Pancreatic Cancer Therapy Research Articles

A phantom to simulate organ motion and its effect on dose distribution in carbon ion therapy for pancreatic cancer

Objective. Carbon ion radiotherapy is a promising radiation technique for malignancies like pancreatic cancer. However, organs’ motion imposes challenges for achieving homogeneous dose delivery. In this study, an anthropomorphic Pancreas Phantom for Ion-beam Therapy (PPIeT) was developed to simulate breathing and gastrointestinal motion during radiotherapy. Approach. The developed phantom contains a pancreas, two kidneys, a duodenum, a spine and a spinal cord. The shell of the organs was 3D printed and filled with agarose-based mixtures. Hounsfield Units (HU) of PPIeTs’ organs were measured by CT. The pancreas motion amplitude in cranial-caudal (CC) direction was evaluated from patients’ 4D CT data. Motions within the obtained range were simulated and analyzed in PPIeT using MRI. Additionally, GI motion was mimicked by changing the volume of the duodenum and quantified by MRI. A patient-like treatment plan was calculated for carbon ions, and the phantom was irradiated in a static and moving condition. Dose measurements in the organs were performed using an ionization chamber and dosimetric films. Main results. PPIeT presented tissue equivalent HU and reproducible breathing-induced CC displacements of the pancreas between (3.98 ± 0.36) mm and a maximum of (18.19 ± 0.44) mm. The observed maximum change in distance of (14.28 ± 0.12) mm between pancreas and duodenum was consistent with findings in patients. Carbon ion irradiation revealed homogenous coverage of the virtual tumor at the pancreas in static condition with a 1% deviation from the treatment plan. Instead, the dose delivery during motion with the maximum amplitude yielded an underdosage of 21% at the target and an increased uncertainty by two orders of magnitude. Significance. A dedicated phantom was designed and developed for breathing motion assessment of dose deposition during carbon ion radiotherapy. PPIeT is a unique tool for dose verification in the pancreas and its organs at risk during end-to-end tests.

Develop a Novel Therapy for Pancreatic Cancer

Develop a Novel Therapy for Pancreatic Cancer

Non-invasive biomarkers for early diagnosis of pancreatic cancer risk: metabolite genomewide association study based on the KCPS-II cohort

BackgroundPancreatic cancer is a lethal disease with a high mortality rate. The difficulty of early diagnosis is one of its primary causes. Therefore, we aimed to discover non-invasive biomarkers that facilitate the early diagnosis of pancreatic cancer risk.MethodsThe study subjects were randomly selected from the Korean Cancer Prevention Study-II and matched by age, sex, and blood collection point [pancreatic cancer incidence (n = 128) vs. control (n = 256)]. The baseline serum samples were analyzed by non-targeted metabolomics, and XGBoost was used to select significant metabolites related to pancreatic cancer incidence. Genomewide association study for the selected metabolites discovered valuable single nucleotide polymorphisms (SNPs). Moderation and mediation analysis were conducted to explore the variables related to pancreatic cancer risk.ResultsEleven discriminant metabolites were selected by applying a cut-off of 4.0 in XGBoost. Five SNP presented significance in metabolite-GWAS (p ≤ 5 × 10–6) and logistic regression analysis. Among them, the pair metabolite of rs2370981, rs55870181, and rs72805402 displayed a different network pattern with clinical/biochemical indicators on comparison with allelic carrier and non-carrier. In addition, we demonstrated the indirect effect of rs59519100 on pancreatic cancer risk mediated by γ-glutamyl tyrosine, which affects the smoking status. The predictive ability for pancreatic cancer on the model using five SNPs and four pair metabolites with the conventional risk factors was the highest (AUC: 0.738 [0.661–0.815]).ConclusionsSignatures involving metabolites and SNPs discovered in the present research may be closely associated with the pathogenesis of pancreatic cancer and for use as predictive biomarkers allowing early pancreatic cancer diagnosis and therapy.

Abstract B026: Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer

Abstract Pancreatic cancer is a devastating disease with an overall five-year survival rate of ~12% according to the American Cancer Society. Novel chemotherapeutics and targeted therapies in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received accelerated FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin is a chemotherapeutic synthetic tetrahydroisoquinoline alkaloid that inhibits active transcription by binding to guanine rich sequences in the minor groove of DNA. Lurbinectedin has been shown to reduce oncogenic transcription by stalling and degrading RNA Polymerase II and inducing breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin’s highly efficient killing of pancreatic tumor cells as a single agent in PANC-1, BxPC-3, and HPAF-II cell lines, with 72-hour IC-50s ranging from 0.266 – 0.964 nM. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells in vitro. Synergism was calculated using SynergyFinder, with HSA scores exceeding 15 in every cell line (synergy scores greater than 10 are considered synergistic according to the website manufacturer). Western Blot analysis of combination therapy indicates an upregulation of γH2AX and ATR, indicating DNA damage likely plays a role in the synergistic effects of the drugs. Bcl-2 downregulation in combination therapy indicates that the Bcl-2 family proteins likely play a role in the apoptosis of the cancer cells. Cytokine profiling analysis indicates an upregulation of the Fas apoptosis-inducing ligand under lurbinectedin and irinotecan monotherapy and combination therapy. VEGF and prolactin were downregulated in combination therapy. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-Fluorouracil (5-FU) enhances % inhibition as each drug concentration increases, and the presence of lurbinectedin enhances the synergism between irinotecan and 5-FU. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer. Citation Format: Tej Tummala, Arielle De La Cruz, Ash Uruchurtu, Nicholas R Liguori, Abbas E Abbas, Leiqing Zhang, Christopher Azzoli, Lanlan Zhou, Wafik S El-Deiry. Preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5-fluorouracil in pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B026.

EPI-X4, a CXCR4 antagonist inhibits tumor growth in pancreatic cancer and lymphoma models

Endogenous peptide inhibitor for CXCR4 (EPI-X4) is a CXCR4 antagonist with potential for cancer therapy. It is a processed fragment of serum albumin from the hemofiltrate of dialysis patients. This study reports the efficacy of fifteen EPI-X4 derivatives in pancreatic cancer and lymphoma models. In vitro, the peptides were investigated for antiproliferation (cytotoxicity) by MTT assay. The mRNA expression for CXCR4 and CXCL12 was determined by RT-PCR, chip array and RNA sequencing. Chip array analysis yielded 634 genes associated with CXCR4/CXCL12 signaling. About 21% of these genes correlated with metastasis in the context of cell motility, proliferation, and survival. Expression levels of these genes were altered in pancreatic cancer (36%), lymphoma models (53%) and in patients’ data (58%). EPI-X4 derivatives failed to inhibit cell proliferation due to low expression of CXCR4 in vitro, but inhibited tumor growth in the bioassays with significant efficacy. In the pancreatic cancer model, EPI-X4a, f and k inhibited mean tumor growth by > 50% and even caused complete remissions. In the lymphoma model, EPI-X4b, n and p inhibited mean tumor growth by > 70% and caused stable disease. Given the non-toxic and non-immunogenic properties of EPI-X4, these findings underscore its status as a promising therapy of pancreatic cancer and lymphoma and warrant further studies. Simple summaryThis study examined the value of chemokine receptor CXCR4 as an antineoplastic target for the endogenous peptide inhibitor of CXCR4 (EPI-X4), a 12-meric peptide derived from serum albumin. EPI-X4 inhibits CXCR4 interaction with its natural ligand, CXCL12 (SDF1). Therefore, malignancies (including pancreatic cancer and lymphoma) that depend on the CXCR4/CXCL12 pathway for progression can be targeted with EPI-X4. Of 634 genes that were linked to the CXCR4/CXCL12 pathway, 21% were associated with metastasis. In cultured human Suit2–007 pancreatic cancer cells, CXCR4 showed low to undetectable expression, which was why EPI-X4 did not inhibit pancreatic cancer cell proliferation. These findings were different in vivo, where CXCR4 was highly expressed and EPI-X4 inhibited tumor growth in rodents harboring pancreatic cancer or lymphoma. In the pancreatic cancer model, EPI-X4 derivatives a, f and k caused complete remissions, while in lymphomas EPI-X4 derivatives b, n and p caused stable disease.

