Therapeutics For Pancreatic Ductal Adenocarcinoma Research Articles

Caffeic acid, a dietary polyphenol, pre-sensitizes pancreatic ductal adenocarcinoma to chemotherapeutic drug

Resistance to chemotherapeutics is an eminent cause that leads to search for options that help in diminution of pancreatic ductal adenocarcinoma (PDAC) by overcoming resistance issues. Caffeic acid (CFA), a polyphenol occurring in many dietary foods, is known to show antidiabetic and anticancer properties potential. To unveil the effect of CFA on PDAC, we carried out this research in PDAC cells, following which we checked the combination effect of CFA and chemotherapeutics and pre-sensitization effects of CFA. Multitudinous web-based approaches were applied for identifying CFA targets in PDAC and then getting their interconnections. Subsequently, we manifested CFA effects by in-vitro analysis showing IC50 concentrations of 37.37 and 15.06 µM on Panc-1 and Mia-PaCa-2, respectively. The combination index of CFA with different drugs was explored which showed the antagonistic effects of combination treatment leading to further investigation of the pre-sensitizing effects. CFA pre-sensitization reduced IC50 concentration of doxorubicin in both PDAC cell lines which also triggered ROS generation determined by 2′,7′-dichlorofluorescin diacetate assay. The differential gene expression analysis after CFA treatment showed discrete genes affected in both cells, i.e. N-Cad and Cas9 in Panc-1 and Pi3K/AkT/mTOR along with p53 in Mia-PaCa-2. Collectively, this study investigated the role of CFA as PDAC therapeutics and explored the mechanism in mitigating resistance of PDAC by sensitizing to chemotherapeutics. Communicated by Ramaswamy H. Sarma

Inhibiting stromal Class I HDACs curbs pancreatic cancer progression

Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.

Regulation of metabolism in pancreatic ductal adenocarcinoma via nanotechnology-enabled strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with insidious onset and early distal metastasis. Metabolic reprogramming, the autonomous changes in cellular bioenergetics driven by aberrant genetic events and crosstalk between cancer and non-cancer cells in the desmoplastic microenvironment, is pivotal for the rapid progression of PDAC. As an attractive therapeutic target, nucleoside metabolism is regulated by various anti-metabolic drugs for the clinical treatment of PDAC. Despite various challenges, such as poor drug delivery efficiency and off-target side effects, metabolic modification and intervention are emerging as promising strategies for PDAC therapy, enabled by the rapid development of nanotechnology-based drug delivery strategies. In this review, we discuss the metabolic characteristics of PDAC and highlight how the development of nanomedicine has boosted the development of new therapeutics for PDAC by modulating critical targets in metabolic reprogramming.

Abstract C073: CRO-67 is a novel therapeutic for pancreatic cancer: Implications for tumor and stromal reprogramming

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and new therapeutic strategies are urgently required. A key drug delivery barrier and promoter of tumor progression is the fibrotic and heterogeneous microenvironment of PDAC which is mainly orchestrated by stromal cancer-associated fibroblasts (CAFs). Thus, any novel therapeutic strategy should not only target PDAC cells but should also aim to inhibit the pro-tumor properties of the PDAC stroma. However, to accurately evaluate the clinical potential of novel PDAC therapeutics, preclinical models are required that closely mimic the heterogeneity and multicellular architecture of human disease. Aim: We aimed to investigate the therapeutic potential of novel functionalized benzopyrans (CRO-05 & CRO-67) in a patient-derived PDAC tumor explant model. Methods: We collected PDAC tumor samples from patients undergoing resection of their primary tumor. We cultured whole tumor explants (1-2mm diameter) on gelatin sponges. This model accurately maintains the multicellular tumor and stromal architecture of human PDAC [Kokkinos et al, Scientific Reports, 11,1941 (2021)]. Tumor explants were treated every 3 days with the racemic compound CRO-05 or its active enantiomer CRO-67 and explants were fixed in paraformaldehyde at day-12. Therapeutic response was assessed by immunohistochemistry for markers of tumor cells (cytokeratin), CAFs (α-Smooth Muscle Actin), cell-proliferation (Bromodeoxyuridine), and cell-death (TUNEL). Results: Treatment of human PDAC explants with CRO-05 resulted in reduced tumor cell frequency in 3/4 patients and in 4/4 patients, reduced CAF frequency, decreased cell-proliferation, and increased cell-death relative to controls. CRO-67 treatment in explants from 4/5 patients led to reduced tumor cell frequency, and in 5/5 patients, reduced CAF frequency, decreased cell-proliferation, and increased cell-death relative to controls. Conclusions: This work identifies the functionalized benzopyrans CRO-05 and CRO-67 as novel dual-cell therapeutics that potently inhibit both PDAC tumor cells and their surrounding CAFs and provides support for their clinical development as novel PDAC therapeutics. Citation Format: John Kokkinos, George Sharbeen, Koroush S. Haghighi, Janet Youkhana, Aparna Raina, Omali Pitiyarachchi, Quach Truong, Daniel Wenholz, Olivier Laczka, Naresh Kumar, David Goldstein, Phoebe A. Phillips. CRO-67 is a novel therapeutic for pancreatic cancer: Implications for tumor and stromal reprogramming [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C073.

