Strategy For Treatment Of Pancreatic Cancer Research Articles

Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status.

BackgroundOncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028.MethodsThe effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo.ResultsThe co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone.ConclusionsThe synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status.

Treatment strategy for pancreatic cancer with simultaneous liver metastasis

The prognosis of pancreatic cancer is very poor, 40%-50% of patients have liver metastasis at the time of initial diagnosis, and only 15%-20% of patients have the chance of surgical resection. At present, there is no consensus on the treatment strategy of pancreatic cancer with simultaneous liver metastasis. Surgeons are still looking forward to surgical resection for patients with longer survival time. The application of neoadjuvant therapy and radiofrequency ablation may bring new breakthroughs in the treatment of pancreatic cancer with simultaneous liver metastasis. This article reviews the surgical, neoadjuvant and palliative treatment of pancreatic cancer with simultaneous liver metastasis. Key words: Pancreatic neoplasms; Liver; Neoplasm metastasis; Treatment outcome; Simultaneity

Diarylidenylpiperidones, H-4073 and HO-3867, Induce G2/M Cell-Cycle Arrest, Apoptosis and Inhibit STAT3 Phosphorylation in Human Pancreatic Cancer Cells.

Pancreatic cancer has a 5-year survival rate below 10% and the treatment options are limited. Signal transducer and activator of transcription (STAT3) is a constitutively expressed protein in human pancreatic cancers and is associated with their poor prognosis. Targeting of STAT3 signaling using novel therapeutic agents is a potential strategy for pancreatic cancer treatment. Diarylidenylpiperidone (DAP) compounds, such as H-4073 and HO-3867, have been shown to be STAT3 inhibitors in several human ovarian cancers. Particularly, HO-3867 is an N-hydroxypyrroline derivative of DAP that has targeted cytotoxicity toward cancer cells without affecting healthy cells. In the present study, we evaluated the anticancer efficacy of H-4073 and HO-3867 in a human pancreatic cell line (AsPC-1). We found that both the compounds exhibited potential cytotoxicity to AsPC-1 cells by inducing G2/M cell-cycle arrest, apoptosis, and cell death, by mitochondrial damage and inhibition of STAT3 phosphorylation. In summary, H-4073 and HO-3867 are cytotoxic to AsPC-1 cells and seem to act through similar mechanisms, including STAT3 inhibition, cell-cycle arrest, and apoptosis.

ATAD2 is associated with malignant characteristics of pancreatic cancer cells.

Pancreatic cancer is one of the most aggressive human cancers and is associated with a poor prognosis. To develop a novel strategy for pancreatic cancer treatment, it is essential to elucidate the molecular mechanisms underlying the invasion and proliferation of cancer cells. ATPase family AAA domain containing protein 2 (ATAD2) is a highly conserved protein with an AAA+ domain and a bromodomain. Accumulating studies have demonstrated that ATAD2 is associated with the progression of multiple cancers. The present study demonstrated that ATAD2 depletion suppressed cell invasion and migration. In addition, ATAD2 knockdown suppressed anchorage-independent growth of pancreatic cancer cells. Finally, ATAD2 depletion was demonstrated to sensitize pancreatic cancer cells to gemcitabine. The results of the present study indicate that ATAD2 is involved in the malignant characteristics of pancreatic cancer.

The role of the fat mass and obesity-associated protein in the proliferation of pancreatic cancer cells.

Fat mass and obesity-associated (FTO) protein has been identified as a critical demethylase in regulating cellular mRNA stability by removing N6-methyladenosine (m6A) residues in mRNA. Even though the role of FTO in body energy metabolism has been well established, its role in cancer cell homeostasis remains unclear. In the present study, by using RNA interference, it was indicated that FTO is required for pancreatic cancer cell proliferation. Knockdown of FTO resulted in compromised proliferation of pancreatic cancer cells. Furthermore, DNA synthesis was compromised, followed by an increase in apoptosis in FTO small interfering RNA (siRNA)-treated cells. In terms of its underlying mechanism, FTO has been indicated to interact with MYC proto-oncogene, bHLH transcription factor and to enhance its stability by decreasing its m6A level. Therefore, the aforementioned observations indicate a novel mechanism for the regulation of pancreatic cancer cells by FTO, which may provide insight on pancreatic cancer treatment strategies.