Targeted delivery of genistein for pancreatic cancer treatment using hyaluronic-coated cubosomes bioactivated with frankincense oil

Pancreatic cancer is an aggressive malignancy that remains a major cause of cancer-related deaths. Research for innovative anticancer therapeutic options is thus imperative. In this regard, phytotherapeutics offer great promise as efficient treatment modalities, especially leveraging nanodrug delivery. Herein, we innovatively coloaded the flavonoid genistein (Gen) and frankincense essential oil (FO) within cubosomes, which were then coated with the bioactive ligand hyaluronic acid (HA/Gen-FO-Cub) for active-targeting of pancreatic cancer. The novel HA/Gen-FO-Cub displayed optimum nanosize (198.2 ± 4.5 nm), PDI (0.27 ± 0.01), zeta-potential (−34.7 ± 1.2 mV), Gen entrapment (99.3 ± 0.01 %), and controlled Gen release (43.7 ± 1.2 % after 120 h). HA/Gen-FO-Cub exerted selective anticancer activity on pancreatic cancer cells (PANC-1; 8-fold drop in IC50), cellular uptake and anti-migratory effect compared to Gen solution. HA/Gen-FO-Cub revealed prominent cytocompatibility (100 ± 5.9 % viability of human dermal fibroblast). Moreover, HA/Gen-FO-Cub boosted the in vivo anticancer activity of Gen in an orthotopic cancer model, affording tumor growth suppression (2.5-fold drop) and downregulation of NFκB and VEGF (2.9- and 1.8-fold decrease, respectively), compared to Gen suspension. Antimetastatic efficacy and Bcl-2-downexpression was histologically confirmed. Our findings demonstrate the promising anticancer aptitude of HA/Gen-FO-Cub as an effective phytotherapeutic nanodelivery system for pancreatic cancer therapy.

Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment.

Pancreatic cancer remains a formidable challenge due to limited treatment options and its aggressive nature. In recent years, the naturally occurring anticancer compound juglone has emerged as a potential therapeutic candidate, showing promising results in inhibiting tumor growth and inducing cancer cell apoptosis. However, concerns over its toxicity have hampered juglone's clinical application. To address this issue, we have explored the use of polymeric micelles as a delivery system for juglone in pancreatic cancer treatment. These micelles, formulated using Poloxamer 407 and D-α-Tocopherol polyethylene glycol 1000 succinate, offer an innovative solution to enhance juglone's therapeutic potential while minimizing toxicity. In-vitro studies have demonstrated that micelle-formulated juglone (JM) effectively decreases proliferation and migration and increases apoptosis in pancreatic cancer cell lines. Importantly, in-vivo, JM exhibited no toxicity, allowing for increased dosing frequency compared to free drug administration. In mice, JM significantly reduced tumor growth in subcutaneous xenograft and orthotopic pancreatic cancer models. Beyond its direct antitumor effects, JM treatment also influenced the tumor microenvironment. In immunocompetent mice, JM increased immune cell infiltration and decreased stromal deposition and activation markers, suggesting an immunomodulatory role. To understand JM's mechanism of action, we conducted RNA sequencing and subsequent differential expression analysis on tumors that were treated with JM. The administration of JM treatment reduced the expression levels of the oncogenic protein MYC, thereby emphasizing its potential as a focused, therapeutic intervention. In conclusion, the polymeric micelles-mediated delivery of juglone holds excellent promise in pancreatic cancer therapy. This approach offers improved drug delivery, reduced toxicity, and enhanced therapeutic efficacy.

Understanding Surgical Attrition for “Resectable” Pancreatic Cancer

ObjectivesWe used a novel combined analysis to evaluate various factors associated with failure to undergo surgery in non-metastatic pancreatic cancer. MethodsWe identified rates of surgery and reasons for surgical attrition from clinical trials, which studied neoadjuvant therapy in resectable pancreatic cancer. Next, we queried the National Cancer Database (NCDB) for Stage I-III, T1-3 pancreatic adenocarcinoma patients. We investigated the rates and factors associated with the receipt of surgery. Finally, we evaluated variable importance predicting the receipt of surgery. ResultsIn clinical trials, 25-30% of patients did not undergo surgery, mostly due to disease progression. In the NCDB, the overall surgical rate was only 49%, but increased to 67% in a curated cohort meant to mirror clinical trial patients. Patients treated at and low-volume institutions (OR=0.64, 95% CI: 0.61-0.67) and who were uninsured (OR=0.56, 95% CI: 0.52-0.62) and Medicaid-insured (OR=0.67, 95% CI: 0.64-0.71) were less likely to receive potentially curative surgery. ConclusionWe have identified a realistic target surgery rate of 70%-75% in potentially-resectable pancreatic cancer. While attrition to pancreatic cancer surgery is mostly due to tumor biology, our study identified the most important non-medical barriers, such as facility volume and insurance, affecting pancreatic cancer surgery.

