Treatment Of Pancreatic Ductal Adenocarcinoma Research Articles

Abstract C027: Perioperative immune perturbations of the metastatic microenvironment in a murine PDAC orthotopic resection model

Abstract Surgical resection is currently the mainstay of treatment for pancreatic ductal adenocarcinoma (PDAC). After “curative intent” resection, distant metastasis occurs in majority of patients, indicating that PDAC is a systemic disease and should be considered as such at the time of surgical resection. Despite this, the effects of tumor resection on the systemic disease are not fully elucidated. Surgical trauma induces systemic immunosuppression, that can result in a “window of opportunity”, affecting metastatic seeding and outgrowth, as well as responsiveness to therapy. We used an orthotopic resection model in immunocompetent mice by performing a distal pancreatectomy and splenectomy. Using this model system, we identified outcomes similar to human disease, such as a survival benefit upon resection, systemic disease at the time of resection, and metastatic dissemination predominantly in the liver, lung, and peritoneum. Since the liver is the most common site of recurrence in human PDAC and portends a poorer prognosis than other metastases, we investigated the effect of tumor resection on the hepatic microenvironment. In surgically stressed mice undergoing sham resection and splenectomy, we identified an increase in eosinophils and a decrease in neutrophils, and these immune perturbations were augmented upon tumor resection. Time-course analysis identified transient changes in tissue resident and conventional NK cells, as well as macrophage and monocyte populations. Taken together, we have utilized a preclinical model that simulates human disease progression and response to surgery, and identified tumor resection specific alterations in the liver metastatic microenvironment. An improved understanding of the immune perturbations during this perioperative window may identify new immunotherapy strategies benefiting PDAC patients to help treat this systemic disease. Citation Format: Anthony Sorrentino, Carolina Alcantara-Hirsch, Beny Shapiro, Erica Ma, Ammar Javed, Christopher Wolfgang, Dafna Bar-Sagi. Perioperative immune perturbations of the metastatic microenvironment in a murine PDAC orthotopic resection model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C027.

Abstract C064: Chronic platinum exposure induces cell-intrinsic type1 interferon/STING pathway activation in homologous recombination-deficient pancreatic cancer to drive sensitivity to checkpoint immunotherapy

Abstract Background: Although platinum-based chemotherapy is standard treatment for pancreatic ductal adenocarcinoma (PDAC) patients with germline/somatic mutations in homologous recombination (mutHRD), a subset become platinum-resistant. We have shown that patients with mutHRD PDAC progressing on platinum chemotherapy respond to dual immune checkpoint blockade (ICB) with anti-PD1+CTLA-4. We sought to model these clinical findings in preclinical models to interrogate mechanisms in platinum-resistant mutHRD PDAC that drive ICB sensitivity. Methods: We examined the association between objective disease response following anti-PD1+CTLA-4 ICB and duration of platinum chemotherapy exposure in platinum-resistant mutHRD PDAC patients. Cisplatin- resistant and sensitive Brca2-silenced (via shRNA knockdown) KPC cancer cells were generated and characterized in vitro and in vivo. Results: In 12 mutHRD PDAC patients treated with salvage dual ICB after progression on platinum-based chemotherapy, 7 (58%) demonstrated either partial response or stable disease. Notably, duration of prior platinum exposure was associated with post-ICB disease response. To model these findings preclinically, syngeneic mice implanted with cisplatin-sensitive or resistant shBrca2 or wildtype KPC tumor cells and subsequently treated with gemcitabine+cisplatin chemotherapy demonstrated expected rapid tumor growth of cisplatin-resistant shBrca2 tumors. However, we observed a profound reduction in tumor volumes when these chronically cisplatin-resistant KPC-shBrca2 tumors were subsequently treated with anti-PD-1+CTLA4 ICB, compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 tumors (P<0.001). To understand mechanistic underpinnings of these observations, whole transcriptome sequencing revealed significant differential upregulation of type1 interferon and cGAS-STING pathways in cisplatin-resistant KPC-shBrca2 tumor cells compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 controls (P-adj≤0.05). Confocal immunofluorescence imaging confirmed constitutively upregulated cGAS and STING expression in cisplatin-resistant KPC-shBrca2 compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 tumor cells. Activation of type1 interferon/STING manifested in a secretome enriched for T-cell trafficking cytokines CXCL10, CXCL9, and CCL5 from cisplatin-resistant KPC-shBrca2 cells. Intriguingly, evaluable mutHRD patient tumors responsive to dual ICB also demonstrated baseline increase in CXCL9/10 and CCL5 expression compared with ICB-resistant mutHRD tumors (n=3 each) via Nanostring analysis. As such, we observed increased transwell (in vitro) and intratumoral (in vivo) CD8+ T-cell trafficking to cisplatin-resistant KPC-shBrca2 tumors compared with cisplatin-sensitive KPC-shBrca2 controls. Conclusions: Chronicity of platinum exposure in mutHRD PDAC potentiates ICB sensitivity via induction of cell-autonomous type-1 interferon/cGAS-STING signaling and ensuing T-cell trafficking to the PDAC tumor microenvironment. Citation Format: Ifeanyichukwu Ogobuiro, Anna Bianchi, Lucas Caeiro, Haleh Amirian, Luis Nivelo, Iago De Castro Silva, Karthik Rajkumar, Andrew Adams, Vanessa Garrido, Samara Singh, Nagaraj Nagathihalli, Nipun Merchant, Ramiro Verdun, Peter Hosein, Jashodeep Datta. Chronic platinum exposure induces cell-intrinsic type1 interferon/STING pathway activation in homologous recombination-deficient pancreatic cancer to drive sensitivity to checkpoint immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C064.

