Pancreatic Ductal Adenocarcinoma

This phenotype is unique only to azole-containing benzodiazepines, including midazolam. Mechanistically, an unbiased phosphoproteomic approach revealed that ALP abrogates TLR4-mediated cytokine production in CAFs. These findings cumulatively support that ALP dampens CAF-mediated inflammatory signaling within the PDAC TME.

Multiplex immunofluorescence and semi-quantitative analysis confirmed increased prevalence of FABP4+ and VWF+ endothelial cells in areas with high MFAP5+ fibroblast expression, along with elevated VEGF and FGF signaling. Our study reveals a potential pro-tumorigenic mechanism of MFAP5+ fibroblasts in PDAC, suggesting that the MFAP5+ fibroblast-endothelial cell axis may represent a potential target for future therapeutic strategies.

Here, we use photoactivatable multi-inhibitor liposomes (PMILs) as a clinically translatable strategy to immunomodulate and enhance PDAC treatment using FDA-approved agents: minocycline for tumor priming by downregulating Tdp1, benzoporphyrin derivative incorporated into the liposomal bilayer for photodynamic priming (PDP) of the microenvironment, and irinotecan (IRI) for cytotoxicity. This combination achieved sustained local tumor regression, abscopal effects in untreated distant tumors, and a significant improvement in long-term survival (63%). By integrating clinically approved agents with non-overlapping mechanisms within a light-activated delivery platform, this approach enhances IRI efficacy, reprograms the TME, and promotes antitumor immunity, offering a translatable strategy to sensitize PDAC to chemo- and immunotherapy.

High cGDF-15 levels at baseline are a negative prognostic and predictive biomarker in localized, non-metastatic PDAC. Considering that GDF-15 is further up-regulated by neoadjuvant multiagent chemotherapy, our data, together with recent findings on clinical effects of GDF-15, provide a strong rationale for upfront therapeutic GDF-15 blockade in localized PDAC.

The observed synergistic or additive effects with gemcitabine depend on both specific PDAC cell line and chemical form of lomitapide, underscoring complexity of personalized combination therapies and need to consider drug properties and tumor biology. These findings support therapeutic repositioning of lomitapide mesylate and lomitapide for PDAC.

We compared against a two-step AAV method, and treated dexamethasone (Dex) during manufacture...Dex augmented the cytotoxic activity of CAR-NK cells by promoting oxidative phosphorylation and ATP production. We designed robust, TGFβ1-resistant allogeneic CAR-NK cells using a virus-free, one-step engineering strategy, establishing a versatile, clinically scalable method for engineering metabolically fortified CAR-NK cells capable of overcoming TME-mediated suppression in solid tumors.

CA19-9 expression increased AKT signaling in PDAC cells and liver metastases, and CA19-9 levels correlated with AKT activation in human PDAC tissues. These findings show that CA19-9 promotes PDAC liver metastasis through E-selectin-dependent metastatic seeding and AKT-associated metastatic outgrowth, highlighting CA19-9 as a functional mediator of PDAC metastasis and a potential therapeutic target.

Although CSF1R inhibition alone was insufficient to improve tumor control, combinatorial blockade of PD-L1 and CD73 augmented systemic antitumor responses, and the addition of CSF1R inhibition in this context further enhanced both local and distant tumor control. These findings identify a CSF1-dependent myeloid resistance program that constrains ablation-induced systemic immunity and demonstrate that rational combination immunotherapy can potentiate the systemic efficacy of tumor ablation in PDAC.

Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.

Collectively, our study identifies that SMAD4 acts as a transcriptional activator of SLC27A3 and FADS2, driving linoleic acid uptake and its conversion to arachidonic acid, which may subsequently trigger ferroptosis and enhance radiosensitivity.

GGT prevalence has increased at RPCCC and informed treatment decisions. Universal point-of-care testing is being implemented with the goal of completing testing for all patients with PDAC seen at RPCCC.

P1, N=213, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting