scholarly journals Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander G. Raufi ◽  
Nicholas R. Liguori ◽  
Lindsey Carlsen ◽  
Cassandra Parker ◽  
Liz Hernandez Borrero ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Alternative Energy ◽  
Mapk Pathway ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Targeting ◽  
Aggressive Disease ◽  
Alternative Energy Sources ◽  
Novel Treatment ◽  
Late Detection ◽  
Autophagy Inhibition

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by early metastasis, late detection, and poor prognosis. Progress towards effective therapy has been slow despite significant efforts. Novel treatment approaches are desperately needed and autophagy, an evolutionary conserved process through which proteins and organelles are recycled for use as alternative energy sources, may represent one such target. Although incompletely understood, there is growing evidence suggesting that autophagy may play a role in PDAC carcinogenesis, metastasis, and survival. Early clinical trials involving autophagy inhibiting agents, either alone or in combination with chemotherapy, have been disappointing. Recently, evidence has demonstrated synergy between the MAPK pathway and autophagy inhibitors in PDAC, suggesting a promising therapeutic intervention. In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibition. We discuss autophagy in PDAC tumorigenesis, metabolism, modulation of the immune response, and preclinical and clinical data with selected autophagy modulators as therapeutics.

scholarly journals Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges

2017 ◽  
Vol 313 (5) ◽  
pp. G524-G536 ◽  
Author(s):  
Sandrina Maertin ◽  
Jason M. Elperin ◽  
Ethan Lotshaw ◽  
Matthias Sendler ◽  
Steven D. Speakman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Oxidative Phosphorylation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Environmental Stresses ◽  
Ductal Adenocarcinoma ◽  
Cell Adaptation ◽  
Autophagy Inhibition ◽  
Dependent Mechanism

Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC. NEW & NOTEWORTHY Cancer cells in the highly desmoplastic pancreatic ductal adenocarcinoma confront nutrient [i.e., amino acids (AA)] deprivation and hypoxia, but how pancreatic cancer (PaCa) cells adapt to these conditions is poorly understood. This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism.

Combined SHP2 and ERK inhibition for the treatment of KRAS-driven Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Katrin J Ciecielski ◽  
Antonio Mulero-Sanchez ◽  
Alexandra Berninger ◽  
Laura Ruiz Canas ◽  
Astrid Bosma ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Single Agent ◽  
Ductal Adenocarcinoma ◽  
Good Tolerability ◽  
Recent Emergence ◽  
Erk Inhibition

Mutant KRAS is present in over 90% of pancreatic as well as 30-40% of lung and colorectal cancers and is one of the most common oncogenic drivers. Despite decades of research and the recent emergence of isoform-specific KRASG12C-inhibitors, most mutant KRAS isoforms, including the ones frequently associated with pancreatic ductal adenocarcinoma (PDAC), cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive mechanisms leading to tumor recurrence or resistance. We report here on the combined inhibition of SHP2, a non-receptor tyrosine phosphatase upstream of KRAS, and ERK, a serine/threonine kinase and a key molecule downstream of KRAS in PDAC. This combination shows synergistic anticancer activity in vitro, superior disruption of the MAPK pathway, and significantly increased apoptosis induction compared to single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination. Concurrent inhibition of SHP2 and ERK induces significant tumor regression in multiple PDAC mouse models. Finally, we show evidence that 18F-FDG PET scans can be used to detect and predict early drug responses in animal models. Based on these compelling results, we will investigate this drug combination in a clinical trial (SHERPA, SHP2 and ERK inhibition in pancreatic cancer, NCT04916236), enrolling patients with KRAS-mutant PDAC.

scholarly journals From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 21 (11) ◽  
pp. 4067 ◽  
Author(s):  
Christopher Montemagno ◽  
Shamir Cassim ◽  
Jacques Pouyssegur ◽  
Alexis Broisat ◽  
Gilles Pagès
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Malignant Progression ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Therapeutic Targeting ◽  
Normal Tissues ◽  
Attractive Candidate ◽  
Rising Incidence ◽  
Resistance To Chemotherapy

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic.

