Strategy For Pancreatic Cancer Research Articles

Epigenetic therapeutic strategies in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, characterized by its aggressiveness and metastatic potential, with a 5-year survival rate of only 8-11%. Despite significant improvements in PDAC treatment and management, therapeutic alternatives are still limited. One of the main reasons is its high degree of intra- and inter-individual tumor heterogeneity which is established and maintained through a complex network of transcription factors and epigenetic regulators. Epigenetic drugs, have shown promising preclinical results in PDAC and are currently being evaluated in clinical trials both for their ability to sensitize cancer cells to cytotoxic drugs and to counteract the immunosuppressive characteristic of PDAC tumor microenvironment. In this review, we discuss the current status of epigenetic treatment strategies to overcome molecular and cellular PDAC heterogeneity in order to improve response to therapy.

Glutamine addiction and therapeutic strategies in pancreatic cancer

Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis, early metastasis, and poor prognosis. Because current therapeutic options are limited, there is an urgent need to investigate novel targeted treatment strategies. Pancreatic cancer faces significant metabolic challenges, principally hypoxia and nutrient deprivation, due to specific microenvironmental constraints, including an extensive desmoplastic stromal reaction. Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation. Increased glucose uptake and glycolytic pathway activity during this process have been extensively described. However, growing evidence suggests that pancreatic cancer cells are glutamine addicted. As a nitrogen source, glutamine directly (or indirectly via glutamate conversion) contributes to many anabolic processes in pancreatic cancer, including amino acids, nucleobases, and hexosamine biosynthesis. It also plays an important role in redox homeostasis, and when converted to α-ketoglutarate, glutamine serves as an energy and anaplerotic carbon source, replenishing the tricarboxylic acid cycle intermediates. The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer, focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.

Abstract 5258: Preclinical testing of CD73 inhibitor AB680 for pancreatic cancer immunoprevention

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profoundly immunosuppressive microenvironment. Innovative therapeutic strategies are urgently needed to stop the progression of precancerous lesions into aggressive PDAC, which remains a lethal malignancy. The goal of this research project is to test immunopreventive strategies by targeting the 5’ ectonucleotidase enzyme, CD73, one of the gatekeeper enzymes responsible for conversion of adenosine monophosphate (AMP), to an immunosuppressive metabolite, adenosine, in the tumor microenvironment (TME). We hypothesize that inhibition of CD73 will prevent pancreatic intraepithelial neoplasia (PanIN) formation and progression to PDAC by reversing adenosine directed immunosuppression. This research explores immunopreventive strategies aimed to restore tumor immune surveillance to prevent cancer initiation or progression. Materials and methods: We used two models: a syngeneic model of PDAC using cells derived from KrasG12D;Trp53R172H/+;PdxCre (KPC) mice and a KrasG12D;PdxCre (KC) genetically engineered mouse model (GEM) of PDAC. Oral gavage of AB680 (small molecule CD73 inhibitor) was given three days/week at 10mg/kg starting the day after KPC injections and tumor sizes were measured weekly. In the GEM model, the same treatment regimen began when the mice were between 6 and 9 weeks old and were euthanized either between 15 and 20 weeks of age or around 27 weeks of age, and pancreas tissue was harvested. Histology was analyzed and 6 fields per mouse were quantified using ImageJ. Results: As we have described (Singh, et al, bioRxiv), in the syngeneic model, there was a significant reduction in tumor growth and significant increase in activated CD8-positive T cells, dendritic cells, and macrophages from AB680 treated mice. The intratumoral adenosine levels were significantly decreased in AB680 treated mice compared to vehicle treated mice. In the KC GEM model, we quantified significantly fewer early PanIN lesions (p=0.0328), a trend in decreased advanced PanIN (p=0.0641), and significant decrease in PDAC (p=0.0058) in the AB680 treated mice when compared to the vehicle treated mice. We quantified abundance of collagen deposition as a marker of fibrosis and observed significantly decreased collagen (p<0.0001) in AB680 treated KC mice. In addition, we quantified abundance of CK19+ lesions and observed a significant decrease in CK19+ lesions in AB680 treated mice (p=0.0061) compared to vehicle treated mice. Conclusion: Inhibiting CD73 restructures TME and reduces PanIN incidence and progression to PDAC. CD73 inhibition may be a candidate immunoprevention strategy in pancreatic cancer. [Supported by NCI 75N91019D00021/75N91020F00002] Citation Format: Lincoln N. Strickland, Erika Y. Faraoni, Nicolette R. Mardik, Lana Vornik, Michelle I. Savage, Shizuko Sei, Mark S. Miller, Holger K. Eltzschig, Powel H. Brown, Florencia McAllister, Jennifer M. Bailey-Lundberg. Preclinical testing of CD73 inhibitor AB680 for pancreatic cancer immunoprevention. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5258.

