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>
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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.
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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.
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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.
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2026-06-28 | Cellular prion protein suppresses colitis and colorectal carcinogenesis via modulating inflammatory responses.
Reducing prion protein (PrP) levels is a leading therapeutic strategy against prion disease. However, the normal function of PrP remains incompletely understood, creating uncertainty about the potential consequences of this approach. We investigated the role of PrP on intestinal tumorigenesis using the ApcMin/+ familial adenomatous polyposis model and the Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) induced colitis-associated colorectal cancer model. In Prnp-/- background, both tumor burden and survival rates of ApcMin/+ mice were significantly improved; in contrast, the absence of PrP significantly intensified AOM/DSS-induced carcinogenesis. PrP's capability to promote cell proliferation accounts for the findings in ApcMin/+ mice, but it cannot explain the substantial increase in carcinogenesis in AOM/DSS model. We found that AOM/DSS-treated Prnp-/- mice had elevated numbers of pro-inflammatory M1 macrophages, which transitioned to an antigen-presenting state, thereby prolonging the inflammatory response. In bone marrow-derived macrophages (BMDMs), the absence of PrP resulted in delayed but sustained NFκB nuclear localization, leading to an extended inflammatory response to lipopolysaccharide (LPS). The exacerbated chronic inflammatory response in Prnp-/- mice was further corroborated by LPS-induced colitis, which resulted in more severe diarrhea, higher levels of pro-inflammatory cytokine expression, and increased infiltration of CD4+ cell during the later phases of inflammation. Our results indicate that PrP deletion delays and extends the inflammatory response, resulting in severer colitis and associated colorectal carcinogenesis. These findings raise the potential implication that monitoring for chronic inflammation may be warranted in patients undergoing PrP-reduction therapy.
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