Current Immunotherapeutic Approaches in Pancreatic Cancer

Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer.

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Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma

Cancers ◽

10.3390/cancers13163969 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3969

Author(s):

Juliana B. Candido ◽

Oscar Maiques ◽

Melanie Boxberg ◽

Verena Kast ◽

Eleonora Peerani ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Standard Of Care ◽

Tumour Microenvironment ◽

Ductal Adenocarcinoma ◽

Therapeutic Approaches ◽

Novel Treatments ◽

Pancreatic Cancer Cells ◽

Invasive Tumour ◽

Mrna And Protein Expression

As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.

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ROCK2 Confers Acquired Gemcitabine Resistance in Pancreatic Cancer Cells by Upregulating Transcription Factor ZEB1

SSRN Electronic Journal ◽

10.2139/ssrn.3439545 ◽

2019 ◽

Cited By ~ 1

Author(s):

Yang Zhou ◽

Yunjiang Zhou ◽

Keke Wang ◽

Tao Li ◽

Minda Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells

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New Aspects of the Epigenetics of Pancreatic Carcinogenesis

Epigenomes ◽

10.3390/epigenomes4030018 ◽

2020 ◽

Vol 4 (3) ◽

pp. 18

Author(s):

Murat Toruner ◽

Martin E. Fernandez-Zapico ◽

Christopher L. Pin

Keyword(s):

Pancreatic Cancer ◽

Dna Methylation ◽

Survival Rate ◽

Epigenetic Mechanisms ◽

Therapeutic Approaches ◽

Cancer Epigenetics ◽

Pancreatic Carcinogenesis ◽

New Therapeutic Approaches ◽

Environmental Events ◽

Underlying Pathogenesis

Pancreatic cancer remains among the deadliest forms of cancer with a 5 year survival rate less than 10%. With increasing numbers being observed, there is an urgent need to elucidate the pathogenesis of pancreatic cancer. While both contribute to disease progression, neither genetic nor environmental factors completely explain susceptibility or pathogenesis. Defining the links between genetic and environmental events represents an opportunity to understand the pathogenesis of pancreatic cancer. Epigenetics, the study of mitotically heritable changes in genome function without a change in nucleotide sequence, is an emerging field of research in pancreatic cancer. The main epigenetic mechanisms include DNA methylation, histone modifications and RNA interference, all of which are altered by changes to the environment. Epigenetic mechanisms are being investigated to clarify the underlying pathogenesis of pancreatic cancer including an increasing number of studies examining the role as possible diagnostic and prognostic biomarkers. These mechanisms also provide targets for promising new therapeutic approaches for this devastating malignancy.

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Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells

International Journal of Cancer ◽

10.1002/ijc.20304 ◽

2004 ◽

Vol 112 (2) ◽

pp. 184-189 ◽

Cited By ~ 31

Author(s):

Shin-ichiro Maehara ◽

Shinji Tanaka ◽

Mitsuo Shimada ◽

Ken Shirabe ◽

Yoshiro Saito ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Human Pancreatic Cancer ◽

Selenoprotein P ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells

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Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

International Journal of Oncology ◽

10.3892/ijo.2015.2885 ◽

2015 ◽

Vol 46 (4) ◽

pp. 1849-1857 ◽

Cited By ~ 14

Author(s):

RANGANATHA R. SOMASAGARA ◽

GAGAN DEEP ◽

SANGEETA SHROTRIYA ◽

MANISHA PATEL ◽

CHAPLA AGARWAL ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Bitter Melon ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells

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Biologically optimized schedule of gemcitabine and nab-paclitaxel regimen in metastatic pancreatic adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps4168 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS4168-TPS4168

Author(s):

Laith I. Abushahin ◽

Anne M. Noonan ◽

John L. Hays ◽

Pannaga G. Malalur ◽

Ashish Manne ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Pancreatic Adenocarcinoma ◽