Retraction notice to Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase (RRM2): a novel therapeutic strategy in pancreatic cancer [Surgery 136 (2004) 261-269

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editors-in-Chief, because an investigation by Harvard Medical School and the Brigham and Women’s Hospital has concluded that Figure 1A is invalid and no underlying research data are available to resolve the discrepancies or validate the reported results. RETRACTED: Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in pancreatic cancerSurgeryVol. 136Issue 2PreviewThis article has been retracted: please see Elsevier Policy on Article Withdrawal ( http://www.elsevier.com/locate/withdrawalpolicy ). Full-Text PDF

Rapamycin-Induced Feedback Activation of eIF4E-EIF4A Dependent mRNA Translation in Pancreatic Cancer.

Pancreatic cancer cells adapt molecular mechanisms to activate the protein synthesis to support tumor growth. This study reports the mTOR inhibitor rapamycin's specific and genome-wide effect on mRNA translation. Using ribosome footprinting in pancreatic cancer cells that lack the expression of 4EBP1, we establish the effect of mTOR-S6-dependent mRNAs translation. Rapamycin inhibits the translation of a subset of mRNAs including p70-S6K and proteins involved in the cell cycle and cancer cell growth. In addition, we identify translation programs that are activated following mTOR inhibition. Interestingly, rapamycin treatment results in the translational activation of kinases that are involved in mTOR signaling such as p90-RSK1. We further show that phospho-AKT1 and phospho-eIF4E are upregulated following mTOR inhibition suggesting a feedback activation of translation by rapamycin. Next, targeting eIF4E and eIF4A-dependent translation by using specific eIF4A inhibitors in combination with rapamycin shows significant growth inhibition in pancreatic cancer cells. In short, we establish the specific effect of mTOR-S6 on translation in cells lacking 4EBP1 and show that mTOR inhibition leads to feedback activation of translation via AKT-RSK1-eIF4E signals. Therefore, targeting translation downstream of mTOR presents a more efficient therapeutic strategy in pancreatic cancer.

Stroma-targeting strategies in pancreatic cancer: a double-edged sword.

Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with limited treatment options and terrible long-term survival, and it is expected to become the second leading cause of cancer-related death by 2030. One reason why this cancer is so aggressive and resistant is the formation of dense stroma that surrounds the neoplastic epithelium, which promotes tumor progression, invasion, metastasis, and resistance. The three major components of PDAC stroma are extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and vasculature. The dense ECM acts as a natural physical barrier, impeding drug penetration to PDAC tumor cells. Consequently, the method that combines stroma-targeting with anticancer therapy may be a viable alternative for increasing drug penetration. Additionally, blood vessels are key entities of the tumor stroma, serving as a pathway for nutrition as well as the only way for chemical medicines and immune cells to act. Finally, PDAC CAFs and tumor cells have crosstalk effects in the tumor microenvironment, where they are responsible for enhanced matrix deposition. In this review, we aim to provide an overview of our current comprehension of the three key components of PDAC stroma and the new promising therapeutic targets for PDAC.

S1454 Association of Body Mass Index in Patients After Bariatric Surgery With the Onset of Pancreatic Cancer: A Nationwide Inpatient Sample Database Analysis

Introduction: Obesity (Body Mass Index [BMI] >= 30) has been associated with a 3.5-fold increased risk of cancer. Higher BMI has led to increased cancer-related mortality and chemotherapy resistance. Prior studies have demonstrated a protective effect of weight loss in certain cancers such as endometrial, breast, and pancreatic. However, the literature behind weight loss and the protective effect on pancreatic cancer remains controversial. In this study, we evaluate the relationship between different BMI ranges in patients who underwent bariatric surgery and the onset of pancreatic cancer. Methods: The National Inpatient Sample (NIS) database was used to identify hospitalized patients over 18 years old who had bariatric surgery between 2012 to 2017 using ICD9 and ICD10 codes. Patients were divided into a cancer and non-cancer group. Those with pancreatic cancer were identified and were matched by age, race, and gender. Primary outcomes were associations between BMI ranges in patients who underwent bariatric surgery and pancreatic cancer. Multivariate analyses were performed to assess outcomes. Results: From 2012 to 2017, there was a total of 1,695,860 patients who had bariatric surgery. Of these patients, 4,225 patients had pancreatic cancer. The mean age was 60 years old, 27.3% were male, and 79.2% were White. The results were significant (P< 0.001) for decreased risk of cancer in patients who underwent bariatric surgery and had BMI 40-49.9 (OR 0.46) and BMI >=50 (OR 0.31) (Table). Conclusion: Weight loss through bariatric surgery has been shown to reduce the risks of various cancers. This is likely due to the reduction in adipose tissue regulated chemokine signaling involved in oncogenesis. Our data suggests that patients with higher stages of obesity (BMI >=40) who underwent bariatric surgery would benefit the most by risk reduction from pancreatic cancer. These findings could be a platform for future prospective studies to investigate risk reduction strategies in pancreatic cancer, which still is the 3rd leading cause of cancer-related deaths. Table 1. - Association between Body Mass Index in Patients with Bariatric Surgery and the Onset of Pancreatic Cancer Odds Ratio (95% CI) P-Value BMI 30-34.9 0.96 (0.80-1.15) 0.645 BMI 35-39.9 1.02 (0.85-1.23) 0.814 BMI 40-49.9 0.46 (0.39-0.55) < 0.001 BMI >=50 0.31 (0.23-0.44) < 0.001 CI = Confidence Interval

Abstract 5800: Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients

Abstract Purpose: Genetic attribution for pancreatic cancer has been reported as 2-10%. However, the incidence of genetic predisposition and germline pathogenic variants (PVs) in Korean pancreatic cancer patients has not been well investigated. Therefore we studied to identify the clinical characteristics of the causative gene mutations and incidence of PV for future treatment strategies in pancreatic cancer. Methods: Total of 283 (145 male and 138 female) patients were enrolled in National Cancer Center in Korea (IRB no. NCC2019-0034, NCC2021-0338) and their median age was 67 years (range: 33-90). Resectable (25.1%), borderline resectable or locally advanced (25.5%), and metastatic (46.3%) stages were included. Germline hereditary cancer panel tests with 28 genes and BRCA1/2 gene were done in 97.2% (n=275) and 2.8% (n=8) of patients, respectively. Results: PVs were detected in 17 patients (median age 64, range 49-80) in ATM (n=5, 29.4%), BRCA1 (n=3, 17.6%), BRCA2 (n=2, 11.8%), RAD51D (n=2, 11.8%), TP53 (n=1, 5.9%), PALB2 (n=1, 5.9%), PMS2 (n=1, 5.9%), RAD50 (n=1, 5.9%), and SPINK1 (n=1, 5.9%). Eight patients (4 ATM PVs, 2 BRCA1 1 BRCA2, 1 PALB2 PV) presented various type of cancers in their families and three patients with ATM PVs showed pancreatic cancer in their first degree relatives. Nine patients without family cancer history represented median age as 66 (49-80) which was not significantly different of those with family history as 63 (51-75). Conclusions: This study showed 6.0% of incidence of germline PVs in Korean pancreatic cancer patients. Though we still don’t have guidelines for germline predisposition gene test in pancreatic cancer patients in Korea, this result showed that the incidence of PVs were comparable with that of the country which have recommendation to do genetic tests for all pancreatic cancer patients. To expand our knowledge for the incidence and involving genes of cancer predisposition for Korean pancreatic cancer patients, further analysis in larger number of patients is needed. (This study was supported by National cancer center, Korea, Grant no. 2110181).Keywords: Germ-line Mutation; Pancreatic Neoplasms; Incidence Citation Format: Yena Kim, Min Kyeong Kim, Kum Hei Ryu, Hyoeun Shim, Ji Sun Han, Jung Won Chun, Yun-Hee Kim, Ju Sun Song, Young-gon Kim, Sang Myung Woo, Sun-Young Kong. Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients [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 5800.