Abstract A018: Exercise stimulates anti-tumoral immunity in metastatic PDAC

Abstract The majority of pancreatic ductal adenocarcinoma (PDAC) patients are metastatic at presentation with limited treatment options and a poor overall 5-year survival of 3%. The liver is the predominant site of distant metastasis in PDAC. Our group has previously shown that aerobic exercise can inhibit tumorigenesis in a primary PDAC mouse model by promoting anti-tumor immunity, however, the effects of exercise in the metastatic setting have not been explored. As such, we developed a model of PDAC liver metastasis by isolating primary pancreatic and liver metastatic cell lines from 18–20-week-old LSL-KRasG12D/+; LSL-Trp53R172H/+; p48Cre; Rosa26LSL-tdTomato/+ (KPCTpancreas or KPCTliver, respectively) mice. KPCTpancreas cells were surgically implanted into the pancreata of syngeneic wild-type mice. One week after pancreatic implantation, KPCTliver cells were implanted into the liver either by direct injection into the parenchyma or via the portal vein. The portal vein method enables us to account for the extravasation step of the metastatic cascade, while the direct parenchymal injection offers a less invasive surgery. Both models preserve the spleen, which is the largest secondary lymphoid organ and essential to the immune response. Treadmill running was initiated in the aerobic exercise cohort 5 days per week for 2 weeks or mice were allowed to rest. Endpoint analysis revealed that aerobic exercise treatment decreased tumor burden in both primary tumors and liver metastasis as measured by tumor weights and tdTomato fluorescence imaging when compared to the rested controls. Immune profiling of the liver metastases revealed elevated IL-15Rɑ+ CD8+ T cells as well as CD19+ B cells in the exercise cohort. While identification of IL-15Rɑ+ CD8+ T cells is consistent with the immune changes we have previously reported in the primary pancreatic tumor of exercised mice, the latter changes reveal organ specific immune cell recruitment not observed in the primary pancreatic tumor of exercised mice. The combined immune profiling and phenotypic changes suggest that aerobic exercise reduces PDAC metastatic growth by modulating systemic and intra-tumoral immunity. The induction of an anti-tumorigenic immune response by aerobic exercise could open avenues for potential pharmacological intervention in downstream pathways to aid in the treatment of metastatic PDAC. Citation Format: Mansour E. Riachi, Carolina G. Alcantara Hirsch, Erica Ma, Beny Shapiro, Ammar Javed, Christopher L. Wolfgang, Dafna Bar-Sagi. Exercise stimulates anti-tumoral immunity in metastatic PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A018.

Abstract C003: RAMP 205: A phase 1b/2a study of gemcitabine, nab-paclitaxel, avutometinib, and defactinib in untreated metastatic pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) accounts for ~90% of pancreatic cancer. Surgery is the only curative treatment. Unfortunately, most patients are diagnosed with advanced disease and are not candidates for resection. Combination chemotherapy approaches have provided incremental improvements to PDAC outcomes. However, impact on survival for patients with inoperable disease remains modest, with a 2-year survival rate of less than 7%. Activating mutations in the KRAS oncogene are a key initiating event in ~80-90% of PDAC. Permanent activation of KRAS drives tumor cell proliferation and survival, tumor microenvironment modulation, and metabolic alterations in PDAC. Patients with KRAS mutant PDAC have worse outcomes compared to those with KRAS wild-type PDAC. In addition, hyperactivation of focal adhesion kinase (FAK) has been correlated with high stromal density, resulting in therapeutic resistance and poor survival. Avutometinib is a first-in-class oral RAF/MEK clamp that potently inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. Defactinib is a selective inhibitor of focal adhesion kinase (FAK), which has been shown to mediate resistance to multiple anticancer agents. Preclinical data have shown that the combination of avutometinib + FAK inhibition (FAKi) + chemotherapy (gemcitabine + paclitaxel as a surrogate for nab-paclitaxel) induced tumor regression in a autochthonous KRAS/TP53 mutant PDAC mouse model. Prior clinical experience of defactinib + pembrolizumab + chemotherapy was safe, showed responses, decreased stromal density, and increased CD8+ T cell infiltration in patients with PDAC (NCT02546531). Methods: RAMP 205 is a multi-center, open-label, single arm Phase 1b/2a study of gemcitabine and nab-paclitaxel in combination with avutometinib and defactinib in patients with previously untreated metastatic PDAC (NCT05669482). The study is being conducted in 2 parts: Parts A (dose evaluation) and Part B (dose expansion). The starting dose is 2.4 mg avutometinib orally (PO) twice weekly + 200 mg defactinib PO twice per day, in combination with standard once weekly gemcitabine/nab-paclitaxel (QW IV). All study drugs are dosed 3 weeks on, 1 week off. Following determination of the Recommended Phase 2 Dose (RP2D) in Part A, Part B will evaluate efficacy of the RP2D via objective response rate (primary endpoint). Mandatory tumor biopsies and blood samples will be collected for correlative studies, including circulating tumor DNA, molecular profiling and pharmacodynamic markers. Eligible patients must have histologic or cytologic evidence of metastatic PDAC and measurable disease according to RECIST v1.1. Patients with prior or concomitant treatment for metastatic PDAC or prior treatment with RAS/MAPK or FAK inhibitors are not eligible. The study will enroll ~35 patients with 6-12 patients in Part A, and 23 patients in Part B. Citation Format: Kian-Haut Lim, Manuel Hidalgo, Mark H. O'Hara, Kristen R. Spencer, Ignacio Garrido-Laguna, David G. DeNardo, Vijeta Bhambhani, Gloria Patrick, Yaofeng Cheng, Silvia Coma, Jonathan A. Pachter, Louis J. Denis. RAMP 205: A phase 1b/2a study of gemcitabine, nab-paclitaxel, avutometinib, and defactinib in untreated metastatic pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C003.