Abstract 5007: Discovery of stromal targets in pancreatic cancer

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited treatment options. Development of stroma targeting therapeutics for PDAC is gaining attention because PDAC has a unique tumor microenvironment with dense tumor stroma and the tumor stroma is a critical mediator of PDAC progression. Herein, we discovered pancreatic cancer stroma-specific cell surface markers by integrative analysis of single cell RNA sequencing and cell surface marker database. Methods: Single cell RNA sequencing data of PDAC tissue (n = 3, GSE154778) and normal pancreas tissue (n = 3, GSE131886) was obtained from Gene Expression Omnibus database. Using Seurat package, the data from each sample integrated and the cells were clustered. We selected stroma cell cluster for differential analysis to obtain the genes enriched in PDAC stroma. Then, the intersection of the PDAC stroma specific genes with the gene set of SurfaceomeDB was obtained, which allowed us to obtain the stroma cell surface markers that are highly expressed in PDAC. The marker genes were validated in 1) 36 pairs of PDAC and normal tissue samples from a RNA sequencing data (GSE15471), and 2) 143 PDAC samples in The Cancer Genome Atlas (TCGA), 328 normal pancreatic tissues in Genotype-Tissue Expression (GTEx) database (https://www.gtexportal.org). Results: The cells from PDAC and normal pancreas were clustered into ductal/tumor, stromal and immune cell clusters according to the expression of cell-type specific marker genes. We identified variably expressed genes between PDAC and normal cells within the stromal cell cluster. Among the PDAC stroma-specific genes, we could obtain 360 cell surface markers using SurfaceomeDB. The top ten PDAC stroma-specific cell surface marker genes were MXRA8, ANTXR1, THY1, SCD1, LY6E, BST2, GPNMB, CDH11, GJB2, and CD55. To validate the results, we compared the expression levels of the top 10 genes between pancreatic cancer tissue and adjacent normal pancreatic tissue. We found that the expression levels of the genes were significantly higher in the cancer tissue compared to the normal pancreatic tissue. We also confirmed that the expression levels of 10 genes were significantly higher in all stages of PDAC compared to normal tissues in a combined RNA sequencing dataset from healthy human pancreatic tissue from GTEx and pancreatic cancer patients from TCGA. Conclusion: We identified pancreatic cancer stroma-specific cell surface markers using single-cell RNA sequencing data and SurfaceomeDB. The markers can be utilized in development of various pancreatic cancer stroma targeted therapeutics including antibodies, antibody-drug conjugates, peptides, cell therapeutic and nanoparticles. Citation Format: Shengjun Li, Jeong-Bin Park, Hyung-Jun Im. Discovery of stromal targets in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5007.

Translational genomics in pancreatic ductal adenocarcinoma: A review with re-analysis of TCGA dataset.

Malignancy of the pancreas is a leading cause of cancer-related mortality, with the highest case-fatality of all cancers. Nevertheless, the lack of sensitive biomarkers and presence of biological heterogeneity precludes its early detection and effective treatment. The recent introduction of next-generation sequencing allows characterization of multiple driver mutations at genome- and exome-wide levels. Sequencing of DNA and RNA from circulating tumour cells has also opened an exciting era of non-invasive procedures for tumour detection and prognostication. This massively-parallel sequencing technology has uncovered the previously obscure molecular mechanisms, providing clues for better stratification of patients and identification of druggable targets for the disease. Identification of active oncogenic pathways and gene-gene interactions may reveal oncogene addiction and synthetic lethality. Relevant findings can be extrapolated to develop targeted and personalized therapeutic interventions. In addition to known mutational events, the role of chromosomal rearrangements in pancreatic neoplasms is gradually uncovered. Coupled with bioinformatics pipelines and epidemiological analyses, a better framework for risk stratification and prognostication of pancreatic cancer will be possible in the near future. In this review, we discuss how translational genomic studies facilitate our understanding of pathobiology, and development of novel diagnostics and therapeutics for pancreatic ductal adenocarcinoma with emphases on whole genome sequencing, whole exome sequencing, and liquid biopsies. We have also re-analyzed The Cancer Genome Atlas (TCGA) dataset to look for genetic features associated with altered survival in patients with pancreatic ductal adenocarcinoma.

Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics.

Mortality remains alarmingly high for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), with 93% succumbing to the disease within five years. The vast majority of PDAC cases are driven by activating mutations in the proto-oncogene KRAS, which results in constitutive proliferation and survival signaling. As efforts to target RAS and its downstream effectors continue, parallel research aimed at identifying novel targets is also needed in order to improve therapeutic options and efficacy. Recent studies demonstrate that self-renewing cancer stem cells (CSCs) contribute to metastatic dissemination and therapy failure, the causes of mortality from PDAC. Here, we discuss current challenges in PDAC therapeutics, highlight the contribution of mesenchymal/CSC plasticity to PDAC pathogenesis, and propose that targeting the drivers of plasticity will prove beneficial. Increasingly, intrinsic oncogenic and extrinsic pro-growth/survival signaling emanating from the tumor microenvironment (TME) are being implicated in the de novo generation of CSC and regulation of tumor cell plasticity. An improved understanding of key regulators of PDAC plasticity is providing new potential avenues for targeting the properties associated with CSC (including enhanced invasion and migration, metastatic outgrowth, and resistance to therapy). Finally, we describe the growing field of therapeutics directed at cancer stem cells and cancer cell plasticity in order to improve the lives of patients with PDAC.

Abstract B19: Rapid in vivo screen of pancreatic ductal adenocarcinoma therapeutics

Abstract Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer related deaths. Limited progress has been made in developing effective therapy for PDA. Compounding this challenge has been the lack of a systematic and robust in vivo screen for effective drug combinations. Kras mutations (e.g. KrasG12D) are found in over 90% of human PDA and occur early in tumor progression. Protein kinase and G-Protein Coupled Receptor (GPCR) signaling can initiate Ras activation. Regulators of G-protein Signaling (RGS) proteins are coincidence detectors that can be induced by and integrate multiple inputs to feedback regulate GPCR signaling. We previously described Rgs16 expression during embryonic and postnatal pancreas development in pancreatic progenitors, endocrine cells and ductal-associated cells. Here, we show that the Rgs16::GFP transgene is a KrasG12D dependent marker of all stages of neoplasia in the p48Cre; LSL-KrasG12D; Cdkn2af/f PDA mice. Although KrasG12D is expressed in embryonic pancreas progenitor cells and in all mature acinar cells, Rgs16::GFP expression in tumors first emerges in ductal pancreatic intraepithelial neoplasms as early as 12 days post birth. The distribution and intensity of expression is proportional to and coincident with tumor burden. Rgs16::GFP expression in acinar cells of distal lobes initiates only after tumor occlusion of proximal ducts. The gene expression signature of primary PDA cells in culture obtained via RNA-seq is closely related to embryonic progenitors of pancreatic ducts and endocrine cells. PDA cells in culture are highly sensitive to the chemotherapic drug gemcitabine mediated cell death. In a proof-of-principle for drug screens, we find PDA weanling mice treated with gemcitabine and Nab-paclitaxel for two weeks have significantly lower Rgs16::GFP expression and reduced tumor size and occurrence. Rgs16::GFP is a novel in vivo reporter of PDA progression and sensitivity to new drug regimens that inhibit KrasG12D mediated oncogenesis. Supported by NCI-CA161624 Citation Format: Ozhan Ocal, Blake Heath, Lee B. Rivera, Victor Pashkov, Galvin H. Swift, Rolf A. Brekken, Tom M. Wilkie. Rapid in vivo screen of pancreatic ductal adenocarcinoma therapeutics. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B19. doi: 10.1158/1557-3125.RASONC14-B19

Abstract A69: The novel strategy for treatment of pancreactic ductal adenocarcinoma targeting tumor microenvironment.