Abstract 1506: APOBEC3A a causative agent in cancer-related chromosomal instability and STING driven metastasis

Abstract Chromosomal instability (CIN), a hallmark of cancer, has been associated with a highly metastatic phenotype in numerous cancers. Mechanisms by which these genomic events occur during the lifespan of a neoplasm have yet to be fully delineated. In our study we identified a novel function for APOBEC3A (A3A), a primate-specific cytidine deaminase upregulated in multiple cancers including Pancreatic ductal adenocarcinoma (PDAC), in the initiation of CIN.We demonstrate that A3A is not routinely detected in non-diseased pancreata; however, expression was detected in the epithelial and stromal compartments from patients with chronic pancreatitis and in precursor lesions of PDAC and is further significantly increased in invasive neoplasia. Strikingly, we found that A3A expression but not A3A-induced mutagenesis, was associated with a significantly reduced overall survival in PDAC. By employing a variety of genetic tools, we identified a novel function for A3A in initiating CIN, underscoring its potential role in driving the observed early metastatic propensity in PDAC. Using a series of in vivo and in vitro models, we demonstrate that A3A-induced CIN leads to aggressive cancer, featuring enhanced, STING-dependent, distant organ seeding and metastatic growth. As a consequence of aberrant A3A function and CIN-mediated upregulation of STING, NfkB and Stat3 pathways were activated. More importantly, all these effects were independent of the deaminase domain, underscoring a novel role of A3A beyond its established canonical function. Remarkably, in a novel autochthonous murine model of PDA expressing human A3A, we identified numerous copy number changes, homologous to those altered in A3A overexpressing patient tumors, including deletions in DNA repair pathway genes. While we showed that A3A-expressing PDAC cells do not fully phenocopy a BRCA mutation-like phenotype, A3A-expressing PDAC cells are exceptionally sensitive to PARP inhibition and DNA cross linking agents, recapitulating a state of “chemical BRCAness”. The combined effect of deletions in these genes has yet to be ascertained, and we hypothesize that these losses further add to ongoing DNA damage overall in PDAC. In summary, our study shows, that A3A drives metastasis and specific deletions through a deaminase-independent initiation of CIN, with potential implications for targeted treatment strategies in pancreatic cancer. Citation Format: Sonja Maria Woermann, Amy Zhang, Fredrik I. Thege, Chris Gates, Reuben S. Harris, Susan R. Ross, Faiyaz Notta, Anirban Maitra, Andrew D. Rhim. APOBEC3A a causative agent in cancer-related chromosomal instability and STING driven metastasis [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 1506.

Future therapies for pancreatic carcinoma: Insights into cancer precision medicine.

Pancreatic carcinoma (PC) has one of the highest rates of cancer-related death worldwide. Except for surgery, adjuvant chemotherapy, chemoradiotherapy, and immunotherapy have shown various efficacies depending on the stage of the patient. We read the review “Current and emerging therapeutic strategies in pancreatic cancer: Challenges and opportunities” and offer some opinions that may improve its precision and completeness. This review presents a map of appropriate therapies for PC at different stages. Based on the clinical trial outcomes mentioned in the review, we evaluated the potential therapeutic options for PC and helped explain the contradictory efficacy between different programmed cell death protein 1/programmed cell death ligand 1 clinical trials, which may have resulted from the unique features of PC. Although R0 resection and adjuvant chemotherapy are still the gold standards for PC, new modalities, with or without clinical validation, are needed to establish more specific and precise treatments for PC.