CASP1 is a target for combination therapy in pancreatic cancer

Gemcitabine (GEM) is commonly used as the first-line chemotherapeutic agent for treating pancreatic cancer (PC) patients. However, drug resistance is a major hurdle in GEM-based chemotherapy for PC. Recent studies have shown that pyroptosis, a type of programmed death, plays a significant regulatory role in cancer development and therapy. In this study, we observed an increase in the expression of Caspase-1(CASP1)/Gasdermin-D (GSDMD) in PC and found that high expression of CASP1 and GSDMD was associated with poor overall survival (OS) and progression-free survival (PFS) of PC patients. Knockdown of either CASP1 or GSDMD resulted in the inhibition of cell viability and migration in PC cells. More importantly, the knockdown of CASP1 or GSDMD enhanced GEM-induced cell death in PC cells. Interestingly, subsequent investigations demonstrated that enzymatically active CASP1 promoted GEM-induced cell death in PC cells. The activation of CASP1 by the DPP8/DPP9 inhibitor (Val-boroPro, VbP) increased GEM-induced cell death by inducing pyroptosis. These findings suggest that inhibiting CASP1 to suppress its oncogenic effects or activating it to promote cell pyroptosis both enhance the sensitivity of PC cells to GEM therapy.

Donor T Cell Infusions Limit Novel Immune Checkpoint Therapy in Pancreatic Cancer: Implications for Adoptive T Cell Therapy

Background: We have previously published that pancreatic cancers over-express an immunosuppressive peptide, vasoactive intestinal polypeptide (VIP), and that a novel combination of antin-PD1 antibodies and small molecule antagonists to the VIP receptor can induce complete remission of pancreatic ductal adenocarcinoma (PDAC) in multiple mouse models (Ravibndranathan, Nat. Comm. 2022). To enhance the efficacy of this novel immunotherapy approach, we hypothesized that infusions of additional donor T cells to PDAC-bearing mice receiving the combination of anti-PD1/VIP receptor antagonists would lead to more intra-tumoral effector T cells and increased tumor regression rates. To investigate the potential impact of adoptive splenocyte infusion on checkpoint immunotherapy, we established sub-cutaneous KPC PDAC tumors in C57Bl/6 mice. As previously described, we treated them with a combination of ANT308 (VIP-receptor antagonists) and anti-PD1. We tested whether adding splenocyte infusions from donor mice that were immunologically naïve or donor mice previously engrafted with PDAC with regressed (positive control) or progressed tumors (negative control) would enhance the efficacy of the immune checkpoint blockade therapy. Methods: C57BL/6 B6 CD45.1 recipient mice were inoculated subcutaneously with 1 x 10 6 KPC-luc PDAC cell line cells on day -5. Recipient mice received anti-PD1 (200mg) every three days (totaling four doses) and 21 daily s.c. injections of 20 ug ANT308. Splenocytes from three groups of CD45.2+ C57BL/6 donor mice were injected into tumor-bearing recipients: naive mice, mice with a history of KPC regression post-ANT308/anti-PD1 treatment, and mice with progressed KPC tumors without any treatment. Anti-PD1 and ANT308 treatments were initiated simultaneously with adoptive splenocyte infusion (25 x 10 6 cells) on day 0. Tumor size was measured biweekly, and IVIS imaging was performed weekly. Blood was drawn weekly from recipient mice for flow cytometric analysis of immune cell subsets. A fraction of tumor-bearing recipient mice was euthanized ten days after donor splenocyte infusion and initiation of immune checkpoint therapy or at IAUCAC-defined endpoints. When tumor-bearing mice were euthanized, the spleen, lymph nodes, and tumors were harvested for further flow cytometric analysis. The remaining mice were monitored for tumor growth and survival kinetics. Results: Contrary to our original hypothesis, we observed substantially lower survival rates and faster tumor growth in the group that received splenocytes from immunologically naive donor mice versus the group treated with splenocytes from tumor-bearing mice (Figures 1A and 1B). Splenocytes from immunologically naive donors contained fewer Treg cells, whereas myeloid-derived suppressor cells (CD11b+Ly-6G+ Gr-1+) were increased in donor splenocytes from tumor-bearing mice. We next repeated the experiment utilizing the adoptive transfer of splenocytes from immunologically naïve donors separated into 8 x 10 6 MACS-purified T cell or 17 x 10 6 non-T cell fractions. Remarkably, the transfer of 8 x 10 6 immunologically naïve T cells abrogated the efficacy of immune checkpoint therapy leading to rapid tumor growth compared to tumor regression in mice treated with immune checkpoint therapy without added donor splenocytes or mice that received immune checkpoint therapy with 17 x 10 6 T-cell-depleted donor splenocytes. Flow cytometric and gene expression analyses of splenocytes from the recipient mice, and those not receiving donor T cell infusions, revealed that the tetramer population in the infusion group was significantly higher than in the group treated only with immune checkpoint inhibitors. Conclusion: Our findings indicated that natural suppressor/ Treg in immunologically naïve splenocytes could exert a profound negative regulatory effect on immune checkpoint therapy's efficacy in a murine PDAC model. Despite having fewer Treg than splenocytes from tumor-bearing donors, immunologically naïve natural Treg had increased potency in suppressing anti-cancer immunity. These findings suggest the importance of the depletion of natural Treg in adoptive cell therapy strategies to treat solid tumor malignancies. This research underscores the critical role of immune contexture in shaping therapeutic outcomes and proposes a novel biomarker for patient stratification in PDAC immunotherapy.

