Current Therapeutic Options for Pancreatic Ductal Adenocarcinoma

Brossart, Peter; Feldmann, Georg

doi:10.1159/000493868

Cited by 10 publications

(4 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pancreatic cancer carries an exceptionally poor overall prognosis and shows relative insensitivity towards many antineoplastic agents, including classical cytotoxic chemotherapeutic drugs as well as currently available immunotherapies [ 43 , 44 , 45 , 46 ]. Hence, therapeutic options for the majority of advanced disease stages are limited, and novel therapeutic approaches are urgently required [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer

Wang,

Breuer,

Garbe

et al. 2024

IJMS

Self Cite

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of human malignancies and carries an exceptionally poor prognosis. It is mostly driven by multiple oncogenic alterations, with the highest mutation frequency being observed in the KRAS gene, which is a key oncogenic driver of tumorogenesis and malignant progression in PDAC. However, KRAS remained undruggable for decades until the emergence of G12C mutation specific KRAS inhibitors. Despite this development, this therapeutic approach to target KRAS directly is not routinely used for PDAC patients, with the reasons being the rare presence of G12C mutation in PDAC with only 1–2% of occurring cases, modest therapeutic efficacy, activation of compensatory pathways leading to cell resistance, and absence of effective KRASG12D or pan-KRAS inhibitors. Additionally, indirect approaches to targeting KRAS through upstream and downstream regulators or effectors were also found to be either ineffective or known to cause major toxicities. For this reason, new and more effective treatment strategies that combine different therapeutic modalities aiming at achieving synergism and minimizing intrinsic or adaptive resistance mechanisms are required. In the current work presented here, pancreatic cancer cell lines with oncogenic KRAS G12C, G12D, or wild-type KRAS were treated with specific KRAS or SOS1/2 inhibitors, and therapeutic synergisms with concomitant MEK inhibition and irradiation were systematically evaluated by means of cell viability, 2D-clonogenic, 3D-anchorage independent soft agar, and bioluminescent ATP assays. Underlying pathophysiological mechanisms were examined by using Western blot analyses, apoptosis assay, and RAS activation assay.

show abstract

Section: Discussionmentioning

confidence: 99%

Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer

Wang,

Breuer,

Garbe

et al. 2024

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…In recent years, research on targeted-, microbial-, and immune-therapy has become increasingly prevalent in treating various forms of cancers [9]. While targeted therapy, such as vascular endothelial growth factor (VEGF)-directed antibodies have shown success in other cancer types, a plethora of adverse effects including induced toxicity and tumour recurrence were observed in PDA making it unfeasible for treatment [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Therapeutic Opportunities of the Tumour Microenvironment in Treating Pancreatic Ductal Adenocarcinoma: A Literature Review

Dhaliwal

2022

URNCST Journal

View full text Add to dashboard Cite

Introduction: Pancreatic ductal adenocarcinoma (PDA) is an invasive cancer of the exocrine pancreas with a 5-year survival rate (<8%), highlighting the need for new therapies to increase patient survivability and remission rates. Current treatment options with chemotherapeutics have yielded minimal success, warranting further research into targeting alternative pathways in tumour progression. The complex tumour microenvironment (TME) of PDA contributes significantly to tumorigenesis and may contain promising novel targets. The therapeutic potential of some known TME elements will be explored, namely hypoxia, MMPs, and TGF-β. These options each have their merits and differences, which are crucial to evaluate and assess the trajectory of PDA research in the future. Methods: A literature review was performed to summarize all available research on the different current therapeutic options and TME components that can be utilized for PDA treatment. The terms "hypoxia," "MMPs," and "TGF-β'' were used as keywords to search databases including Medline, Embase, and CINAHL. These were searched in combination with terms relevant to PDA and TME. Studies that were peer-reviewed and written in English were taken into consideration, with a focus on those that were published between 2017 and 2022. Results: Each TME element of hypoxia, MMPs, and TGF-β have specific distinctive targets of HIF-1α, TIMP-1, and SMAD-independent pathways, respectively. These present varying mechanisms of action which differ in their efficacies and limitations. Several of these therapies are currently undergoing clinical trials to better understand the role of each inhibitor. Discussion: This literature review provides insight into the current and future treatments for PDA. Exploiting the TME to develop therapeutic interventions presents a promising strategy to inhibit disease progression, yet research done in PDA is still preliminary due to the disease complexity, but it is moving towards a clinical settings. Conclusion: Accumulating evidence has suggested that several opportunities for targeted therapy in the PDA TME are very promising and not yet thoroughly investigated. This review aids in accessibility by summarizing important information regarding PDA and the necessary further research into targeting the TME to develop a novel therapeutic treatment.