Genomic testing for pancreatic cancer in clinical practice as real-world evidence

BackgroundPrecision medicine guided by comprehensive genome sequencing represents a potential treatment strategy for pancreatic cancer. However, clinical sequencing for pancreatic cancer entails several practical difficulties. We have launched an in-house clinical sequencing system and started genomic testing for patients with cancer in clinical practice. We have analyzed the clinical utility of this system in pancreatic cancer. MethodsWe retrospectively reviewed 20 patients with pancreatic cancer who visited our division. Genomic DNA was extracted from both tumor tissue and peripheral blood mononuclear cells obtained from the patients. We performed a comprehensive genomic testing using targeted amplicon sequencing for 160 cancer-related genes. The primary endpoints were the detection rates of potential actionable and druggable gene alterations. The secondary endpoints were the detection rate of secondary germline findings, the rate of re-biopsy required for genome sequencing, survival time after the initial visit (post-sequencing survival time), and turnaround time. ResultsAlthough re-biopsy was required for 25% (5/20) of all patients, genomic testing was performed in all patients. Actionable and druggable gene alterations were detected in 100% (20/20) and 35% (7/20) of patients, respectively, whereas secondary germline findings were detected in 5% (1/20) of patients. The median turnaround times for physicians and patients were 20 and 26 days, respectively. The median post-sequencing survival time was 10.3 months. Only 10% (2/20) of all patients were treated with therapeutic agents based on the outcomes of genomic testing. ConclusionsThe clinical application of comprehensive genomic testing for pancreatic cancer was feasible and promising in clinical practice.

Different Roles of Sphingosine Kinase 1 and 2 in Pancreatic Cancer Progression

BackgroundPancreatic cancer is a disease with poor prognosis, and development of new treatments is necessary. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays a critical role in progression of many types of cancer. However, little is known about the role of sphingosine kinases in pancreatic cancer. This study investigated the roles of sphingosine kinases in pancreatic cancer progression. Materials and methodsS1P levels in pancreatic cancer and noncancerous pancreatic tissue were measured in 10 patients. We generated PAN02 murine pancreatic cancer cell lines with a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system genes 9 (Cas9)-mediated deletion of SphK1 or SphK2 and assessed cell growth and migration. In an animal model, we assessed the survival of mice injected with PAN02 cells intraperitoneally. ResultsS1P levels in the pancreatic cancer tissue were significantly higher than those in noncancerous tissue. SphK1 knockout (KO) cells showed greater proliferation and migration than wild type (WT) cells, and SphK2 KO cells showed less proliferation and migration than WT cells. Animal experiments showed that the survival of mice injected with SphK1 KO cells was significantly shorter than those injected with WT cells, and the survival of mice injected with SphK2 KO cells was longer than those injected with WT cells. Surprisingly, cytotoxic assay using gemcitabine showed that SphK1 KO cells survived less than WT cells, and SphK2 KO cells survived more than WT cells. ConclusionsS1P produced by SphK1 and SphK2 may have different functions in pancreatic cancer cells. Targeting both SphK1 and SphK2 may be a potential strategy for pancreatic cancer treatment.

WAVE3 promotes proliferation, migration and invasion via the AKT pathway in pancreatic cancer.

Alterations in Wiskott-Aldrich syndrome protein family verprolinhomologous protein 3 (WAVE3) expression play various roles in certain types of cancer. However, the roles of WAVE3 expression in pancreatic cancer remain unknown. The present retrospective study demonstrated that WAVE3 expression was higher in cancerous pancreatic tissues than in non-neoplastic tissues. Moreover, WAVE3 overexpression was related to lymphatic metastasis, a poor differentiation and high pre-operative CA19-9 levels and was an adverse prognostic factor for patients with pancreatic cancer. In vitro, the knockdown of WAVE3 inhibited the proliferative, migratory and invasive potential of pancreatic cancer cells and promoted cell apoptosis. Western blot analysis demonstrated that WAVE3 influenced the protein kinase B (PBK/AKT) pathway by suppressing the expression of pyruvate dehydrogenase kinase isoform 2 (PDK2) and then negatively inhibiting the phosphorylation of Ser473 on AKT. Furthermore, the expression of AKT pathway downstream proteins [certain epithelial-mesenchymal transition (EMT)-related proteins, p53, Bcl-2 and cyclin D1] was accordingly altered. Taken together, our findings suggest that WAVE3 influences cell proliferation, migration and invasion via the AKT pathway, and targeting WAVE3 and/or the AKT pathway may potentially serve as a treatment strategy for pancreatic cancer.