Abstract Background and Aim: Previously, we have reported a genetically engineered mouse pancreatic ductal adenocarcinoma (PDAC) progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation. This model shows PDAC with 100 % penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC targeting tumor microenvironment. Materials and Methods: To investigate whether the mice model is suitable for the drug screening, the mice were treated with gemcitabine or S-1, which are the standard drug for human PDAC, To the next, for single agent treatment, mice were treated with axitinib (A) or sunitinib (S), which are multi-kinase inhibitors, or candesartan (C) or telmisartan (T), which are anigiotensin II receptor blockers (ARBs), respectively. For combined agent experiment, mice were treated with A, C, or T combined with gemcitabine or S-1. Treatment continued until 8 weeks of age. Moreover, for the survival analysis, the drug treatment was continued until the mice became distressed. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, F4/80, α-SMA, and VEGF was performed. Azan staining also performed for the assessment of fibrosis in the tumor. Results: Gemcitabine and S-1 showed anti-proliferative effect and prolonged overall survival of these mice compared to control, as well as human cases. Median survival time of single use of A and S group was significantly longer and that of C and T group was tended to be longer than that of control group. The entire drug-treatment group showed significantly stronger anti-tumor effect in vivo compared to control. Combined treatment led to statistically significant longer survival and more anti-tumor effect than that of single agent-treated group. A and S group showed significantly higher caspase 3 staining and lower Ki67 staining than that of control, however, C and T group showed no change of these staining, compared to control. Microvessel density, F4/80, and α-SMA staining, VEGF expression, and azan staining of the entire drug-treated group was significantly lower than that of control. Conclusion: Targeting tumor microenvironment, such as angiogenesis, immune cell infiltration and fibrosis, using multi-kinase inhibitor or ARB in addition to cytotoxic agents, such as gemcitabine or S-1, may be a promising therapeutics for PDAC. Citation Format: Motohisa Tada, Hideaki Ijichi, Koji Miyabayashi, Yoshinari Asaoka, Dai Mohri, Tsuneo Ikenoue, Rintarou Mikata, Takeshi Ishihara, Fumihiko Kanai, Masao Omata, Harold L. Moses, Osamu Yokosuka. The novel strategy for treatment of pancreactic ductal adenocarcinoma targeting tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A69.

Abstract A39: The exploration of novel strategy for treatment of pancreactic ductal adenocarcinoma targeting tumor microenvironment with multi-kinase inhibitors

Abstract Background and Aim: Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Previously, we have reported a genetically engineered mouse PDAC progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation (Ijichi H, et al 2006). This model shows PDAC with 100% penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC. Materials and Methods: At first, to investigate whether the mice model is suitable for the drug screening, the mice were treated with gemcitabine (12.5 mg/kg) by intraperitoneal (i.p.) injection or S-1 (8.4 mg/kg) per oral, which are the standard drug for human PDAC. To the next, for single agent treatment, mice were treated orally 6 times a week with vehicle (0.5 % carboxymethyl cellulose, CMC), sunitinib (40 mg/kg), and axitinib (30mg/kg), both of which are multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) from the 3 weeks of age. For combined agent experiment, mice were treated orally with vehicle (0.5 % CMC) or axitinib from the 3 weeks of age and also treated with saline or gemcitabine, i.p. twice a week from the 4 weeks of age. Treatment continued until 8 weeks of age. Moreover, for the survival analysis, the drug treatment was continued until the mice became distressed according to the same schedule stated above. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, F4/80 and VEGF was performed. Azan staining also performed for the assessment of fibrosis in the tumor. Results: Gemcitabine and S-1 showed antiproliferative effect and prolonged overall survival of these mice compared to control, as well as human cases. Median survival time of single use of axtinib and sunitinib group was significantly longer (p <0.01) than that of control group. Axitinib and sunitinib group showed significantly stronger anti-tumor effect in vivo (p <0.01). In the combined treatment experiment, gemcitabine plus axitinib-treated group showed statistically significant longer survival and more anti-tumor effect than that of gemcitabine or axtinib alone-treated group (p <0.01). Axitinib and sunitinib group showed significantly higher caspase 3 stainng and lower Ki67 staining than that of control (p <0.01). Microvessel density (CD 31 staining) of axitinib and sunitinib group was significantly lower than that of control (p <0.01). F4/80 staining was significantly lower in axitinib and sunitinib-treated group than that of control (p <0.05). VEGF expression of axitinib and sunitinib group was significantly lower than that of control a (p <0.001). Azan staining showed significantly lower fibrosis in axitinib and sunitinib-treated group compared to control (p <0.01). Conclusion: Targeting not only cancer cells but also tumor microenvironment, such as angiogenesis, infiltration of immune cells, and fibrosis, with the use of multikinase inhibitors in addition to gemcitabine, may be a promising therapeutics for PDAC.