Cetuximab, gemcitabine and radiotherapy in locally advanced pancreatic cancer: Long-term results of the randomized controlled phase II PARC trial

PurposeAddressing the epidermal growth factor receptor (EGFR)-pathway by the competitive receptor ligand cetuximab is a promising strategy in pancreatic cancer. In the prospective randomized controlled phase II PARC-study (PARC: Pancreatic cancer treatment with radiotherapy (RT) and cetuximab), we evaluated safety and efficacy of a trimodal treatment scheme consisting of cetuximab, gemcitabine and RT in locally advanced pancreatic cancer (LAPC). MethodsBetween January 2005 and April 2007, 68 patients with inoperable pancreatic ductal adenocarcinoma were randomized in either trimodal therapy followed by gemcitabine maintenance (Arm A) or in trimodal therapy followed by gemcitabine plus cetuximab maintenance (Arm B). Intensity-modulated RT (IMRT) was performed with a total dose of 45 Gy in 25 fractions and with a simultaneous integrated boost to the gross tumor (54 Gy). Within the trimodal therapy, gemcitabine and cetuximab were administered weekly. Maintenance therapy consisted of gemcitabine only or gemcitabine plus cetuximab. Toxicity, overall survival (OS), secondary resection rate, local control and progression free survival (PFS) were evaluated. ResultsWith a median followup time of 13 months (range: 2 – 184 months), one patient is still alive and one patient is lost to follow-up. Nausea and gastrointestinal hemorrhage were the most important higher-graded (>°II) acute and late non-hematological toxicity (13% and 7%). Median OS was 13.1 months without significant difference between both treatment arms (Arm A: 11.9 months; Arm B: 14.2 months). Compared to historical data, cetuximab did not improve OS. One- and two-year local control rates were 76.6% and 68.9%. Local tumor control and secondary resection rate (Arm A: 4%; Arm B: 16%) were significantly improved in Arm B. Median PFS was 6.8 months with distant metastasis as main treatment failure. ConclusionTrimodal therapy consisting of IMRT, gemcitabine and cetuximab can be considered safe and feasible. Compared to historical data, cetuximab does not improve treatment efficacy in LAPC patients treated with chemoradiation.

Immunotherapy in Combination with Well-Established Treatment Strategies in Pancreatic Cancer: Current Insights.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and fourth most common cause of death in developed countries. Despite improved survival rates after resection combined with adjuvant chemotherapy or neoadjuvant chemotherapy, recurrence still occurs in a high percentage of patients within the first 2 years after resection. Immunotherapy aims to improve antitumor immune responses and reduce toxicity providing a more specific, targeted therapy compared to chemotherapy and has been proved an efficient therapeutic tool for many solid tumors. In this work, we present the latest advances in PDAC treatment using a combination of immunotherapy with other interventions such as chemotherapy and/or radiation both at neoadjuvant and adjuvant setting. Moreover, we outline the role of the tumor microenvironment as a key barrier to immunotherapy efficacy and examine how immunotherapy biomarkers may be used to detect immunotherapy’s response.

A Review on the Efficacy and Safety of Nab-Paclitaxel with Gemcitabine in Combination with Other Therapeutic Agents as New Treatment Strategies in Pancreatic Cancer.

Pancreatic cancer has one of the highest mortality rates among cancers, and a combination of nab-paclitaxel with gemcitabine remains the cornerstone of first-line therapy. However, major advances are required to achieve improvements in patient outcomes. For this reason, several research groups have proposed supplementing treatment with other therapeutic agents. Ongoing studies are being conducted to find the optimal treatment in a first-line setting. In this work, we used a search strategy to compare studies on the efficacy and safety of nab-paclitaxel with gemcitabine in combination with other therapeutic agents based on the criteria of the Preferred Reporting Items for Systematic Reviews. We found seven studies in different clinical phases that met the inclusion criteria. The seven therapeutic agents were ibrutinib, necuparanib, tarextumab, apatorsen, cisplatin, enzalutamide, and momelotinib. Although these therapeutic agents have different mechanisms of action, and molecular biology studies are still needed, the present review was aimed to answer the following question: which formulations of the nab-paclitaxel/gemcitabine regimen in combination with other therapeutic agents are safest for patients with previously untreated metastatic pancreas ductal adenocarcinoma? The triple regimen is emerging as the first-line option for patients with pancreatic cancer, albeit with some limitations. Thus, further studies of this regimen are recommended.

