ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 4 citations in OpenAlex.
- Desmoplasia and therapeutic resistance in pancreatic ductal adenocarcinoma.Cancer letters · 2026Review
- Breaking barriers: nano-boosted drug delivery systems in overcoming the defenses of pancreatic cancer.Molecular cancer · 2026Review
- Article
- Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review).International journal of oncology · 2026Review
- Mild microwave hyperthermia promotes mitotic catastrophe, induces time-delayed cGAS-STING activation and restores sensitivity to anti-PDL1 therapy in Pan02 pancreatic cancer model.Oncoimmunology · 2025Article
- Magnetic chromatography improves colloidal and MRI attributes of magnetoliposomes enabling evaluation of the impact of size on bio-distribution in anJournal of materials chemistry. B · 2025Article
- Systems Genome: Coordinated Gene Activity Networks, Recurring Coordination Modules, and Genome Homeostasis in Developing Neurons.International journal of molecular sciences · 2024Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
Abstract
purposeParacrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. EXPERIMENTAL
designAnimals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction.
resultsMultiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect.
conclusionsThis dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.
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