The therapeutic targeting of the FGFR1/Src/NF-κB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity

2018 ◽  
Vol 35 (7) ◽  
pp. 663-677 ◽  
Author(s):  
Shiue-Wei Lai ◽  
Oluwaseun Adebayo Bamodu ◽  
Wen-Chiuan Tsai ◽  
Yi-Ming Chang ◽  
Wei-Hwa Lee ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Targeting ◽  
Signaling Axis

scholarly journals Amplified centrosomes may underlie aggressive disease course in pancreatic ductal adenocarcinoma

Cell Cycle ◽  
2015 ◽  
Vol 14 (17) ◽  
pp. 2798-2809 ◽  
Author(s):  
Karuna Mittal ◽  
Angela Ogden ◽  
Michelle D Reid ◽  
Padmashree CG Rida ◽  
Sooryanarayana Varambally ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Disease Course ◽  
Aggressive Disease

scholarly journals Tumor -Associated MUC1 Regulates TGF-β Signaling and Function in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Author(s):  
Priyanka Grover ◽  
Sritama Nath ◽  
Mukulika Bose ◽  
Alexa J. Sanders ◽  
Cory Brouwer ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Tumor Promoter ◽  
Ductal Adenocarcinoma ◽  
Potential Biomarker ◽  
Tgf Β1

AbstractPancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-β) is a cytokine that switches from a tumor-suppressor to a tumor promoter throughout tumor development, by a yet unknown mechanism. Tumor associated MUC1 (tMUC1) is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) interacts with other oncogenic proteins promoting tumor progression and metastasis. We hypothesize that tMUC1 levels regulate TGF-β functions in PDA in vitro and in vivo. We report that high-tMUC1 expression positively correlates to TGF-βRII and negatively to TGF-βRI receptors. In response to TGF-β1, high tMUC1 expressing PDA cells undergo c-Src phosphorylation, and activation of the Erk/MAPK pathway; while low tMUC1 expressing cells activate the Smad2/3 pathway, enhancing cell death. Correspondingly, mice bearing tMUC1-high tumors responded to TGF-β1 neutralizing antibody in vivo showing significantly retarded tumor growth. Analysis of clinical data from TCGA revealed significant alterations in gene-gene correlations in the TGF-β pathway in tMUC1 high versus tMUC1 low samples. This study deepens our understanding of tMUC1-regulated TGF-β’s paradoxical function in PDA and establishes tMUC1 as a potential biomarker to predict response to TGF-β-targeted therapies.

scholarly journals Activating Immune Recognition in Pancreatic Ductal Adenocarcinoma Using Autophagy Inhibition, MEK blockade and CD40 Agonism

2020 ◽  
Author(s):  
Honglin Jiang ◽  
Tristan Courau ◽  
Leonard Lupin-Jimenez ◽  
Joseph Borison ◽  
Alexa J. Ritchie ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ductal Adenocarcinoma ◽  
Cytotoxic T Cell ◽  
Type I ◽  
Immune Recognition ◽  
Immunosuppressive Tumor Microenvironment ◽  
Sting Pathway ◽  
Autophagy Inhibition

AbstractPancreatic ductal adenocarcinoma (PDA) patients have not yet benefitted from the revolution in cancer immunotherapy due in large part to the dominantly immunosuppressive tumor microenvironment (TME). MEK inhibition combined with autophagy inhibition leads to transient tumor responses in some PDA patients. We find that co-inhibition of MEK (using cobimetinib, COBI) and autophagy (using mefloquine, MFQ), but not either treatment alone, activates the Type I Interferon/STING pathway in tumor cells which in turn reprogram tumor associated macrophages (TAMs) in paracrine to foster an immunogenic switch. This effect is augmented by a CD40 agonist (aCD40). Triple therapy (COBI+MFQ+aCD40) achieved cytotoxic T cell activation in an immunologically “cold” mouse PDA model, leading to enhanced anti-tumor immunity. Collectively, MEK and autophagy co-inhibition coupled with CD40 agonism invokes immuno-reprograming and is an attractive therapeutic approach for PDA immunotherapy development.

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