Homologous recombination repair pathway alterations and their relationship to homologous recombination deficiency in advanced pancreatic cancer patients.

609 Background: Homologous recombination repair (HRR) is critical for limiting DNA damage arising from double strand breaks. Disrupting HRR has emerged as a therapeutic strategy in pancreatic cancer given the development of PARP inhibitors that can specifically target tumors with homologous recombination deficiency (HRD). While HRD is strongly associated with loss-of-function mutations in BRCA1/2, a broad range of pathogenic alterations have been identified in other HRR genes. Identification of pathogenic alterations that predict response to PARP inhibition remains a critical knowledge gap in the field. Methods: We retrospectively analyzed de-identified records from 895 patients with advanced pancreatic cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, matched normal, full transcriptome RNA-seq). HRD-positivity and genome-wide loss of heterozygosity (LOH) were compared across groups, which were defined based on alterations to BRCA1/2 or other HRR pathway genes. Results: We identified 293/895 (33%) pancreatic cancer patients to be HRD-positive. Among HRD positive patients, 23/895 (2.6%) tumors harbored two alterations in BRCA1/2 (BRCA++), 179/895 (20%) harbored a single alteration in BRCA1/2 (BRCA+), 25/895 (2.8%) harbored two alterations in at least one other non-BRCA HRR gene (other HRR++), 367/895 (41%) harbored a single alteration in one other HRR gene (other HRR+), and 143/895 (16%) had pathogenic alterations in neither BRCA1/2 nor other HRR genes. In terms of HRD status, 23/23 (100%) of BRCA++ cases, 179/337 (53%) of BRCA+ cases, 4/25 (16%) of other HRR++ cases, and 87/367 (24%) of other HRR+ cases were HRD-positive. We observed no cases that were HRD-positive without an alteration in either BRCA1/2 or other HRR gene. Within the other HRR+ group, we found that single alterations in CHEK1/2, FANCA/L, MRE11, PALB2, and RAD51B were all significantly associated with HRD-positivity whereas CDK12, for instance, was not (Table). Conclusions: Comprehensive genomic profiling demonstrates that approximately 1 in 4 patients without BRCA alterations may potentially benefit from PARP inhibition due to alterations in other HRR genes. Future studies may examine the role of PARP inhibition in this population of HRR+ pancreatic cancer patients.[Table: see text]

Clustering of Chromatin Remodeling Enzymes Predicts Prognosis and Clinical Benefit of Therapeutic Strategy in Pancreatic Cancer.

In recent years, translational research and pharmacological targeting of epigenetic modifications have become the focus of personalized therapy for patients with pancreatic cancer. Preclinical and clinical trials targeting post-translational modifications have been evaluated as monotherapy or in combination with standard chemotherapy. In this study, we selected 43 genes from seven families of chromatin-modifying enzymes and investigated the influences of epigenetic modifications and their interactions on pancreatic ductal adenocarcinoma (PDAC) using hierarchical clustering analysis. Our analysis also evaluated their effects on treatment modalities and regimens of chemotherapy for PDAC. RNA-seq data for a total of 177 patients with pancreatic cancer, obtained from The Cancer Genome Atlas database, were analyzed. Our results suggested that high-risk patients of survival significant chromatin remodeling-associated gene cluster (gene cluster 2), composed of histone methyltransferases, histone acetyltransferases, histone deacetylases, histone demethylases, and 10-11 translocation family, demonstrated inferior progression-free survival and overall survival in patients with PDAC, especially in men. Our novel biomarker, survival significant chromatin remodeling-associated gene cluster, showed superior prediction performance compared with the conventional TNM system. Overall, these findings suggest that epigenetic modifications and interactions play an important role in the prognosis and therapeutic response of patients with PDAC.

Current and emerging therapeutic strategies in pancreatic cancer: Challenges and opportunities.