SUVmax after (18)fluoro-deoxyglucose positron emission tomography/computed tomography: A tool to define treatment strategies in pancreatic cancer

Background(18)fluoro-deoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) might be a useful tool in the management of pancreatic ductal adenocarcinoma (PDAC). AimsThe aim of this study was to analyze maximum standard uptake value (SUVmax) after 18FDG-PET/CT as predictor of survival outcomes and method to determine treatment strategies. MethodsA consecutive series of patients who underwent preoperative 18FDG-PET/CT and subsequent resection for PDAC were retrospectively reviewed. Patients who underwent neoadjuvant chemotherapy were excluded. Results46 patients were included in the analysis. Median follow-up was 27 months (4–67). Patients who recurred within 12 months showed a significantly higher preoperative median SUVmax (8.1 vs 6.1, p=0.039). Receiver operating characteristics (ROC) curves for disease-free survival (DFS) and disease-specific survival (DSS) identified SUVmax of 6.0 as optimal cut-off. Multivariate analysis showed that SUVmax ≥ 6.0 was an independent predictor of poor DFS (HR 2.288, p=0.024) and DSS (HR 4.875, p<0.001). The combination of SUVmax ≥6.0 with CA19.9 ≥200U/ml was significantly associated with survival outcomes in comparison to patients without concordantly elevated values. ConclusionSUVmax ≥6.0 is an independent predictor of DFS and DSS in resected PDAC. 18FDG-PET/CT might be considered in the preoperative evaluation of patients with pancreatic cancer.

Abstract 1241: A preclinical study of the combined treatment of arginase and canavanine in pancreatic cancer

Abstract Background: Arginine deprivation is a novel approach for cancer treatment as some cancers were found to be arginine auxotrophic. PEG-BCT-100, a pegylated form of recombinant human arginase, was used to investigate the effect of arginine deprivation on pancreatic cell lines. On the other hand, Canavanine (CAV), a natural toxic analog of arginine isolated from leguminous plant, has also demonstrated its ability in inhibiting cancer cell proliferation. It alters the protein structure and causes critical metabolic defects in the cells by replacing arginine into newly synthesized proteins during translation. In this study, we have also tested the efficacy of combined arginase and CAV treatment on pancreatic cell lines. Methods: Pancreatic cell lines (MIA PaCa-2, CFPAC-1) and normal fibroblast cell line (WI-38), were either incubated in normal or arginine free condition. The corresponding IC50 of CAV was determined by cell viability assay. To evaluate the responsiveness to the combined treatment, cells were monitored by live cell imaging under the conditions of PEG-BCT-100 treatment alone (0.3IU/ml) or in combination with CAV (10μM or 50μM). The apoptotic effect of the combined treatment was examined by Western blotting and Annexin V assay. Results: Either arginase or CAV treatment could inhibit pancreatic cancer cell growth. The cells treated with CAV in arginine free condition demonstrated an inhibition of cell proliferation and its corresponding IC50 was significantly lowered from millimolar to micromolar concentration when arginine was withdrawn. Strong synergism of CAV and PEG-BCT-100 was observed after 48-hour treatment with enhanced apoptosis in pancreatic cell lines, but not in normal fibroblast cells. Both early and late apoptosis were observed in co-treated pancreatic cancer cells as indicated by Annexin V assay and the detection of polyADP ribosyl polymerase (PARP) in Western blot. Conclusion: Arginine deprivation by PEG-BCT-100 combined with CAV treatment showed a strong synergetic effect on inducing cell death in pancreatic cell lines, suggesting that the supplement of CAV could facilitate the treatment outcome of arginine deprivation by arginase. This combined treatment may serve as a treatment strategy for pancreatic cancer. Citation Format: Tsz Tung Kwong, Chi Hang Wong, Herbert Ho Fung Loong, Stephen Lam Chan. A preclinical study of the combined treatment of arginase and canavanine in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1241. doi:10.1158/1538-7445.AM2017-1241

Abstract 901: The mechanobiome of pancreatic cancer: a viable, targetable drug space

