Pancreatic Cancer Immunotherapy: A Team-Based Approach.

Pancreatic Cancer Prevention and the 2010 Dietary Guidelines for Americans

Pancreatic cancer incidence and the associated mortality are increasing worldwide. This indicates that there is a clear lack of understanding about pancreatic cancer pathogenesis. This can be attributed to the lack of specific symptoms to diagnose the disease at an early stage. Various growth factor receptors are known to play a vital role in the development of pancreatic cancer. In the present investigation, we have attempted to target insulin-like growth factor-1 receptor (IGF-1R) due to its well-established role in progression of pancreatic cancer. RNA interference (small interfering RNA [siRNAs]) approach targeted to IGF-IR was used to study the effect of IGF-1R silencing on pancreatic cancer growth and metastasis. For this we used HPAC and PANC-1 pancreatic cancer cell lines and primary pancreatic cancer tissue array. Our results demonstrated that silencing IGF-1R remarkably inhibited pancreatic cancer growth and metastasis. Silencing IGF-1R significantly altered key signaling molecules such as PI3K, AKT, MAPK, ERK1/2, mTOR, PTEN, p70S6K, JAK2 and STAT3. Further IGF-1R silencing also reduced epithelial to mesenchymal transition (N-Cad, Notch, Snail, Slug and Vimentin). In addition, silencing IGF-1R inhibited cell viability, invasive and migratory capabilities of PANC-1 and HPAC pancreatic cancer cell lines. Colony forming ability was also drastically reduced in IGF-1R silenced cells. Flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R decreased the expression of Kras, which is altered in almost 95% of pancreatic cancers. Overall, our data clearly demonstrates the significance of IGF-1R in pancreatic cancer pathogenesis and also identifies IGF-1R as a potential target for pancreatic cancer treatment and therapy. Citation Format: Ramadevi Subramani Reddy, Arunkumar Arumugam, Sushmita Bose Nandy, Elizabeth Gonzalez, Viviana Gonzalez, Sandrine Bonkoungou, Andrew Ortega, Rajkumar Lakshmanaswamy. Role of insulin-like growth factor 1 receptor in pancreatic cancer pathogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5055. doi:10.1158/1538-7445.AM2015-5055

Surveillance Imaging in Individuals at High Risk for Pancreatic Cancer: Not a Ceiling, but Rather a Floor Upon Which to Build

Cancer immunotherapy is considered to be one of the biggest breakthroughs in cancer therapy in the last decade. However, the success of immunotherapy has so far been limited to a few solid malignancies including melanoma, renal cell carcinoma, non-small-cell lung cancer (NSCLC) and a few hematologic malignancies. In 2011, ipilimumab, a therapeutic monoclonal antibody that blocks CTLA-4, the bona fide immune checkpoint, was US FDA-approved for advanced melanoma [1]. Subsequently, other checkpoint inhibitors including anti-PD-1 and anti-PD-L1 blockade antibodies were also demonstrated to yield an objective response in approximately 20–30% of patients of these malignant diseases; and among the patients who had an objective response, many had a durable response [2–4]. One of anti-PD-1 antibodies (pembrolizumab) was most recently approved by US FDA for unresectable or metastatic melanoma. In addition, sipuleucel-T, a dendritic cell vaccine, has been shown to improve the overall survival of metastatic prostate cancer and subsequently gained FDA approval [5]. Nevertheless, significant objective response and durable responses were not seen in sipuleucel-T-treated pancreatic cancer patients. Melanoma, renal cell carcinoma and NSCLC were unique in their high infiltration of effector lymphocytes in tumor microenvironment (TME) [6]. By contrast, many other solid malignancies including pancreatic cancer are characterized by a highly immunosuppressive TME [7]. Immune tolerance mechanisms within the TME are a major obstacle to effective treatment of these cancers with immunotherapy. Pancreatic cancer and many other malignancies are thus considered ‘nonimmunogenic’ neoplasms. This notion has drastically slowed the development and application of immune-based therapies for these diseases.