show abstract

“…Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis with a 5‐year survival rate of around 6% 1 . The disease is generally diagnosed at an advanced stage with limited opportunities for surgical intervention, leaving chemotherapy as a current standard of care with significant adverse side effects and poor efficacy 2 . Immunotherapy studies with checkpoint inhibitors in PDAC have failed to elicit a similar therapeutic response as seen in some other tumor types 3 .…”

Section: Introductionmentioning

confidence: 99%

“… 1 The disease is generally diagnosed at an advanced stage with limited opportunities for surgical intervention, leaving chemotherapy as a current standard of care with significant adverse side effects and poor efficacy. 2 Immunotherapy studies with checkpoint inhibitors in PDAC have failed to elicit a similar therapeutic response as seen in some other tumor types. 3 The molecular markers that are involved in the invasive and metastatic process of PDAC are not yet clearly defined and hence lack targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

A potential signaling axis between RON kinase receptor and hypoxia‐inducible factor‐1 alpha in pancreatic cancer

Thangasamy

Han

et al. 2021

Molecular Carcinogenesis

View full text Add to dashboard Cite

The Cancer Genome Atlas (TCGA) of a pancreatic cancer cohort identified high MST1R (RON tyrosine kinase receptor) expression correlated with poor prognosis in human pancreatic cancer. RON expression is null/minimal in normal pancreas but elevates from pan‐in lesions through invasive carcinomas. We report using multiple approaches RON directly regulates HIF‐1α, a critical driver of genes involved in cancer cell invasion and metastasis. RON and HIF‐1α are highly co‐expressed in the 101 human PDAC tumors analyzed and RON expression correlated with HIF‐1α expression in a subset of PDAC cell lines. knockdown of RON expression in RON positive cells blocked HIF‐1α expression, whereas ectopic RON expression in RON null cells induced HIF‐1α expression suggesting the direct regulation of HIF‐1α by RON kinase receptor. RON regulates HIF‐1α through an unreported transcriptional mechanism involving PI3 kinase‐mediated AKT phosphorylation and Sp1‐dependent HIF‐1α promoter activity leading to increased HIF‐1α mRNA expression. RON/HIF‐1α modulation altered the invasive behavior of PDAC cells. A small‐molecule RON kinase inhibitor decreased RON ligand, MSP‐induced HIF‐1α expression, and invasion of PDAC cells. Immunohistochemical analysis on RON knockdown orthotopic PDAC tumor xenograft confirmed that RON inhibition significantly blocked HIF‐1α expression. RON/HIF‐1α co‐expression also exists in triple‐negative breast cancer cells, a tumor type that also lacks molecular therapeutic targets. This is the first report describing RON/HIF‐1α axis in any tumor type and is a potential novel therapeutic target.

show abstract

Current Therapeutic Options for Pancreatic Ductal Adenocarcinoma

Cited by 10 publications

References 44 publications

Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer

Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer

Exploring the Therapeutic Opportunities of the Tumour Microenvironment in Treating Pancreatic Ductal Adenocarcinoma: A Literature Review

A potential signaling axis between RON kinase receptor and hypoxia‐inducible factor‐1 alpha in pancreatic cancer

Contact Info

Product

Resources

About