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an annual mortality rate of 37,000 in the US alone. Its 5-year survival rate of ~6% remains relatively unchanged over the past 4 decades. Because PDAC has elevated rates of de novo and acquired resistance to traditional chemotherapies, we are exploring new drug spaces that target metastatic hepatic disease, the primary mortality factor for patients. Specifically, we have identified the cluster of proteins that sense and respond to mechanical stimuli - collectively known as the mechanobiome. This cytoskeletal machinery is responsible in large part for endowing metastatic cells with the ability to navigate through different tissue types. Based on their mechanoresponsiveness profile, we have predicted and identified via western blot and immunohistochemistry proteins in the mechanobiome that are upregulated in patient-derived pancreatic tissues. These proteins include non-muscle myosin IIA and IIC, alpha-actin-4, and filamin B. We are performing knockdown and overexpression studies of these isoforms on 2D and 3D behaviors - cell mechanics, migration, invasion, and tissue sphere formation and are poised to begin mouse studies on the metastatic sufficiency in altering the expression of these proteins. In addition, we are testing 4-HAP, a small molecule mechanics modulator that we previously identified that targets myosin IIC, thus affecting PDAC mechanics in PDAC murine models. Limited studies reveal that 4-HAP reduces metastasis. These data suggest that direct targeting of the mechanobiome may eventually expand treatment strategies for pancreatic cancer. Citation Format: Alexandra Surcel, Eric S. Schiffhauer, Dustin Thomas, Qingfeng Zhu, Robert Anders, Douglas Robinson. The mechanobiome of pancreatic cancer: a viable, targetable drug space [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 901. doi:10.1158/1538-7445.AM2017-901

Operative treatment strategy for pancreatic cancer is highly region depended: A Finnish register study covering the entire nation.

Operative treatment strategy for pancreatic cancer is highly region depended: A Finnish register study covering the entire nation.

An overview of pre-clinical studies on the effects of (-)-epigallocatechin-3-gallate, a catechin found in green tea, in treatment of pancreatic cancer

Human pancreatic cancer is one of the leading causes of mortality and morbidity worldwide. Despite surgical resection remains the only curative therapeutic treatment for this disease, only the minority of patients can be resected due to late diagnosis. Recently, new chemotherapy schemes with the combination of different drugs have been shown to improve disease-free survival, although best results were obtained mostly as neoadjuvant chemotherapy in the minority of patients with resectable tumor. Consequently, there is stimulated interest in new chemotherapeutic approaches and alternative medicines. Several studies showed that the use of natural compounds, such as phytochemicals, represents a promising strategy for pancreatic cancer treatment. One popular phytochemical with great anticancer properties, is the (-)-epigallocate-chin3-O-gallate (EGCG), the most abundant catechin found in green tea. Accumulating evidences demonstrated that EGCG induces apoptosis and inhibits tumor progression by modulating different signaling pathways in pancreatic cancer. For these encouraging results, this catechin is currently used in clinical trials for treatment of various type of cancer and other diseases, although its poor bioavailability and poor stability represent severe limitations. Therefore, many researchers tried to develop a new strategy based of the use of nanotechnology which increases EGCG stability and bioavailability and simultaneously targets cancer cells in order to improve its anti-tumor effects. The aim of this article is to dissect the use of EGCG for management of pancreatic cancer, by reviewing the pre-clinical studies reported in literature.

The effects of SAHA on radiosensitivity in pancreatic cancer cells by inducing apoptosis and targeting RAD51.

Suberoyl anilide hydroxamic acid (SAHA) is one of the most promising Histone deacetylases(HDAC) inhibitors which has shown significant anti-tumor activity for many malignancies. We explored the potential mechanism of the radiosensitivity effect of SAHA in Panc-1 cells and attempted to develop SAHA as a systemic treatment strategy for pancreatic cancer. Growth inhibition was detected by CCK-8 assay. Radiosensitizing enhancement ratio was determined by clonogenic assay. The cell cycle and apoptosis assay was detected using flow cytometry and annexin-V/PI. The level of Bax, Bcl-2, Ku70, Ku86, RAD51, RAD54 protein expression were detected using Western blot analysis. Gene silencing was processed by lentiviral vector and qRT-PCR was performed to detect mRNA expression. The results revealed that SAHA inhibited the proliferation of Panc-1 cells. SAHA enhanced the radiosensitivity with a sensitization enhancement ratio(SER) of 1.10 of the Panc-1 cells. SAHA induced G2-M phase arrest and apoptosis of Panc-1 cells with radiation. SAHA upregulated Bax and downregulated Bcl-2, Ku70, Ku86, RAD51, RAD54 protein expression of irradiated Panc-1 cells. SAHA enhanced the radiosensitivity of Panc-1 cells by modulating RAD51 expression. SAHA enhanced radiosensitivity to pancreatic carcinoma Panc-1 cells. It was associated with the G2-M phase arrest and apoptosis via modulation of Bax and Bcl-2 expression. Downregulation of Ku70, Ku86, RAD51 and RAD54 expression caused suppression of HR-mediated DNA repair. SAHA is a good radiosensitizer for pancreatic cancer treatment.

