P2, N=20, Recruiting, Sixth Affiliated Hospital, Sun Yat-sen University | Trial completion date: Feb 2027 --> Jun 2029 | Trial primary completion date: Apr 2026 --> Sep 2026

Orthotopic KRAS-mutant xenograft models (LOVO-Luc2 (N = 52) and SW480-Luc2 (N = 52)) were treated with standard-of-care regimens (FOLFOX, bevacizumab, or combination) and longitudinally imaged by CT (N = 104 tumour scans, N = 156 liver scans collected over 4 timepoints)...The most predictive features, GLSZM Gray Level Non-Uniformity, GLRLM Run Length Non-Uniformity Normalized, and GLDM Small Dependence Emphasis, were significantly associated with metastatic burden and survival in a clinical CRC cohort (N = 41), indicating species conservation and translational relevance. Collectively, these data demonstrate that preclinical CT radiomics can identify quantitative imaging features associated with treatment sensitivity and early metastatic progression, supporting translational potential.

Even though this molecule is two-fold less active than reference drug 5-fluorouracil (5-FU), the pharmacophore of the compound 10d would be considered for future derivatisation as a notable anticancer agent, due to its safety profile against normal cell line HEK...The compound 10d demonstrated the greatest affinity for both targets (- 8.8 and - 7.9 kcal/mol, respectively), whereas other compounds showed favourable binding energies. These findings suggest that compound 10d may serve as a promising lead for further biological evaluation.

GALNT5 facilitates malignant progression in CRC by promoting O-GalNAc glycosylation of EGFR and thereby activating the PI3K/Akt pathway, and confers resistance to L-OHP and 5FU through upregulation of ABCC1. These findings suggest GALNT5 as a potential diagnostic biomarker and a promising therapeutic target for overcoming chemoresistance in CRC.

Despite apparently favorable pathological staging and adjuvant FOLFIRINOX chemotherapy, the patient developed early biochemical progression with rapidly rising carbohydrate antigen 19-9 (CA 19-9) levels, followed by widespread metastatic dissemination involving the liver, lung, spine, skeletal muscle, and multiple visceral sites...This case highlights the limitations of anatomical staging in PDAC and emphasizes the prognostic importance of tumor biology, including KRAS mutation status, lymphovascular invasion, and perineural invasion. It also demonstrates the potential limitations of CA 19-9 as a solitary marker of treatment response in biologically aggressive disease.

Here, we discovered that EphA2-positive cells constitute a persistent, ALDH-positive cell subpopulation in CRC-PDOs that withstood exposure to oxaliplatin (OXA) and 5-fluorouracil (5-FU). The enforced suppression of EphA2 or diminished Ser897 stress results in a chemosensitization effect. This sheds further light on the role of EphA2 in the adaptive stress response of CRC.

Compared to the reference drug 5-fluorouracil (5-FU), several compounds displayed notable antiproliferative activity...Among these, compounds 4 and 10 exhibited the most favorable anticancer profiles, combining potent antiproliferative activity with minimal toxicity to normal cells. Furthermore, to support the experimental anticancer findings, in silico molecular docking studies were performed using the crystal structures of caspase-3 (1GFW), human metalloproteinase-13 (3KEJ), human estrogen receptor (3ERT), and EGFR (1M17) against compounds 1, 2, 4, and 10, and their binding modes were analyzed.

This study identifies the novel RRM1-USP19-NEDD4 regulatory axis as a core mediator of autophagy-driven 5-FU resistance in CRC, uncovers a non-canonical, metabolism-independent role of RRM1 as a USP19 stabilizer via competitive inhibition of NEDD4-mediated ubiquitination, and validates GAGGVGKSAL as a promising lead compound targeting this axis to reverse 5-FU resistance. The RRM1-USP19-NEDD4 axis represents a novel therapeutic target for overcoming chemoresistance in CRC.

Reported PFS values were: replacement EGFR-TKI (1.9-4.4 months), platinum-pemetrexed chemotherapy (1.6-20.7 months), osimertinib plus platinum-pemetrexed (3.9-6.9 months), chemotherapy plus anti-angiogenic agents (1.8-16.8 months), and chemotherapy plus immune checkpoint inhibitors (3.8 months). Post-progression molecular testing and, where feasible, tissue re-biopsy are important to guide subsequent treatment decisions. Second-line outcomes were variable, with chemotherapy combined with anti-angiogenic agents showing numerically longer progression-free survival in a small subgroup; however, these findings are descriptive due to the small sample size and treatment heterogeneity.

Overall, alpelisib combined with capecitabine demonstrated modest antitumor activity in a molecularly selected subset of patients with metastatic colorectal cancer. However, frequent treatment-limiting toxicities may limit the future clinical applicability of this regimen and highlight the need for improved toxicity management and optimized patient selection.

P2/3, N=380, Active, not recruiting, University of Birmingham | Trial primary completion date: Apr 2027 --> Aug 2027