Diffusion-weighted imaging for determining response to neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis

ObjectivesTo determine the role of diffusion-weighted imaging (DWI) for predicting response to neoadjuvant therapy (NAT) in pancreatic cancer.Materials and methodsMEDLINE, EMBASE, and Cochrane Library databases were searched for studies evaluating the performance of apparent diffusion coefficient (ADC) to assess response to NAT. Data extracted included ADC pre- and post-NAT, for predicting response as defined by imaging, histopathology, or clinical reference standards. ADC values were compared with standardized mean differences. Risk of bias was assessed using the Quality Assessment of Diagnostic Studies (QUADAS-2).ResultsOf 337 studies, 7 were included in the analysis (161 patients). ADC values reported for the pre- and post-NAT assessments overlapped between responders and non-responders. One study reported inability of ADC increase after NAT for distinguishing responders and non-responders. A correlation with histopathological response was reported for pre- and post-NAT ADC in 4 studies. DWI’s diagnostic performance was reported to be high in three studies, with a 91.6–100% sensitivity and 62.5–94.7% specificity. Finally, heterogeneity and high risk of bias were identified across studies, affecting the domains of patient selection, index test, reference standard, and flow and timing.ConclusionDWI might be useful for determining response to NAT in pancreatic cancer. However, there are still too few studies on this matter, which are also heterogeneous and at high risk for bias. Further studies with standardized procedures for data acquisition and accurate reference standards are needed.Clinical relevance statementDiffusion-weighted MRI might be useful for assessing response to neoadjuvant therapy in pancreatic cancer. However, further studies with robust data are needed to provide specific recommendations for clinical practice.Key Points•The role of DWI with ADC measurements for assessing response to neoadjuvant therapy in pancreatic cancer is still unclear.•Pre- and post-neoadjuvant therapy ADC values overlap between responders and non-responders.•DWI has a reported high diagnostic performance for determining response when using histopathological or clinical reference standards; however, studies are still few and at high risk for bias.