The Charlson age comorbidity index to predict prognosis in patients with resected pancreatic cancer.

495 Background: The Charlson age comorbidity index (CACI) is a useful measure of comorbidity to standardize the evaluation of surgical patients and has been reported to predict postoperative mortality in various cancers. Methods: A total of 379 patients who underwent R0/R1 resection for pancreatic cancer between 2003 and 2014 were enrolled in this study. According to the CACI, the age-adjusted comorbidity index was calculated by weighting individual comorbidities; CACI &lt; 4 was considered the low-CACI group, whereas CACI ≥ 4 was considered the high-CACI group. The correlations between the CACI and clinicopathologic features and survival outcomes were statistically analyzed. Results: The patients with a high CACI were more likely to be old and had higher CA19-9 levels and lower incidences of portal vein resection and blood transfusion. The rate of patients who received chemotherapy was significantly higher in the low-CACI group than in the high-CACI group (87% vs. 69%, P&lt; 0.0001). There was no difference in relapse-free survival (RFS) between the low- and high-CACI groups; however, the overall survival (OS) rate was significantly higher in the low-CACI group than in the high-CACI group ( P= 0.047). Multivariable analysis showed that a high CACI was a predictor of poor survival. In the high-CACI group, patients with high relative dose intensity (RDI) for postoperative adjuvant chemotherapy had significantly better RFS and OS than those with low RDI (both P&lt; 0.0001). Conclusions: The CACI was a significant independent predictor of prognosis and compliance for postoperative adjuvant chemotherapy and could be clinically useful for decision-making in the treatment strategy for pancreatic cancer.

Abstract B13: Novel treatment strategy for pancreatic cancer by targeting the ‘undruggable’ Ras oncoprotein

Abstract Background and Aims: Mutations in RAS and various other components of the Ras signaling pathways are among the most common genetic alterations in human cancers, including up to 25% of lung cancers and over 90% of pancreatic cancers. Ras function as ‘molecular switches’ in a number of signaling pathways that regulate vital cellular functions. Over the past few decades, it has become clear that the activity or the oncogenic potential of Ras is dependent on the non-receptor tyrosine kinase Src to regulate essential cellular pathways for proliferation, differentiation and survival of eukaryotic cells. Recently, we showed that Src binds to and phosphorylates Ras on a conserved tyrosine residue at position 32 within the switch I region to promote Ras GTPase activity. We then identified Shp2 as the critical tyrosine phosphatase that is responsible for the dephosphorylation and activation of Ras. However, it is unknown whether pharmacologic manipulation of Shp2 activity would suppress the growth of Ras-driven pancreatic cancer (PDACs), a highly aggressive disease currently without effective treatment options or cure. Methods: We generated the available Ras, Src, and SHP2 reagents (wild-type, oncogenic, truncation, dominant-negative, catalytically active or inactive, mutants) to determine the structure/function relationship between Ras, Src, and SHP2. The interaction was assessed by immunoprecipitation and western blotting. We utilized several PDAC cell lines and patient-derived xenografts cell lines (PDX-C). The cell growth was evaluated by Alarmar Blue assay. Results: We identified SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signaling. In comparison to K-Ras WT pancreatic cancer cells, the level of phospho-Shp2 was observed to be higher in K-Ras mutated cell lines in both absence and presence of growth factors. Pharmacologic inhibition of Shp2 using a specific cell-permeable Shp2 inhibitor decreased the level of phosphorylation of Shp2 as well as downstream signaling such as pAKT and pERK especially in the presence of growth factor. Notably, we show that treatment with this inhibitor suppressed the cell proliferation in both K-Ras WT and mutated pancreatic cancer cells as well as PDX-C in a caspase-dependent manner. Conclusion: Our results identify SHP2 as a direct activator of Ras and potential therapeutic target for pancreatic cancer driven by a previously ‘undruggable’ oncogenic or hyperactive Ras. Citation Format: Yoshihito Kano, Severa Bunda, Jen Jen Yeh, Zhong-Yin Zhang, Michael Ohh.{Authors}. Novel treatment strategy for pancreatic cancer by targeting the ‘undruggable’ Ras oncoprotein. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B13.