Pancreatic cancer is the fourth leading cause of cancer death in the United States with current 5-year survival rates at 6%. Greater than 90% of all pancreatic cancers harbor an activating mutation in codon 12 of the Kras gene (KrasG12D). Protein Kinase C iota (PKCι) has been shown to mediate KrasG12D downstream signaling and acinar-to-ductal metaplasia in an explant model of pancreatic cancer initiation. Additionally, inhibition of PKCι in human pancreatic cancer cells leads to decreased tumor size, angiogenesis, and metastasis in an orthotopic tumor model, suggesting that PKCι plays a role in maintaining the oncogenic phenotype of pancreatic cancer cells. We sought to test the hypothesis that PKCι plays a role development and maintenance of pancreatic cancer using a mouse model of KrasG12D-induced pancreatic cancer. Purpose: To identify the effect of PKCι loss on pancreas function and development of KrasG12D-induced pancreatic cancer. Procedures: Pancreata from mice with pancreas-specific deletion of PKCι, with and without pancreas-specific KrasG12D expression, were analyzed for histological and protein expression alterations. Acinar cells isolated from these transgenic mouse models were subjected to in vitro analyses to determine the role of PKCι in pancreatic cell homeostasis. Results: Mice lacking pancreatic PKCι survived and developed normally. Pancreatic knockout of PKCι expression resulted in a phenotype consistent with a defect in autophagic flux. In vitro analyses of isolated acinar cells supported the hypothesis that PKCι promotes autophagy in pancreatic cells. Autophagy exhibits a dual functionality in pancreatic cancer, acting as a tumor suppressor in normal cells and a tumor promoter in established tumor cells. We sought to determine the effect of PKCι knock-out on both of these cell types in a mouse model of pancreatic cancer. Using the LSL mouse model of K-ras induced pancreatic cancer, we demonstrated that pancreatic loss of PKCι lead to an increase in the number of Pancreatic Intraepithelial (PanIN) lesions formed in young mice. However, these lesions were protected from progressing past the early PanIN1/2 stage such that no mice lacking PKCι developed cancer, even after 1.5 years of age. By contrast, over 50% of mice with wild-type PKCι developed cancer; of those without cancer, many had progressed to the PanIN-3 stage, a stage representative of carcinoma in-situ. These data are similar to that seen in mouse models of pancreatic cancer with genetic inhibition of autophagy. Analysis of PanINs in these mice revealed that those lacking PKCι expressed significantly more P62 protein, a selective autophagy substrate, compared to PanINs with wild-type PKCι, supporting a block in the autophagic flux. These data suggest that PKCι plays an important role in both the initiation and progression of pancreatic cancer, possibly by regulating autophagic flux. Impact: Inhibition of pancreatic PKCι expression prevented progression of PanIN lesions past the early PanIN1/2 stage, resulting in a complete block in cancer development in mouse models of pancreatic cancer. Our preliminary data suggests that PKCι promotes cancer progression by regulating autophagic flux, a process that has been shown to be essential for KrasG12D-mediated pancreatic cancers. Pancreatic cancer is characterized by resistance to current therapies. Novel targets for new and more effective therapies are critical to improve outcomes for patients with this deadly disease. Inhibitors of PKCι are currently in clinical trials for ovarian and lung cancers. Our data supports the feasibility of using PKCι inhibitors for therapy in pancreatic cancer. Citation Format: Kristin S. Inman, Amanda A. Francis, Nicole R. Murray. PKCι in pancreatic cancer development: A possible role for autophagy. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A02.

Desmoplasia of Pancreatic Ductal Adenocarcinoma

Other risk factors for pancreatic cancer: Hormonal aspects

SY20-02: Theranostic nanoparticles for targeted therapy of pancreatic and triple-negative breast cancers

The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3β-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3β stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3β inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3β-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.

Underutilization of Surgical Resection in Patients With Localized Pancreatic Cancer

Therapeutic Advances in Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. Chemotherapy in resectable pancreatic cancer has improved survival by 10-20%. It only converted 10-30% of the borderline resectable and locally advanced pancreatic cancers to be surgically resectable. Radiation therapy has a documented role in managing localized pancreatic cancer, more so for borderline and locally advanced pancreatic cancer, where it can potentially improve the resectability rate of a given neoadjuvant treatment. The role of radiation therapy in resected pancreatic cancer is controversial, but it is used routinely to treat positive margins after pancreatic cancer surgery. Radiation therapy paradigms continue to evolve with advancements in treatment modalities, delivery techniques, and combination approaches. Despite the advances, there continues to be a controversy on the role of radiation therapy in managing this disease. In this review article, we discuss the recent updates, delivery techniques, and motion management in radiation therapy and dissect the applicability of this therapy in pancreatic cancer.

Pancreatic cancer is suppressed by fibroblast-derived collagen I.

Objective To determine the expression of brain-derived neurotrophic factor (BDNF) in pancreatic ductal adenocarcinoma and its clinical significance.Methods SP immunohistochemical staining method was used to detect the expression of BDNF in 46 cases of pancreatic ductal adenocarcinoma,38 cases of benign pancreatic diseases and 20 cases of normal pancreatic tissue.Real time PCR and Western blot was used to detect the protein and mRNA expression levels.The relationship between BDNF expression and clinicopathological parameters of pancreatic cancer was determined.Results The positive expression rate of BDNF was 52.2％ (24/46) in pancreatic ductal adenocarcinoma pancreatic ductal adenocarcinoma,7.8％ (3/38) in benign pancreatic diseases,and none of the normal pancreatic tissue was BDNF positive.The BDNF protein expression levels in pancreatic ductal adenocarcinoma,benign pancreatic diseases and normal pancreatic tissue were 0.38± 0.01,0.56± 0.01,0.97± 0.01,respectively,and the BDNF mRNA expression levels were 0.85 ± 0.14,1.67 ± 0.21,3.45 ± 0.67,respectively,and the expression levels in pancreatic ductal adenocarcinoma and benign pancreatic diseases were significantly higher than that in normal pancreatic tissue,while the expression level in pancreatic ductal adenocarcinoma was significantly higher than that in benign pancreatic diseases (P ＜0.05).Positive BDNF expression was correlated with nerve infiltration and lymph node metastasis of pancreatic ductal adenocarcinoma,but it was not related to age,sex,tumor size,location and differentiated degree (P ＞ 0.05).Conclusions BDNF is involved in the development and growth of pancreatic cancer,and it may be related with patient's prognosis. Key words: Pancreatic neoplasms; Brain-derived neurotrophic factor; Neoplasm metastasis; Gene expression

Mechanistic Insights into Self-Reinforcing Processes Driving Abnormal Histogenesis During the Development of Pancreatic Cancer