-bound. Methylation-specific PCR and bisulfite sequencing each revealed decreased methylation of the STAT1 CpG island upon APC induction. Intestinal tissue explants from mice compromised for nuclear Apc (ApcmNLS/mNLS) secreted more CXCL1 and CXCL2 than wild-type explants. Conditioned media from APC-expressing cells recruited fewer neutrophils in a trans-well migration assay. In vivo, colon and ileal tissues from ApcmNLS/mNLS mice displayed more neutrophils than Apc+/+ mice. Experimental evidence from in vitro and in vivo systems validates that nuclear APC can inhibit inflammation by suppressing neutrophil-recruiting chemokines CXCL1, 2, and 3, potentially via epigenetic regulation of STAT1. These findings offer a new target for managing inflammation in inflammatory bowel disease and reveal a new mechanism by which APC loss enables cancer progression.
2025-06-13 | Enhancing cyclic peptide functionality with hydrophilic diamino acids for improved APC-Asef interaction inhibition.
Cyclic peptides inherently possess advantages in inhibiting protein-protein interactions (PPIs). However, those constructed using traditional disulfide bonds are susceptible to cleavage by disulfide isomerase or reducing environments, leading to diminished biological activity. To address this challenge, our study employed novel hydrophilic diamino acids with enhanced electronegativity to construct cyclic peptides, effectively resolving issues related to stability and aqueous solubility, thereby overcoming the limitations associated with disulfide bond-based cyclic peptides. Furthermore, we applied this diamino acid strategy to the APC-Asef PPI peptide inhibitor MAI-516. Compared to cyclic peptides constructed using traditional disulfide bonds, those generated using the diamino acid strategy exhibited enhanced aqueous solubility, stability, and inhibitory activity. This study provides an application example for the modification of novel hydrophilic diamino acids in peptide cyclization and offers an effective strategy for the development of therapeutic agents for metastatic colorectal cancer.
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Drug Discovery Landscape
25 orphan drug designations for Familial adenomatous polyposis, including 1 approved therapy.
25 orphan drug designations for Familial adenomatous polyposis, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
potent, ATP-competitive small molecule inhibitor of glycogen synthase kinase 3 (GSK3) isoforms alpha and beta | small molecules | FDA | — | Adeno, Inc. |
Sirolimus | small molecules | EMA | Scendea (NL) B.V. | |
selective dual antagonist of the human prostaglandin E2 (PGE2) receptors EP2 and EP4 | small molecules | FDA | Tempest Therapeutics | |
beta-catenin antagonist | peptides | FDA | Sapience Therapeutics, Inc | |
Microencapsulated Interleukin-10 | proteins | FDA | — | Therapyx, Inc. |
Lithium carbonate | small molecules | EMA | Amsterdam UMC | |
(R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione | small molecules | EMA | Propharma Group The Netherlands B.V. | |
3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione | small molecules | FDA | Recursion Pharmaceuticals, Inc. | |
encapsulated rapamycin | small molecules | FDA | Emtora Biosciences Inc | |
magnesium lysinate bis eicosapentaenoate | small molecules | FDA | — | Thetis Pharmaceuticals |
pyrvinium | small molecules | FDA | — | StemSynergy Therapeutics, Inc. |
Eflornithine in combination with sulindac | small molecules | EMA | Cancer Prevention Pharma (Ireland) Limited | |
eflornithine plus sulindac | small molecules | FDA | Panbela Therapeutics, Inc. | |
eicosapentaenoic acid | small molecules | FDA | S.L.A. Pharma Ltd. (UK) | |
eflornithine | small molecules | FDA | Panbela Therapeutics, Inc. | |
live attenuated E. Coli expressing Beta catenin shRNA | gene therapies | FDA | — | Marina Biotech |
Eflornithine | small molecules | EMA | Cancer Prevention Pharma (Ireland) Limited | |
Eicosapentaenoic acid | small molecules | EMA | SLA Pharma (IRE) Limited | |
Valproic acid, sodium | small molecules | FDA | — | Topotarget A/S |
Sodium valproate [Peac/Salvicol] | small molecules | EMA | [INACTIVE] TopoTarget Germany AG | |
Eflornithine hydrochloride [Ornidyl] | small molecules | EMA | [INACTIVE] Ilex Services Limited | |
Celecoxib [Onsenal] | small molecules | EMA | Pfizer Limited | |
Exisulind | small molecules | FDA | — | OSI Pharmaceuticals, Inc. |
Indium In-111 altumomab pentetate | — | FDA | — | Hybritech, Inc. |
Leucovorin [Leucovorin calcium] | — | FDA | Approved | Immunex Corporation |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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