Abstract B014: Immuno-modulation of the tumor microenvironment of pancreatic adenocarcinoma following isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT)

Abstract INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest tumors. Unlike other tumors, the progress of systemic therapies has been very slow, mainly due to the peculiar and resistant tumor microenvironment (TME) of PDAC. The addition of ablative stereotactic body radiation therapy (SBRT) in a total neoadjuvant strategy is promising for the treatment of localized PDAC and is currently being explored in several clinical trials. However, if radiation therapy possesses the ability to modulate the TME, the impact of high-dose SBRT is still poorly known in PDAC. Here, we aim to characterize by immunohistochemistry (IHC) and RNA sequencing (RNAseq) analysis the immuno-modulations of the TME following isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT). MATERIAL: Paraffin-embedded residual tumoral tissues of 50 localized PDAC resected between 2011 and 2020 were used: seventeen patients had surgery first, seventeen received an induction chemotherapy with FOLFIRINOX (FFX) only and sixteen with FFX followed by an iHD-SBRT designed to individually maximize the dose prescribed to the tumor and vessels interfaces up to Dmax(0.5cc)<53Gy in 5 fractions. RESULTS: We found that although collagen deposition increases significantly after iHD-SBRT (COL1: 83.27 vs 78.60 vs 68.04%, p<0.001 for iHD-SBRT, FFX and treatment naïve cohort respectively), the intra-tumoral lymphocyte infiltration is globally not altered, including for cytotoxic CD8+ lymphocytes. Only the IHC expression of CD4+ T helper population is significantly decreased after iHD-SBRT. Using gene set enrichment analysis (GSEA) of the KEGG pathway, the IL-17 signaling pathway related to the T17 cells is particularly significantly increased after iHD-SBRT compared to FFX only. After iHD-SBRT, the IHC expression levels of FOXP3+ cells and PD-L1 are significantly increased. No difference is observed for CD68+ expression however, cell type enrichment analysis from our RNA-seq data using xCell algorithm shows that the M2-polarized CD68+ cells are increased after iHD-SBRT compared to FFX alone. PD-1 expression is significantly decreased after iHD-SBRT. Furthermore, RNAseq data revealed that iHD-SBRT is associated with significant enrichment in basaloid cells (p<0.0024), a subtype of basal–like cells associated with immunomodulatory stroma and better clinical outcomes. GSEA canonical pathway analysis further revealed metabolism-related pathways such as oxidative phosphorylation and gluthathione metabolism significantly enriched in iHD-SBRT treated group, suggesting the potential of mitochondrial inhibitors as candidates for combination therapy. CONCLUSIONS: iHD-SBRT is able to durably immuno-modulate the TME of PDAC. If the overall T-cell infiltration is preserved, we have identified some increased pro-tumoral cells and pathways after iHD-SBRT that could improve the development of better-oriented combination trials involving high-dose SBRT. Citation Format: Christelle Bouchart, Oier Azurmendi Senar, Julie Navez, Laurine Verset, Anaïs Boisson, Matthieu Hein, Nicky D’Haene, Dirk Van Gestel, Luigi Moretti, Pieter Demetter, Jean-Baptiste Bachet, Karen Willard-Gallo, Rémy Nicolle, Tatjana Arsenijevic, Jean-Luc Van Laethem. Immuno-modulation of the tumor microenvironment of pancreatic adenocarcinoma following isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B014.

Abstract C077: Elucidation and exploitation of critical nutrient scavenging regulation in ERK MAPK inhibited pancreatic cancer

Abstract Alteration of essential metabolic pathways is a major mechanism by which oncogenic KRAS promotes tumor development and growth in pancreatic ductal adenocarcinoma (PDAC). KRAS-driven PDAC is dependent on nutrient scavenging pathways, including macropinocytosis and autophagy to fuel the high metabolic demand of rapid proliferation. Thus, these metabolic processes are attractive targets for the development of treatments for PDAC. KRAS loss results in downregulation of macropinocytosis in PDAC. Additionally, our lab demonstrated that KRAS loss or inhibition of ERK MAPK signaling decreased glucose consumption and glycolysis but increased autophagy, thereby enhancing dependency on autophagy for survival and growth. Accordingly, dual ERK MAPK and autophagy inhibition (via chloroquine) synergistically enhanced anti-tumor efficacy in PDAC. Early clinical data has demonstrated that resistance to this treatment arises over time through unknown mechanisms. Our preliminary data indicates that following ERK MAPK inhibition both autophagy induction and macropinocytosis downregulation is transient—with autophagic and macropinocytic activity returning to/surpassing basal levels after prolonged treatment. The underlying mechanistic and signaling crosstalk between autophagy and macropinocytosis remains poorly understood. We hypothesize that there is compensatory regulation between autophagy and macropinocytosis signaling following ERK MAPK inhibition. We propose that prolonged activation of autophagy upregulates macropinocytosis over time, consequently abrogating dependency on autophagy and therefore reducing sensitivity to autophagy inhibition. We demonstrate an inverse temporal relationship between autophagic flux and macropinocytosis following genetic loss of KRAS or pharmacological inhibition of the KRAS-ERK MAPK pathway. Furthermore, we show that chloroquine, which is commonly thought of as a lysosomotropic drug, does not prevent degradation of proteins engulfed via macropinocytosis. Together our data suggest that upregulation of macropinocytosis may mediate resistance to the combination of ERK MAPK inhibition and chloroquine. Additionally, we present the unexpected observation that prolonged pharmacological inhibition of the ERK MAPK pathway results in the upregulation of macropinocytosis. Furthermore, we demonstrate that this upregulation of macropinocytosis is accompanied by increased albumin uptake and sensitivity to albumin-bound paclitaxel (nab-paclitaxel). Given the dependence of PDAC on macropinocytic uptake for tumorigenic growth, as well as the potential to exploit macropinocytosis for drug-delivery, it is imperative to understand how ERK MAPK inhibitors regulate macropinocytosis. A better understanding of the regulation underlying these essential metabolic pathways will better inform future ERK MAPK inhibitor combinations. Citation Format: Ryan Robb, Kirsten L. Bryant. Elucidation and exploitation of critical nutrient scavenging regulation in ERK MAPK inhibited pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C077.

