From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer

Nevala-Plagemann, Christopher; Hidalgo, Manuel; Garrido‐Laguna, Ignacio

doi:10.1038/s41571-019-0281-6

Cited by 276 publications

(231 citation statements)

References 138 publications

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“…The 5-year relative survival rate for pancreatic cancer is the lowest among cancers—only 9% across all stages, and the death rates for pancreatic cancers have risen over the past decade [ 3 ]. The current standard treatments for pancreatic cancers continue to rely on surgical resection and cytotoxic therapies; however, only less than 20% of patients are eligible to complete surgical resection, and many will relapse and die within one year [ 3 , 4 , 5 , 6 ]. To make matters worse, owing to the asymptomatic nature of the early stage of the disease and the absence of efficient diagnostic methods, most patients with PDAC present with the locally advanced and inoperable disease at diagnosis [ 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

Tanaka

Okada

Hozaka

et al. 2020

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal; only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre-miR-30c (miR-30c-5p, guide strand; miR-30c-2-3p, passenger strand) were significantly downregulated, suggesting they function as tumor-suppressors in PDAC cells. Ectopic expression assays demonstrated that these miRNAs attenuated the aggressiveness of PDAC cells, e.g., cell proliferation, migration, and invasiveness. Through a combination of in silico analyses and gene expression data, we identified 216 genes as putative oncogenic targets of miR-30c-5p and miR-30c-2-3p regulation in PDAC cells. Among these, the expression of 18 genes significantly predicted the 5-year survival rates of PDAC patients (p < 0.01). Importantly, the expression levels of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were found to be independent prognostic factors for patient survival (p < 0.01). We focused on TOP2A (DNA Topoisomerase II Alpha) and investigated its potential as a therapeutic target for PDAC. The overexpression of TOP2A and its transcriptional activators (SP1 and HMGB2) was detected in PDAC clinical specimens. Moreover, the knockdown of TOP2A enhanced the sensitivity of PDAC cells to anticancer drugs. Our analyses of the PDAC miRNA signature and tumor-suppressive miRNAs provide important insights into the molecular pathogenesis of PDAC.

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Section: Introductionmentioning

confidence: 99%

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

Tanaka

Okada

Hozaka

et al. 2020

Cancers

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“…PDAC driver mutations have proven difficult to target in the clinical setting, with the exception of microsatellite instability with immune check point inhibitors [ 17 ] or BRCA1/2 mutations with platinum-based chemotherapies and PARP-inhibitors [ 18 , 19 ]; however, these concern only a small number of patients. KRAS wild-type patients comprise between 5 and 8% of sporadic PDAC patients [ 20 ] and have been shown to harbor actionable genomic alterations [ 21 ], such as NTRK [ 22 ] or NRG1 [ 23 , 24 ] fusions. While molecular subtypes and actionable genomic alterations may theoretically help guide precision medicine approaches, the molecular characterization of PDAC in patients with advanced disease has not yet entered routine clinical practice.…”

Section: Pancreatic Cancer: Clinical Situationmentioning

confidence: 99%

The Immune Microenvironment in Pancreatic Cancer

Huber

Brehm

Gress³

et al. 2020

IJMS

166

161

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The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor–stroma interactions will one day lead to a significant advancement in patient care.

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“…Consequently, a more precise profiling of BRCA-mutant patients is required to identify patients who will benefit from a PARPi or platinum-analogue treatment. Further strategies of targeting actionable mutations are ongoing (see also review from Nevala-Plagemann [24]); a prospective proof of effectiveness and performance for biomarker-selected therapies remains to be confirmed in pancreatic cancer patients.…”

Section: Selected Mutant Gene Profiles and Cancer Subtypes Are Eligibmentioning

confidence: 99%

Current Strategies and Future Perspectives for Precision Medicine in Pancreatic Cancer

Regel

Mayerle

Mahajan

2020

Cancers

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Current standard-of-care for patients with pancreatic ductal adenocarcinoma (PDAC) focusses on chemotherapeutic regimens and pancreatic cancer surgery. However, limited treatment options, late diagnosis in advanced tumor stages and the aggressive behavior of PDAC contribute to the high mortality of the disease. Consequently, there is an urgent need of precision medicine for pancreatic cancer patients. All over the world, numerous initiatives started in recent years to translate novel scientific discoveries into prospective clinical trials. One major approach pursues the stratification of PDAC patients according the tumor transcriptome to predict treatment response. Other strategies concentrate on genomic alterations and the identification of individualized targeted therapies. Further experimental studies are ongoing to detect novel biomarkers for cancer diagnosis, subtyping, treatment response prediction or clinical outcome. However, the challenge remains to transfer the knowledge into clinical practice. In this review, we summarize current literature and knowledge and highlight novel concepts of basic and clinical research uncovering suitable biomarkers and targeted therapies. Thus, we provide an overview of preclinical and clinical efforts of precision medicine in pancreatic cancer.

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From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer

Cited by 276 publications

References 138 publications

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

The Immune Microenvironment in Pancreatic Cancer

Current Strategies and Future Perspectives for Precision Medicine in Pancreatic Cancer

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