Cell Lines ◽

Dose Intensity ◽

Standard Of Care ◽

Significance Level ◽

Pancreatic Cancer Cells ◽

Metastatic Pancreatic Adenocarcinoma

TPS4168 Background: Metastatic pancreatic adenocarcinoma has a poor prognosis, and improvements in therapy have been challenging. Alongside efforts in developing novel agents, there is a need to optimize and maximize the benefit of currently approved drugs. Gemcitabine + nab-paclitaxel is a frequently used regimen for pancreatic adenocarcinoma. Nab-paclitaxel is albumin–bound chemotherapy; hence the role of albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. Williams and colleagues have published a series of preclinical studies demonstrating that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of pancreatic cancer cells to Gemcitabine resulted in up-regulation of Cav-1 peaking 48 hours after gemcitabine exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, Williams and colleagues noted that exposure of pancreatic cancer cell lines to Gemcitabine resulted in a time–specific re-entry of cells into the G2/M phase (nab-paclitaxel cytotoxicity phase) between 48-60 hours after gemcitabine treatment. Collectively this data suggest that infusing nab-paclitaxel after 48 hours of gemcitabine infusion would be optimal for both increased uptake as well as increased susceptible tumor cells. We had previously shown this effect on multiple cell lines as well as mouse models. Methods: This is a phase II trial; patients will receive a standard of care chemotherapy regimen consisting of FDA-approved Gemcitabine + nab-paclitaxel with modification of the schedule to deliver nab-paclitaxel 48 hours (2 days) after gemcitabine infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs. a target of 35%. Employing a 2-stage design (minimax) and assuming 80% power and a 0.05 significance level, a total of 53 patients will be required. In the first stage, if at least 7/31 patients respond to therapy, an additional 22 patients will be added for a total of 53 patients. The study will be terminated early if ≤ six patients respond in the first stage. Observation of response in at least 16/53 patients would be required to warrant further investigation of this infusion schedule of combination therapy. The secondary endpoints include the safety of the regimen schedule, Relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrollment in June 2020 and is accepting patients. Clinical trial information: NCT04115163.

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m6A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.696371 ◽

2021 ◽

Vol 11 ◽

Author(s):

Congjun Zhang ◽

Shuangyan Ou ◽

Yuan Zhou ◽

Pei Liu ◽

Peiying Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Western Blotting ◽

Protein Level ◽

Cytidine Deaminase ◽

Critical Role ◽

Human Pancreatic Cancer ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells

ObjectivePancreatic cancer is one of the most lethal human malignancies. Gemcitabine is widely used to treat pancreatic cancer, and the resistance to chemotherapy is the major difficulty in treating the disease. N6-methyladenosine (m6A) modification, which regulates RNA splicing, stability, translocation, and translation, plays critical roles in cancer physiological and pathological processes. METTL14, an m6A Lmethyltransferase, was found deregulated in multiple cancer types. However, its role in gemcitabine resistance in pancreatic cancer remains elusive.MethodsThe mRNA and protein level of m6A modification associated genes were assessed by QRT-PCR and western blotting. Then, gemcitabine‐resistant pancreatic cancer cells were established. The growth of pancreatic cancer cells were analyzed using CCK8 assay and colony formation assay. METTL14 was depleted by using shRNA. The binding of p65 on METTL14 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Protein level of deoxycytidine kinase (DCK) and cytidine deaminase (CDA) was evaluated by western blotting. In vivo experiments were conducted to further confirm the critical role of METTL14 in gemcitabine resistance.ResultsWe found that gemcitabine treatment significantly increased the expression of m6A methyltransferase METTL14, and METTL14 was up-regulated in gemcitabine-resistance human pancreatic cancer cells. Suppression of METTL14 obviously increased the sensitivity of gemcitabine in resistant cells. Moreover, we identified that transcriptional factor p65 targeted the promoter region of METTL14 and up-regulated its expression, which then increased the expression of cytidine deaminase (CDA), an enzyme inactivates gemcitabine. Furthermore, in vivo experiment showed that depletion of METTL14 rescue the response of resistance cell to gemcitabine in a xenograft model.ConclusionOur study suggested that METTL14 is a potential target for chemotherapy resistance in pancreatic cancer.

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