184P Neutropenia as a predictive and prognostic factor in nanoliposomal-irinotecan/fluorouracil/leucovorin therapy for pancreatic cancer: Findings from the NAPOLEON-2 study (NN-2301)

184P Neutropenia as a predictive and prognostic factor in nanoliposomal-irinotecan/fluorouracil/leucovorin therapy for pancreatic cancer: Findings from the NAPOLEON-2 study (NN-2301)

450P Retrospective study of anamorelin therapy for unresectable or recurrent pancreatic cancer with cancer cachexia

450P Retrospective study of anamorelin therapy for unresectable or recurrent pancreatic cancer with cancer cachexia

Cell surface GRP78-directed CAR-T cells are effective at treating human pancreatic cancer in preclinical models

Pancreatic cancer is a highly lethal solid malignancy with limited treatment options. Chimeric antigen receptor T (CAR-T) cell therapy has been successfully applied to treat hematological malignancies, but faces many challenges in solid tumors. One major challenge is the shortage of tumor-selective targets. Cell surface GRP78 (csGRP78) is highly expressed on various solid cancer cells including pancreatic cancer, but not normal cells, providing a potential target for CAR-T cell therapy in pancreatic cancer. Here, we demonstrated that csGRP78-directed CAR-T (GRP78-CAR-T) cells effectively killed the human pancreatic cancer cell lines Bxpc-3-luc, Aspc-1-luc and MIA PaCa-2-luc, and pancreatic cancer stem-like cells derived from Aspc-1-luc cells and MIA PaCa-2-luc cells in vitro by a luciferase-based cytotoxicity assay. Importantly, we showed that GRP78-CAR-T cells efficiently homed to and infiltrated Aspc-1-luc cell-derived xenografts and significantly inhibited pancreatic tumor growth in vivo by performing mouse xenograft experiments. Interestingly, we found that gemcitabine treatment increased csGRP78 expression in gemcitabine-resistant MIA PaCa-2-luc cells, and the coapplication of gemcitabine with GRP78-CAR-T cells led to a robust cytotoxic effect on these cells in vitro. Taken together, our study demonstrates that csGRP78-directed CAR-T cells, alone or in combination with chemotherapy, selectively and efficiently target csGRP78-expressing pancreatic cancer cells to suppress pancreatic tumor growth.

Identification and characterization of interferon-γ signaling-based personalized heterogeneity and therapeutic strategies in patients with pancreatic cancer.

Interferon-γ (IFN-γ) is a key cytokine with diverse biological functions, including antiviral defense, antitumor activity, immune regulation, and modulation of cellular processes. Nonetheless, its role in pancreatic cancer (PC) therapy remains debated. Therefore, it is worthwhile to explore the role of Interferon-γ related genes (IFN-γGs) in the progression of PC development. Transcriptomic data from 930 PC were sourced from TCGA, GEO, ICGC, and ArrayExpress, and 93 IFN-γGs were obtained from the MSigDB. We researched the characteristics of IFN-γGs in pan-cancer. Subsequently, the cohort of 930 PC was stratified into two distinct subgroups using the NMF algorithm. We then examined disparities in the activation of cancer-associated pathways within these subpopulations through GSVA analysis. We scrutinized immune infiltration in both subsets and probed classical molecular target drug sensitivity variations. Finally, we devised and validated a novel IFN-γ related prediction model using LASSO and Cox regression analyses. Furthermore, we conducted RT-qPCR and immunohistochemistry assays to validate the expression of seven target genes included in the prediction model. We demonstrated the CNV, SNV, methylation, expression levels, and prognostic characteristics of IFN-γGs in pan-cancers. Notably, Cluster 2 demonstrated superior prognostic outcomes and heightened immune cell infiltration compared to Clusters 1. We also assessed the IC50 values of classical molecular targeted drugs to establish links between IFN-γGs expression levels and drug responsiveness. Additionally, by applying our prediction model, we segregated PC patients into high-risk and low-risk groups, identifying potential benefits of cisplatin, docetaxel, pazopanib, midostaurin, epothilone.B, thapsigargin, bryostatin.1, and AICAR for high-risk PC patients, and metformin, roscovitine, salubrinal, and cyclopamine for those in the low-risk group. The expression levels of these model genes were further verified through HPA website data and qRT-PCR assays in PC cell lines and tissues. This study unveils IFN-γGs related molecular subsets in pancreatic cancer for the first time, shedding light on the pivotal role of IFN-γGs in the progression of PC. Furthermore, we establish an IFN-γGs related prognostic model for predicting the survival of PC, offering a theoretical foundation for exploring the precise mechanisms of IFN-γGs in PC.