Abstract B015: Toxin-producing bacterial therapy limits tumor growth in autochthonous mouse models of pancreatic ductal adenocarcinoma

Abstract Treating pancreatic ductal adenocarcinoma (PDAC) with systemic chemotherapeutic drugs has remained a challenge, due in part to the hypovascularized and poorly perfused nature of PDAC tumors, impeding the accumulation of systemically delivered drugs. Several clinical trials aimed at improving drug delivery in PDAC, through targeting of ECM components (HALO-301) or stromal angiogenic signaling (IPI-926-03) have unfortunately not been effective. However, the features that have interfered with systemic therapy in PDAC are potential advantages for the use of bacterial therapies, as bacteria can actively migrate through tissues, thrive in hypoxic microenvironments, and benefit from local immune suppression. Recent developments in the field of synthetic biology have made it possible to engineer complex logic circuits into bacteria, enabling the production of anticancer therapies directly within the tumor parenchyma. Furthermore, live bacteria, once colonized within the tumor niche, are capable of providing a stable source of anticancer compounds directly, rather than relying on repeated systemic doses. We have therefore worked to develop novel bacterial strains and demonstrate preclinical efficacy of a novel strain of therapeutic bacteria for targeting PDAC. We began by testing a range of bacteria-produced toxins and identified the pore-forming protein theta toxin as having the greatest effect in both 2D cell culture and PDAC explant (tissue slice) models. We then engineered a non-toxic probiotic bacteria, E. coli Nissle 1917, to produce either theta toxin or GFP. To assess preclinical efficacy, we performed intratumoral injections of live GFP- and theta-expressing bacteria into the “KPC” genetically engineered mouse model (Kras LSL.G12D/+; Tp53 LSL.R172H/+; PdxCre tg/+). While GFP-producing bacteria did not induce a change in tumor growth kinetics, treatment with theta toxin-producing bacteria demonstrated prolonged stabilization of tumor growth, increasing the median survival to 34 days compared to ~12 days for vehicle- or gemcitabine-treated controls and 18.5 days for GFP-producing bacteria without additional therapy. Strikingly, while there was minimal spread of bacteria to non-tumor tissues, we observed translocation of the bacteria to macro- and micro- metastatic lesions and distant papillomas following injection of the primary pancreatic tumor, indicating a mechanism for targeting both known and unknown metastases following local administration. Histological analyses demonstrated that diffuse populations of bacteria co-localized with regions of cell death, but that bacterial presence and evidence of increased cell death was not observed in healthy tissues, such as the lung, liver, intestine, and diaphragm. Additionally, bacterial treatment, independent of the payload, led to a modest influx of anti-tumor immune populations, suggesting potential synergy with immunotherapies. Together these data demonstrate potent preclinical activity of cytotoxic bacterial therapy as a novel strategy to circumvent the challenges of systemic treatment of PDAC. Citation Format: Amanda R. Decker-Farrell, Stephen A. Sastra, Tetsuhiro Harimoto, Marie C. Hasselluhn, Fangda Li, Rosa Vincent, Carmine F. Palermo, Edward R. Ballister, Tal Danino, Kenneth P. Olive. Toxin-producing bacterial therapy limits tumor growth in autochthonous mouse models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B015.

Abstract A072: Keratin 17-signature for stratification of chemotherapy in pancreatic adenocarcinoma

Abstract Introduction: Keratin 17 (K17) is a hallmark of the most aggressive molecular subtype of pancreatic ductal adenocarcinoma (PDAC). However, it is still unknown if K17 can predict the response to the two standard-of care treatments for PDAC: 1) 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FFX) and 2) Gemcitabine/nab-paclitaxel (Gem/Nab). Thus, we hypothesized that K17 expression in patient tumors could be utilized as a biomarker to guide clinical decision-making in predicting the most effective standard-of-care treatment for patients with PDAC. Given that 85% of patients do not undergo resection, to circumvent this limitation we tested the predictive value of K17 using the tissue collected during endoscopic biopsies, which are routine in PDAC diagnosis. Methods: Our pilot study included 68 patients diagnosed with PDAC from Yale-New Haven Hospital treated with either FFX or Gem/Nab. Endoscopic biopsies were evaluated for tumor cellularity and then underwent an immunohistochemical (IHC)-based K17 test using the ABC detection method. Samples were scored by two independent pathologists using the PathSQ method. Results: Of the 68 patients included in the study, 20 (29.4%) were treated with Gem/Nab and 48 (70.6%) were treated with FFX. Based on Akaike’s Information Criterion, a K17 threshold of 45% and 60% were found to maximize stratification of patients by therapy response. At the 45% cutoff, 17 (25.0%) patients were found to have high K17 expression. At the 60% cutoff, 12 (17.6%) patients were found to have high K17 expression. Patients with low K17 expression were found to have similar overall survival (OS) despite treatment. However, patients with high K17 expression both at the 45% cutoff (p=0.031 and HR = 2.68 (CI 0.8, 8.99)) and 60% cutoff (p=0.006, HR = 6.79 (1.20, 38.32)) had decreased survival when treated with Gem/Nab compared to FFX. Conclusions: Patients with high K17 expression had lower overall survival than those with low K17 expression, validating our previous findings of K17 as a negative prognostic biomarker in PDAC. High K17 expression may be a promising predictive biomarker in PDAC, with an observed increase in OS in high K17-expressing patients treated with FFX compared to patients treated with Gem/Nab, indicating a potential biomarker to best determine response to standard-of-care treatments. Citation Format: Sumedha Chowdhury, Deanne Yugawa, Robert Tseng, Mauricio Mejia, Jill Lacy, Timil Patel, Luisa Escobar-Hoyos, Kenneth Shroyer, Guoping Cai, Marie Robert, Michael Cecchini, John Kunstman, James Farrell, Kimberly Johung. Keratin 17-signature for stratification of chemotherapy in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A072.