Current status of biomarker and targeted nanoparticle development: The precision oncology approach for pancreatic cancer therapy

Pancreatic cancer remains one of the major causes of cancer-related mortality. The majority of pancreatic cancer patients are diagnosed at the advanced stage with unresectable and drug resistant tumors. The new treatments with the combination of chemotherapy, molecular targeted therapy, and immunotherapy have shown modest effects on therapeutic efficacy and survival of the patients. Therefore, there is an urgent need to develop effective therapeutic approaches targeting highly heterogeneous pancreatic cancer cells and tumor microenvironments. Recent advances in biomarker targeted cancer therapy and image-guided drug delivery and monitoring treatment response using multifunctional nanoparticles, also referred to as theranostic nanoparticles, offer a new opportunity of effective detection and treatment of pancreatic cancer. Increasing evidence from preclinical studies has shown the potential of applications of theranostic nanoparticles for designing precision oncology approaches for pancreatic cancer therapy. In this review, we provide an update on the current understanding and strategies for the development of targeted therapy for pancreatic cancer using nanoparticle drug carriers. We address issues concerning drug delivery barriers in stroma rich pancreatic cancer and the potential approaches to improve drug delivery efficiency, therapeutic responses and tumor imaging. Research results presented in this review suggest the development of an integrated therapy protocol through image-guided and targeted drug delivery and therapeutic effect monitoring as a promising precision oncology strategy for pancreatic cancer treatment.

Abstract 1071: Mir-145 based magnetic nanoformulation for pancreatic cancer therapy

Abstract Background: Pancreatic cancer (PanCa) is the fourth leading cause of cancer related deaths in the USA, with a 5-year survival rate of less than 5%. MicroRNAs have been identified as attractive targets for therapeutic intervention. The functional significance of lost microRNAs have been reported in several human malignancies, including PanCa. Therefore, restoring lost miRNA function can provide a potential therapeutic benefit. Prior work has identified microRNA-145 (miR-145) as a tumor suppressor miRNA in pancreatic cancer. The restoration of miR-145 downregulates a number of oncogenes including mucin MUC13, a glycoprotein that is aberrantly expressed in PanCa, and efficiently inhibits tumor growth in mice. The main challenge for successful translation of microRNAs into clinical practice remains an effective in vivo delivery system. The focus of this study was to develop and assess the efficacy of a miR-145 based nanoparticle formulation for PanCa treatment. Methods: Magnetic nanoparticle (MNP) based nanoformulation of miR-145 (miR-145-MNPF) was developed for the intracellular delivery and sustained release of miR-145. The positively charged polyethyleneimine molecules were used to increase the loading efficiency of miR-145. MUC13 expressing pancreatic ductal adenocarcinoma cell lines (HPAF-II and AsPC-1) were used for the study. Following transfection of miR-145-MNPF, Western blotting and immunofluorescence techniques were used to investigate the effects of miR-145 restoration on number of proteins including MUC13. Additionally, functional studies of the effects of miR-145 restitution using miR-145-MNPF included cell proliferation, colony formation, cell migration, and cell invasion assays. Results: miR-145 expression was progressively suppressed over the course of development from PanIN I-III to late stage poorly differentiated PDAC. Treatment of cells with miR-145-MNPF led to efficient intracellular delivery of miR-145 mimics as observed through prussian blue staining. This led to the simultaneous upregulation of miR-145 levels in cells as confirmed by qRT-PCR. miR-145 restitution resulted in significant downregulation of target oncogenes including MUC13, HER2, P-AKT and p53 as observed through Western blotting and immunofluorescence techniques. miR-145-MNPF inhibited cell proliferation, clonogenicity, migration, and invasion of PanCa cells. MNPF mediated restitution of miR-145 effectively sensitizes PanCa cells for paclitaxel and TRAIL therapy. Conclusions: 1) MNP based delivery systems can be efficiently used for microRNA replacement therapy in order to restore lost microRNAs in cancer. 2) miR-145-MNPF efficiently restores miR-145 in pancreatic cancer cells and inhibits growth and invasion of PanCa. 3) miR-145 restitution using miR-145-MNPF may offer a potential therapeutic strategy for pancreatic cancer treatment alone or in combination with other therapies. Citation Format: Saini Setua, Sheema Khan, Murali Mohan Yallapu, Mohammed Sikander, Stephen W. Behrman, Meena Jaggi, Subhash C. Chauhan. Mir-145 based magnetic nanoformulation for pancreatic cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1071.