Abstract 4383: Targeting tumor microenvironment with gemcitabine is useful for the treatment of pancreatic ductal adenocarcinoma

Abstract (Background and Aim) Previously, we have reported a genetically engineered mouse pancreatic ductal adenocarcinoma (PDAC) progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation. This model shows PDAC with 100 % penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC targeting tumor microenvironment. (Materials and Methods) To investigate whether the mice model is suitable for the drug screening, the mice were treated with gemcitabine, which is the standard drug for human PDAC, by i.p. injection. To the next, for single agent treatment, mice were treated with axitinib, which is a multi-kinase inhibitor, or candesartan, which is an anigiotensin II receptor blocker (ARB), respectively. For combined agent experiment, mice were treated with axitinib or candesartan and gemcitabine. Treatment continued until 8 weeks of age. Moreover, for the survival analysis, the drug treatment was continued until the mice became distressed according to the same schedule stated above. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, F4/80, α-SMA, and VEGF was performed. Azan staining also performed for the assessment of fibrosis in the tumor. (Results) Gemcitabine showed anti-proliferative effect and prolonged overall survival of these mice compared to control, as well as human cases. Median survival time of single use of axtinib group was significantly longer and that of candesartan group was tended to be longer than that of control group. Axitinib and candesartan group showed significantly stronger anti-tumor effect in vivo. In the combined treatment experiment, gemcitabine plus axitinib or candesartan group showed statistically significant longer survival and more anti-tumor effect than that of gemcitabine, axtinib or candesartan alone-treated group. Axitinib group showed significantly higher caspase 3 staining and lower Ki67 staining than that of control, however, candesartan group showed no change of these staining, compared to control. Microvessel density, F4/80, and α-SMA staining of axitinib and candesartan group was significantly lower than that of control. VEGF expression of candesartan group was significantly lower than that of control. Azan staining showed significantly lower fibrosis in axitinib and candesartan group compared to control. (Conclusion)Targeting tumor microenvironment, such as angiogenesis, immune cell infiltration and fibrosis, using multi-kinase inhibitor or ARB in addition to gemcitabine, may be a promising therapeutics for PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4383. doi:1538-7445.AM2012-4383

Abstract 3292: The exploration of novel strategy for treatment of pancreactic cancer using genetically engineered mice

Abstract (Background and Aim) Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in human. Previously, we have reported a genetically engineered mouse PDAC progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation (Ijichi H, et al 2006). This model shows PDAC with 100 % penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC. (Materials and Methods) For single agent treatment, mice were treated orally 6 times per week with vehicle (0.5 % carboxymethyl cellulose, CMC), sunitinib, axitinib, 5 kinds of anigiotensin II receptor blockers (ARBs), such as candesartan, telmisartan, losartan, valsartan, or olmesartan, respectively from the 3 wk of age. For combined agent experiment, mice were treated orally with vehicle (0.5 % CMC), axitinib or candesartan from the 3 wk of age and also treated with saline or gemcitabine, i.p. twice a week, from the 4 wk of age. Treatment continued until the mice became distressed, and then they were dissected. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, and VEGF was performed. (Results)Median survival time of single use of axtinib and sunitinib group was statistically longer and that of candesartan and telmisartan group was tended to be longer than that of control group. Axtinib, sunitinib, candesartan, and telmisartan group showed significant anti-tumor effect in vivo. In the combined treatment experiment, using gemcitabine showed statistically significant longer survival and more anti-tumor effect than that of single agent treatment group. Axitinib and sunitinib group showed significantly higher caspase 3 score and lower Ki67 score than that of control, however, candesartan and telimisartan group showed no change of these scores, compared to control. Microvessel density of axtinib, sunitinib, candesartan, and telmisartan group was significantly lower than that of control and other ARBs. VEGF expression of candesartan and telmisartan group was significantly lower than that of control and other ARBs. (Conclusion)Targeting angiogenesis with multikinase inhibitor or ARB in addition to gemcitabine may be a promising therapeutics for PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3292. doi:10.1158/1538-7445.AM2011-3292