Abstract B094: The role of paraspeckles and splicing regulation in driving basal-like pancreatic cancer

Abstract The basal-like pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of mesenchymal PDAC that resists treatment and has a poor prognosis. Understanding the mechanisms driving basal-like PDAC biology will be essential for development of treatment strategies for this aggressive tumor. We have previously shown that loss of the tumor-suppressive non-coding RNA Neat1 recapitulate the phenotype of Arid1a-deficient mice (a component of the SWI/SNF chromatin remodeling complex) in a mouse model for PDAC, with loss of exocrine pancreatic identity and development of acinar- and ductal-derived lesions (Mello et al., 2017), suggesting that Neat1 and Arid1a may share a common molecular mechanism. We now demonstrate that the loss of these two divergent genes induce the emergence of basal-like PDAC. This provides an opportunity to probe for shared features specific to Neat1- and Arid1a-deficient PDAC, as compared to PDAC in which both genes are functional. Notably, our data indicate that both Neat1- and Arid1a-deficient pancreatic cells fail to form nuclear paraspeckles, i.e. structures implicated in the retention of RNA splicing factors. Consistent with this idea, we also find significantly increased exon-skipping, including a sub-set of such events shared between Neat1- and Arid1a-deficient PDAC. In addition, nucleotide sequence motifs associated with exon-skipping locations suggest involvement of RNA splicing factors known to accumulate in paraspeckles, such as Srsf1, Srsf2, Srsf10, Rbm38, Dazap1 and others. We also show that, upon genetic or pharmacological attenuation of splicing regulator function, basal-like PDAC develop epithelial features, reminiscent of mesenchymal-epithelial transition, reduce both their proliferation and migration potential and undergo cell death. Our findings provide an important opportunity to elucidate the molecular pathways that link aberrant RNA splicing and paraspeckle deficiency to basal-like PDAC, providing new insight for the development of mechanism-based novel PDAC treatment strategies to improve patient outcome. Citation Format: Zamira G. Soares, Emily Berry, Dakarai Esgdaille, Jennifer Twardowski, Stephano S. Mello. The role of paraspeckles and splicing regulation in driving basal-like pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B094.

Abstract B026: αvβ5 Integrin serves as a tumor-specific marker for immunosuppressive regulatory T cells in pancreatic cancer

Abstract Regulatory T cells (Tregs) contribute to the immunosuppressive nature of pancreatic ductal adenocarcinoma (PDAC). Systemic depletion of Tregs can enhance anti-tumor T cell immunity, but can also cause unwanted autoimmune complications. A tumor-specific Treg-targeted therapy that effectively and safely enhances anti-tumor immunity for PDAC treatment remains an unmet need. We have recently found that αvβ5 integrin is expressed on Tregs that reside in the PDAC, but not those in the spleen, suggesting that the integrin can serve as a targetable marker for tumor-resident Tregs. Indeed, long-term treatment with the iRGD tumor-penetrating peptide, which effectively targets αvβ5+ cells in PDAC tissue, depleted Tregs in a tumor-specific manner leading to a significant expansion of CD8+ T cells in transgenic and syngeneic PDAC mouse models. αvβ5+ Tregs were induced from both naïve CD4+ T cells and naturally occurring Tregs. T cell receptor stimulation was found to be the common inducer of αvβ5+ Tregs. αvβ5+ Tregs formed a subpopulation of CCR8+ Tregs, which are preferentially found in the tumor tissue of various cancer types. Our most recent data show that the αvβ5 integrin marks a highly immunosuppressive fraction of the CCR8+ Tregs, suggesting that targeting αvβ5+ Tregs can lead to effective depletion of immunosuppressive Tregs in a tumor-specific manner. Citation Format: Yuki Kunisada, Kodai Suzuki, Norio Miyamura, Shingo Eikawa, Tatiana Hurtado de Mendoza, Evangeline S. Mose, Caisheng Lu, Yukihito Kuroda, Erkki Ruoslahti, Andrew M. Lowy, Kazuki N. Sugahara. αvβ5 Integrin serves as a tumor-specific marker for immunosuppressive regulatory T cells in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B026.