Preoperative Volume-Based PET Parameter, MTV2.5, as a Potential Surrogate Marker for Tumor Biology and Recurrence in Resected Pancreatic Cancer.

This study aims to evaluate the role of volume-based positron emission tomography parameters as potential surrogate markers for tumor recurrence in resected pancreatic cancer.Between January 2008 and October 2012, medical records of patients who underwent surgical resection for pancreatic ductal adenocarcinoma and completed 18F-fluorodeoxyglucose positron emission tomography/CT as a part of preoperative staging work-up were retrospectively reviewed. Not only clinicopathologic variables but also positron emission tomography parameters such as SUVmax, MTV2.5 (metabolic tumor volume), and TLG (total lesion glycolysis) were obtained.Twenty-six patients were women and 31 were men with a mean age of 62.9 ± 9.1 years. All patients were preoperatively determined to resectable pancreatic cancer except 1 case with borderline resectability. R0 resection was achieved in all patients and 45 patients (78.9%) received postoperative adjuvant chemotherapy with or without radiation therapy. Median overall disease-free survival was 12.8 months with a median overall disease-specific survival of 25.1 months. SUVmax did not correlate with radiologic tumor size (P = 0.501); however, MTV2.5 (P = 0.001) and TLG (P = 0.009) were significantly associated with radiologic tumor size. In addition, MTV2.5 (P < 0.001) and TLG (P < 0.001) were significantly correlated with a tumor differentiation. There were no significant differences in TLG and SUVmax according to lymph node ratio; only MTV2.5 was related to lymph node ratio with marginal significance (P = 0.055). In multivariate analysis, lymph node ratio (Exp [β] = 2.425, P = 0.025) and MTV2.5 (Exp[β] = 2.273, P = 0.034) were identified as independent predictors of tumor recurrence following margin-negative resection. Even after tumor size-matched analysis, MTV2.5 was still identified as significant prognostic factor in resected pancreatic cancer (P < 0.05). However, preoperative neoadjuvant treatment attenuated adverse oncologic impact of high preoperative MTV2.5 (P = 0.210).Preoperatively determined volume-based PET parameter, MTV2.5, can potentially be used as a surrogate marker to estimate tumor biology and tumor recurrence. Individual treatment strategies for pancreatic cancer can be suggested based on patients’ preoperative MTV2.5.

Inhibition of Survival Pathways MAPK and NF-kB Triggers Apoptosis in Pancreatic Ductal Adenocarcinoma Cells via Suppression of Autophagy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a survival rate of 4-6 months from diagnosis. PDAC is the fourth leading cause of cancer-related death in the Western world, with a mortality rate of 10 cases per 100,000 population. Chemotherapy constitutes only a palliative strategy, with limited effects on life expectancy. To investigate the biological response of PDAC to mitogen-activated protein kinase (MAPK) and NF-kappaB (NF-kB) inhibitors and the role of autophagy in the modulation of these signaling pathways in order to address the challenge of developing improved medical protocols for patients with PDAC. Two ATCC cell lines, MIAPaCa-2 and PANC-1, were used as PDAC models. Cells were exposed to inhibitors of MAPK or NF-kB survival pathways alone or after autophagy inhibition. Several aspects were analyzed, as follows: cell proliferation, by [(3)H]TdR incorporation; cell death, by TUNEL assay, regulation of autophagy by LC3-II expression level and modulation of pro-and anti-apoptotic proteins by Western blot. We demonstrated that the inhibition of the MAPK and NF-kB survival pathways with U0126 and caffeic acid phenethyl ester (CAPE), respectively, produced strong inhibition of pancreatic tumor cell growth without inducing apoptotic death. Interestingly, U0126 and CAPE induced apoptosis after autophagy inhibition in a caspase-dependent manner in MIA PaCa-2 cells and in a caspase-independent manner in PANC-1 cells. Here we present evidence that allows us to consider a combined therapy regimen comprising an autophagy inhibitor and a MAPK or NF-kB pathway inhibitor as a possible treatment strategy for pancreatic cancer.