Tumor Microenvironment Responsive CD8+ T Cells and Myeloid-Derived Suppressor Cells to Trigger CD73 Inhibitor AB680-Based Synergistic Therapy for Pancreatic Cancer.

CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid-derived suppressor cells (MDSCs) by tumor-derived CXCL5 in an AMP-dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.

The Role of Radiation Therapy in Pancreatic Cancer

The Role of Radiation Therapy in Pancreatic Cancer

A co-carrier for plasmid DNA and curcumin delivery to treat pancreatic cancer via dendritic poly(l-lysine) modified amylose

Pancreatic cancer is one of the most lethal malignancies in the world and remains one of the leading causes of cancer related death. For its treatment, a lot of investigations have dealt not only with individual chemotherapy by using polymeric carriers to deliver anticancer drugs, but also with individual gene therapy by using polymeric carriers to deliver nucleic acids such as small interfering RNA (siRNA) and plasmid DNA. However, relatively few studies have been focused on the co-delivery of gene and anticancer drug by multifunctional polymeric carriers for its synergistic therapy. In this work, a DPLL-functionalized amylose (ADP) was prepared by the click reaction between azidized amylose and propargyl focal point poly(l-lysine) dendrons, and then used to co-deliver plasmid pIRES2-EGFP-TNFα and curcumin for pancreatic cancer treatment. Due to the internal hydrophobic cavity of amylose component, ADP could load efficiently curcumin with anticancer activity and showed a sustained release behavior. Moreover, the curcumin-loaded ADP could form colloidally stable nanocomplexes with plasmid DNA in aqueous system due to the existence of cationic poly(l-lysine) dendrons and exhibited high gene transfection efficiency. The in vitro and in vivo tests confirmed the effectiveness of using ADP to co-deliver plasmid pIRES2-EGFP-TNFα and curcumin for synergistic therapy of pancreatic cancer.

Palliative treatment of pancreatic cancer

Pancreatic cancer is one of the most serious problems of modern oncology. In the Russian Federation, pancreatic cancer, along with a fairly small share in the structure of the incidence of malignant neoplasms 3%, ranks first in annual mortality (68.2%), and is also a nosology with the most unfavorable prognosis among tumors of the gastrointestinal tract. The current standard of first-line therapy is FOLFRINOX (FOLFIRINOX, a combination of 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin) or gemcitabine plus albumin-bound nab-paclitaxel.
 One of the main obstacles to the action of chemotherapeutic drugs is the microenvironment of fibro-solid stromal tumors, which include pancreatic cancer. In order to potentiate the action of chemotherapy and combat the tumor microenvironment, at the present stage, drugs are being considered for influencing the programmed death 1 (PD-1) gene and cytotoxic T-lymphocyte antigen 4 (CTLA-4). Approximately 1015% of malignant neoplasms of the pancreas are believed to be associated with hereditary mutations, while all neoplasms have somatic mutations in different combinations of driver genes. One of the most common mutations are BRCA1/BRCA2 gene mutations. Poly-ADP-ribose polymerase inhibitors, like cisplatin, have shown promise as a treatment for tumors with BRCA mutations.
 Another subtype of pancreatic cancer is characterized by microsatellite instability. Unlike the above mutations and phenotypes, which affect only a small proportion of patients with pancreatic cancer, mutations in KRAS (Kirsten homologous rat sarcoma viral oncogene) are found in 9095% of cases of pancreatic malignancy and may be a significant factor in pancreatic tumorigenesis. Another frequently mutating gene for a number of malignancies is ARID1A, which encodes a tumor suppressor protein, a subunit of the SWI/SNF chromatin remodeling complex.
 The future of conservative therapy for pancreatic cancer is a complex treatment that includes both chemotherapy and targeted therapy and immunotherapy, the implementation of which is impossible without a deeper study of genetic mutations, molecular mechanisms of invasion and development of pancreatic malignant neoplasms, as well as extensive testing for genetic mutations in the clinical practice of specialized institutions.

Pathologic tumour response to neoadjuvant therapy in resected pancreatic cancer: does it affect prognosis?

Pathologic tumour response to neoadjuvant therapy in resected pancreatic cancer: does it affect prognosis?