Abstract C098: Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma

Abstract Background KRAS is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC). Over the past decade, targeting KRAS has emerged as a promising approach for PDAC treatment. However, the associations between KRAS mutations status and comutation landscape with clinical outcomes remain understudied. We investigated the impact of KRAS mutant allelic status and genomic co-mutations with clinical outcomes. Methods 803 patients with PDAC who underwent CLIA somatic tumor mutation testing at MD Anderson Cancer Center (MDACC) from 1997 to 2023 were identified after an IRB approval. Tumor genomic alterations, demographics, clinical, molecular, and pathological data were extracted from electronic medical records and tumor registry through the Palantir Foundry platform. An external cohort from PanCAN’s Know Your Tumor® dataset with 408 patients served as the validation cohort. Overall Survival (OS) was calculated from the date of initial diagnosis to death or last follow-up. Pearson’s chi-squared tests (or Fisher’s exact tests) were used to determine the association between groups. The Kaplan-Meier method was used to estimate the median OS. Results 703 patients had KRAS gene included in the mutation testing at MDACC from 1997 to 2023. KRAS was the top mutated gene (82%), followed by TP53 (69%), then CDKN2A (20%). In KRAS mutant patients, G12D was the most common variant (39%), followed by G12V (31%), then G12R (14%), and Q61 (6%). In patients tested with multi-gene panels, a co-mutation analysis revealed that the most common co-occurring mutations with KRAS mutation was TP53 (75%), followed by CDKN2A (22%), SMAD4 (14%) and ARID1A (10%). The median follow-up was 41 months and median OS was 19 months in the overall population. KRAS mutation status and subtypes was prognostic of OS (p<0.001). Patients with KRAS wildtype had median OS of 38 months and KRASG12R had median OS of 34 months (HR:1.0, 95% CI 0.71-1.5, p=0.88), while patients with KRASQ61 had worst median OS of 20 months (HR: 1.9, 95% CI 1.2-3.0, p=0.006) and KRASG12D had median OS of 22 months (HR: 1.7, 95% CI 1.3-2.3, p<0.001). Similar findings were observed in patients with stage IV disease (n=302), KRASG12D remained associated with significantly worse OS (HR= 1.7, 95% CI 1.1-2.6, p=0.009). There was a significant enrichment of KRASG12D mutation in metastatic disease compared to localized disease (stage I-III) (OR: 1.7, 95% CI 1.2-2.4, p=0.001) and enrichment of KRASG12R mutation in well and moderately differentiated tumors versus poorly differentiated tumors (OR: 1.7, 95% CI 1.05-2.99, p=0.04). In the external cohort (PanCAN’s Know Your Tumor® dataset), similar findings were observed. KRASG12R was associated with longer median OS (32 months), while KRASQ61 (16 months, HR: 2.6, 95% CI 0.88-7.8, p=0.02) and KRASG12D (23 months, HR: 1.68, 95% CI 1.06-2.65, p=0.04) were associated with significantly worse median OS. Conclusion Allele specific associations of KRAS mutation with clinical outcomes were identified in PDAC. We found better OS with G12R and worse OS with G12D and Q61. Citation Format: Abdelrahman Yousef, Mahmoud Yousef, Saikat Chowdhury, Kawther Abdilleh, Mark Knafl, Paul Edelkamp, Kristin Alfaro-Munoz, Ray Chacko, Jennifer Peterson, Brandon Smaglo, Robert Wolff, Shubham Pant, Michael Lee, Jason Willis, Michael Overman, Sudheer Doss, Lynn Matrisian, Mark Hurd, Rebecca Snyder, Matthew Katz, Huamin Wang, Anirban Maitra, John Paul Shen, Dan Zhao. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C098.

Abstract B041: Keratin 17 excludes CD8-positive T cells and recruits CD163-positive macrophages in pancreatic ductal adenocarcinoma

Abstract Background. Keratin 17 (K17) is a negative prognostic and predictive biomarker, overexpressed in the biologically most aggressive forms of pancreatic ductal adenocarcinoma (PDAC). In other anatomic sites and disease processes, K17 expression impacts the inflammatory microenvironment, correlating with changes in the expression of inflammatory cytokines and the infiltration of CD8+ T cells. Thus, we hypothesized that K17 expression also impacts the immune response in PDAC. Methods. We aimed to determine the relationship between intratumoral and peritumoral immune cell infiltrates versus K17 expression in tumor cells, using brightfield multiplexed immunohistochemistry (mIHC) and our suite of deep learning tools to quantitatively evaluate the expression of four biomarkers of T-cells and macrophages. The study included a multi-institutional cohort of 235 PDAC cases from Stony Brook University Hospital (n=54), Thomas Jefferson University (n=67), Cedars Sinai Medical Center (n=7) and Know Your Tumor PanCAN-Perthera (n=107). Peritumoral immune cells were scored in zones defined as stromal tissue within ≤25 µm of the closest tumor cell. Intratumor immune cells were defined as those that physically touched or overlapped with tumor cells. Immune cell counts in peritumoral and intratumoral K17-negatvie areas of the tumor were normalized to immune cell counts in K17-positive areas. Results. The density of CD8+ T cells in K17-negative peritumoral zones was greater than in K17-positive peritumoral zones in 82.6% of PDACs. Similarly, the density of intratumoral CD8+ T cells in K17-negative areas was greater than in K17-positive areas in 93.2% of cases. Less striking inverse correlations for immune cell density relative to K17 expression were found for CD4+ peritumor lymphocytes and both intratumoral and peritumor CD16+ macrophages. By contrast, CD163+ (tumor-promoting) macrophages were more numerous in K17+ peritumoral and intratumoral zones. All differences were statistically significant and independent of tumor grade, stage, histologic subtype, and neoadjuvant treatment history (p< 0.0001). Conclusions. Correlations between K17 and inflammatory cells suggests K17 expression negatively influences the number and infiltration of T-cells and contributes to the marked immunosuppressive effect of PDAC. These findings suggest that the biologic impact of K17 goes beyond its role as a negative prognostic biomarker that impacts tumor growth, metastasis, and chemoresistance, to suppress the immune response to PDAC. Understanding how K17 influences immune cell function may inform future immunotherapeutic opportunities for PDAC treatment. Citation Format: Lyanne Oblein, Sruthi Babu, Mariana Torrente-Goncalves, Lucia Roa, Michael Horowitz, Mahmudul Hasan, Danielle Fassler, Jaymie Oentoro, Emanuel Petricoin, Lynn M. Matrisian, Natalia Marchenko, Edik Blais, Felicia Allard, Ali Alkalin, Wei Jiang, Brent Larson, Andrew Hendifar, Chao Chen, Shahira Abousamra, Dimitris Samaras, Tahsin Kurc, Joel Saltz, Luisa Escobar-Hoyos, Kenneth Shroyer. Keratin 17 excludes CD8-positive T cells and recruits CD163-positive macrophages in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B041.