Pancreatic carcinoma (PC) is one of the leading causes of cancer-related deaths worldwide. Despite early detection and advances in therapeutics, the prognosis remains dismal. The outcome and therapeutic approach are dependent on the stage of PC at the time of diagnosis. The standard of care is surgery, followed by adjuvant chemotherapy. The advent of newer drugs has changed the landscape of adjuvant therapy. Moreover, recent trials have highlighted the role of neoadjuvant therapy and chemoradiotherapy for resectable and borderline resectable PC. As we progress towards a better understanding of tumor biology, genetics, and microenvironment, novel therapeutic strategies and targeted agents are now on the horizon. We have described the current and emerging therapeutic strategies in PC.

Emerging Treatment Strategies in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the main causes of cancer death in well-developed countries. Therapeutic advances in PDAC to date have been modest. Recent progress to understand the molecular landscape of the disease has opened new treatment opportunities for a small subset of patients, frequently those with KRAS wild-type disease. Novel treatment strategies in PDAC include, among others, the use of nanotechnology and metabolic reprogramming. In addition, new strategies are being investigated, which are designed to overcome the resistance to checkpoint inhibitors, targeting DNA repair pathways including mismatch repair, increasing antigen presentation through the use of vaccines, targeting various signaling pathways, and reprogramming the tumor microenvironment. Here, we review the landscape of PDAC treatment strategies and some of these new agents.

Abstract 1658: Gemcitabine impacts expression of antigen presentation proteins by pancreatic cancer cells

Abstract Background: Pancreatic adenocarcinoma is one of the deadliest type of cancers with a 5-year overall survival rate of 10%. A standard chemotherapy approach for pancreatic cancer is treatment with gemcitabine. Gemcitabine is also considered a potential immunomodulatory agent, capable of increasing human leukocyte antigen (HLA) class I. HLA class I is a heterodimer of a highly polymorphic alpha heavy chain (HLA-A, -B, or -C) and the light chain beta-2-microglobulin (β2m) that is loaded with an endogenous antigen in the endoplasmic reticulum. The pool of antigens available for HLA class I loading is selected by the transporter associated with antigen processing protein (TAP). However, HLA class I peptide loading can occur independently of TAP, causing the HLA class I molecules to present a different antigen pool to cytotoxic T cells. Because many cancers downregulate HLA class I and prevent intracellular tumor antigens from being presented to cytotoxic T cells, understanding more about gemcitabine's capability to increase HLA class I expression is of great importance. Methods: Alterations in HLA class I and TAP protein levels were monitored via western blot analysis in a pancreatic cancer cell line (S2-013) in both a time and dose-dependent manner. The time points and dosages which solicited the largest increase in HLA class I expression were also examined by flow cytometry. Results: Administration of gemcitabine to S2-013 pancreatic cancer cells increased total HLA class I α heavy chain protein, with maximal increases of 141% (HLA-A) and 323% HLA-B/C. Flow cytometry revealed a 3-fold increase in HLA-A2 surface expression post-gemcitabine treatment and a maximal 2-fold increase in HLA-B/C expression at the corresponding gemcitabine concentration, but differing time point. Both western blot and flow cytometry analyses indicate HLA-B/C generally has its largest increase in expression at an earlier time point than HLA-A. In addition, high concentrations of gemcitabine that promoted HLA-A,B,C surface expression were associated with a large decrease in TAP total protein. Conclusion: In summary, gemcitabine demonstrates an ability to stimulate expression of HLA class I in pancreatic cancer cells, with the rate dependent on the HLA class I allele. Because gemcitabine treatment increases HLA class I surface expression with a simultaneous decrease in TAP expression, our findings indicate that gemcitabine may induce TAP-independent peptide loading of HLA class I. These results suggest the potential for gemcitabine treatment as a priming mechanism to enhance immunotherapy efficacy and potentially alter vaccination strategies in pancreatic cancer. Citation Format: Alaina C. Larson, Shelby M. Knoche, Joyce C. Solheim. Gemcitabine impacts expression of antigen presentation proteins by pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1658.

Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects.

Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance. However, emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes. These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression. The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells, stromal fibroblasts, and immune cells. This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease. Here, we provide a concise review on lessons learned from past stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.

Oncolytic Virus Could Improve Treatment Strategy for Pancreatic Cancer

Oncolytic Virus Could Improve Treatment Strategy for Pancreatic Cancer