Multi-Algorithm Analysis Reveals Pyroptosis-Linked Genes as Pancreatic Cancer Biomarkers.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at late stages, limiting treatment options and survival rates. Pyroptosis-related gene signatures hold promise as PDAC prognostic markers, but limited gene pools and small sample sizes hinder their utility. We aimed to enhance PDAC prognosis with a comprehensive multi-algorithm analysis. Using R, we employed natural language processing and latent Dirichlet allocation on PubMed publications to identify pyroptosis-related genes. We collected PDAC transcriptome data (n = 1273) from various databases, conducted a meta-analysis, and performed differential gene expression analysis on tumour and non-cancerous tissues. Cox and LASSO algorithms were used for survival modelling, resulting in a pyroptosis-related gene expression-based prognostic index. Laboratory and external validations were conducted. Bibliometric analysis revealed that pyroptosis publications focus on signalling pathways, disease correlation, and prognosis. We identified 357 pyroptosis-related genes, validating the significance of BHLHE40, IL18, BIRC3, and APOL1. Elevated expression of these genes strongly correlated with poor PDAC prognosis and guided treatment strategies. Our accessible nomogram model aids in PDAC prognosis and treatment decisions. We established an improved gene signature for pyroptosis-related genes, offering a novel model and nomogram for enhanced PDAC prognosis.

Prognostic significance of occult vertebral fracture in patients undergoing pancreatic resection for pancreatic cancer

ObjectiveThe prognostic impact of occult vertebral fracture (OVF) in patients with malignancies is a new cutting edge in cancer research. This study was performed to analyze the prognostic impact of OVF after surgery for pancreatic cancer. MethodsThis study involved 200 patients who underwent surgical treatment of pancreatic ductal adenocarcinoma. OVF was diagnosed by quantitative measurement using preoperative sagittal computed tomography image reconstruction from the 11th thoracic vertebra to the 5th lumbar vertebra. ResultsOVF was diagnosed in 65 (32.5 %) patients. The multivariate analyses showed that male sex (p = 0.01), osteopenia (p < 0.01), OVF (p < 0.01), a carbohydrate antigen 19-9 level of ≥400 U/mL (p < 0.01), advanced stage of cancer (p < 0.01), and non-adjuvant chemotherapy (p = 0.02) were independent risk factors for overall survival. An age of ≥74 years (p < 0.01) and obstructive jaundice (p = 0.03) were independent risk factors for OVF. Furthermore, the combination of OVF and osteopenia further worsened disease-free survival and overall survival compared with osteopenia or OVF alone (p < 0.01; respectively). ConclusionEvaluation of preoperative OVF might be a useful prognostic indicator for patients with pancreatic ductal adenocarcinoma.

NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer

The NAPOLI 3 trial showed the superiority of fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin (NALIRIFOX) over the combination of gemcitabine and nab-paclitaxel (GEM-NABP) as first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Analyses comparing NALIRIFOX and GEM-NABP with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) have not yet been reported. To derive survival, response, and toxic effects data from phase 3 clinical trials and compare NALIRIFOX, FOLFIRINOX, and GEM-NABP. After a systematic search of PubMed, Scopus, Embase, and American Society of Clinical Oncology and European Society for Medical Oncology meetings' libraries, Kaplan-Meier curves were extracted from phase 3 clinical trials conducted from January 1, 2011, until September 12, 2023. Phase 3 clinical trials that tested NALIRIFOX, FOLFIRINOX, or GEM-NABP as first-line treatment of metastatic PDAC and reported overall survival (OS) and progression-free survival (PFS) curves were selected. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses of Individual Participant Data reporting guidelines. Individual patient OS and PFS data were extracted from Kaplan-Meier plots of original trials via a graphic reconstructive algorithm. Overall response rates (ORRs) and grade 3 or higher toxic effects rates were also collected. A pooled analysis was conducted, and results were validated via a network meta-analysis. The primary end point was OS. Secondary outcomes included PFS, ORR, and toxic effects rates. A total of 7 trials with data on 2581 patients were analyzed, including 383 patients treated with NALIRIFOX, 433 patients treated with FOLFIRINOX, and 1756 patients treated with GEM-NABP. Median PFS was longer in patients treated with NALIRIFOX (7.4 [95% CI, 6.1-7.7] months) or FOLFIRINOX (7.3 [95% CI, 6.5-7.9] months; [HR], 1.21 [95% CI, 0.86-1.70]; P = .28) compared with patients treated with GEM-NABP (5.7 [95% CI, 5.6-6.1] months; HR vs NALIRIFOX, 1.45 [95% CI, 1.22-1.73]; P < .001). Similarly, GEM-NABP was associated with poorer OS (10.4 [95% CI, 9.8-10.8]; months) compared with NALIRIFOX (HR, 1.18 [95% CI, 1.00-1.39]; P = .05], while no difference was observed between FOLFIRINOX (11.7 [95% CI, 10.4-13.0] months) and NALIRIFOX (11.1 [95% CI, 10.1-12.3] months; HR, 1.06 [95% CI, 0.81-1.39]; P = .65). There were no statistically significant differences in ORR among NALIRIFOX (41.8%), FOLFIRINOX (31.6%), and GEM-NABP (35.0%). NALIRIFOX was associated with lower incidence of grade 3 or higher hematological toxic effects (eg, platelet count decreased 1.6% vs 11.8% with FOLFIRINOX and 10.8% with GEM-NABP), but higher rates of severe diarrhea compared with GEM-NABP (20.3% vs 15.7%). In this systematic review and meta-analysis, NALIRIFOX and FOLFIRINOX were associated with similar PFS and OS as first-line treatment of advanced PDAC, although NALIRIFOX was associated with a different toxicity profile. Careful patient selection, financial toxic effects consideration, and direct comparison between FOLFIRINOX and NALIRIFOX are warranted.

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3' endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of nontransformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional readthrough in replication-dependent histones, reduces core histone expression, destabilizes chromatin structure, and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.

AMIGO2 is a pivotal therapeutic target related to M2 polarization of macrophages in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a common kind of lethal cancer, with low early diagnostic rate and poor prognosis. In this study, we identified and verified the AMIGO2 with significant diagnostic and prognostic value in PDAC through LASSO regression combined with multiple machines learning methods, including RVM-RFE and Random Forest in TCGA and GEO datasets. The relevance between the expression of AMIGO2 and M2 polarization of macrophages was identified through pancancer, normal tissue, and cell lines data in TCGA, GTEx and CCLE datasets. The relevance between AMIGO2 and M2 polarization was then further identified in our local PDAC cohort. Finally, the role of AMIGO2 as cancer promoter and pivotal factor enrolled in M2 polarization was verified through siRNA transfection and M2 macrophages induction. These findings could facilitate diagnosis and treatment of PDAC. In addition, further research was deemed necessary on the deep mechanism between AMIGO2 and M2 polarization of macrophages in PDAC.

Identification of Transcriptomic Signatures of Pancreatic Ductal Adenocarcinoma-Derived Exosomes That Promote Macrophage M2 Polarization and Predict Prognosis: S100A9 Reveals Tumor Progression.

Exosomes play a role in intercellular communication and participate in the interaction between pancreatic ductal adenocarcinoma (PDAC) cells and immune cells. Macrophages can receive tumor cell-derived exosomes to polarize into M2-type macrophages, which can enhance the invasion and metastasis of pancreatic cancer, leading to poor prognosis. However, the mechanism by which pancreatic cancer cell-derived exosomes promote M2-type macrophages is still unclear. M2 macrophage-associated exosome-derived key module genes were identified by differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) analysis using exoRbase 2.0, The Cancer Genome Atlas (TCGA), and The International Cancer Genome Consortium (ICGC) databases. Multivariate Cox regression analysis was used to identify key prognostic genes and obtain regression coefficients to establish prognostic signature. Immune infiltration, tumor mutations, and GSEA among different risk groups were compared. exoRbase 2.0, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), HPA, and TISCH2 databases were used to further analyze the expression pattern of S100A9 in pancreatic cancer. In vitro experiments, cell-derived exosome isolation, quantitative polymerase chain reaction (qPCR), western blot, flow cytometry analysis, cell transfection, transwell assay, and CCK-8 assay were applied to investigate the roles of S100A9 in macrophage M2 polarization and tumor progression. The key genes of PDAC-derived exosomes promoting M2-type macrophage polarization were identified, and a risk score model was established. The risk score is related to the expression of common immune checkpoints, immune score, and stromal score, and the tumor mutational burden and biological function of high- and low-risk groups were also different. S100A9 was positively correlated with M2-type macrophage marker. In addition, scRNA-seq data from the TISCH2 database revealed that S100A9 is predominantly expressed in pancreatic cancer cells and mono/macrophage cells, suggesting that S100A9 in pancreatic cancer cells could be received by macrophages, thereby inducing macrophage polarization. In vitro, we used exosomes from BxPC-3 cell lines to coculture macrophages and found that macrophages were mainly polarized toward M2 type, which further promoted the proliferation and metastasis of PDAC. Our study established a reliable risk score model for PDAC-derived exosomes and M2 macrophages, identified the important role of S100A9 in macrophage M2 polarization, which provides a new strategy for the diagnosis and treatment of PDAC, and strengthened the understanding of the mechanism of tumor development and metastasis.

Vasohibin-2-Targeting Therapies for the Treatment of Pancreatic Ductal Adenocarcinoma.

As pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and refractory, therapeutic options for this cancer are anticipated worldwide. We isolated vasohihibin-2 (VASH2) and observed its overexpression in various types of cancer. We then noticed that upregulated expression of VASH2 in patients with PDAC resulted in a conspicuous reduction in the postoperative survival period and further revealed that the abrogation of Vash2 expression in pancreatic cancer cells inhibited its growth and metastasis and augmented tumor infiltration of CD8+ cells in the mouse model. We developed VASH2-targeting therapies, 2',4'-BNA-based antisense oligonucleotide targeting VASH2 (VASH2-ASO) as a nucleotide-based therapy, and VASH2-peptide vaccine as an antibody-based therapy. We also showed that the VASH2-peptide vaccine inhibited PDAC metastasis in an orthotopic mouse model. Here, we expanded our analysis of the efficacy of VASH2-targeting therapies for PDAC. VASH2-ASO treatment inhibited the growth of primary tumors by reducing tumor angiogenesis, normalizing tumor vessels, preventing ascites accumulation and distant metastasis to the liver and lungs, and augmenting the infiltration of CD8+ cells in metastatic tumors. VASH2-peptide vaccine did not affect the infiltration of CD8+ cells into tumors. The present study revealed that VASH2-targeting therapies are promising options for the treatment of PDAC. VASH2-ASO therapy can be administered at any stage of PDAC. Because of the increase of CD8+ cell infiltration, the combination therapy with immune checkpoint inhibitors may be an attractive option. The VASH2-peptide vaccine therapy may be useful for preventing metastasis and/or recurrence after successful initial treatment.

Laparoscopic and compared to open pancreatoduodenectomy is safe for the treatment of pancreatic ductal adenocarcinoma treated by chemoradiotherapy

Laparoscopic and compared to open pancreatoduodenectomy is safe for the treatment of pancreatic ductal adenocarcinoma treated by chemoradiotherapy