scholarly journals Lipid nanoparticles delivering constitutively active STING mRNA as a novel anti-cancer therapeutic approach

2022 ◽  
Author(s):  
Wei Liu ◽  
Mohamad-Gabriel Alameh ◽  
June F. Yang ◽  
Jonathan R. Xu ◽  
Paulo JC Lin ◽  
...  
Keyword(s):  
Cd8 T Cells ◽  
Lipid Nanoparticles ◽  
Cell Entry ◽  
Ductal Adenocarcinoma ◽  
Cancer Therapies ◽  
Therapeutic Tool ◽  
Antitumor Response ◽  
Cancer Cell Death ◽  
Cytokines And Chemokines ◽  
Anti Cancer

Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically 'cold' tumor microenvironment (TME). However, we and others have shown that STING is silenced in many cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC), both of which are associated with an immune-dampened TME. In this study, we applied mRNA lipid nanoparticles (LNP) to deliver a permanently active gain-of-function STINGR284S mutant into PDAC and MCC cells. Expression of STINGR284S induces cytokines and chemokines crucial for promoting intratumoral infiltration of CD8+ T cells and, importantly, also leads to robust cancer cell death while avoiding T cell entry and toxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S could be explored as a novel therapeutic tool to reactivate antitumor response in an array of STING-deficient cancers while overcoming the toxicity and limitations of conventional STING agonists.

scholarly journals Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sebastian R. Nielsen ◽  
Jan E. Strøbech ◽  
Edward R. Horton ◽  
Rene Jackstadt ◽  
Anu Laitala ◽  
...  
Keyword(s):  
Cd8 T Cells ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Cancer Therapies ◽  
Cell Type ◽  
Clinical Prognosis ◽  
Tumor Associated Neutrophils ◽  
Poor Clinical Prognosis

AbstractPancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.

scholarly journals NF-κB and Pancreatic Cancer; Chapter and Verse

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4510
Author(s):  
John Silke ◽  
Lorraine Ann O’Reilly
Keyword(s):  
Pancreatic Cancer ◽  
Treatment Options ◽  
Pancreatic Injury ◽  
Ductal Adenocarcinoma ◽  
Cellular Activation ◽  
New Therapeutic Approaches ◽  
Cancer Cell Death ◽  
Anti Cancer ◽  
Smac Mimetics ◽  
Injury Progression

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the world’s most lethal cancers. An increase in occurrence, coupled with, presently limited treatment options, necessitates the pursuit of new therapeutic approaches. Many human cancers, including PDAC are initiated by unresolved inflammation. The transcription factor NF-κB coordinates many signals that drive cellular activation and proliferation during immunity but also those involved in inflammation and autophagy which may instigate tumorigenesis. It is not surprising therefore, that activation of canonical and non-canonical NF-κB pathways is increasingly recognized as an important driver of pancreatic injury, progression to tumorigenesis and drug resistance. Paradoxically, NF-κB dysregulation has also been shown to inhibit pancreatic inflammation and pancreatic cancer, depending on the context. A pro-oncogenic or pro-suppressive role for individual components of the NF-κB pathway appears to be cell type, microenvironment and even stage dependent. This review provides an outline of NF-κB signaling, focusing on the role of the various NF-κB family members in the evolving inflammatory PDAC microenvironment. Finally, we discuss pharmacological control of NF-κB to curb inflammation, focussing on novel anti-cancer agents which reinstate the process of cancer cell death, the Smac mimetics and their pre-clinical and early clinical trials.

scholarly journals Cytokine and Chemokine Signals of T-Cell Exclusion in Tumors

2020 ◽  
Vol 11 ◽  
Author(s):  
Yu Zhang ◽  
Xin-yuan Guan ◽  
Peng Jiang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Early Stage ◽  
Effector T Cells ◽  
Cancer Therapies ◽  
Preclinical Models ◽  
Cytokines And Chemokines ◽  
Anti Cancer ◽  
Malignant Lesions ◽  
T Cell Exclusion

The success of cancer immunotherapy in solid tumors depends on a sufficient distribution of effector T cells into malignant lesions. However, immune-cold tumors utilize many T-cell exclusion mechanisms to resist immunotherapy. T cells have to go through three steps to fight against tumors: trafficking to the tumor core, surviving and expanding, and maintaining the memory phenotype for long-lasting responses. Cytokines and chemokines play critical roles in modulating the recruitment of T cells and the overall cellular compositions of the tumor microenvironment. Manipulating the cytokine or chemokine environment has brought success in preclinical models and early-stage clinical trials. However, depending on the immune context, the same cytokine or chemokine signals may exhibit either antitumor or protumor activities and induce unwanted side effects. Therefore, a comprehensive understanding of the cytokine and chemokine signals is the premise of overcoming T-cell exclusion for effective and innovative anti-cancer therapies.

ANTICANCER EFFECT OF UVARIA GENUS

2014 ◽  
pp. 98-101
Author(s):  
Thi Bich Hien Le ◽  
Viet Duc Ho ◽  
Thi Hoai Nguyen
Keyword(s):  
Biological Activities ◽  
Current Trend ◽  
Healthcare Systems ◽  
Chemical Compositions ◽  
Cancer Therapies ◽  
Pharmacological Effects ◽  
Anticancer Effect ◽  
Anti Cancer ◽  
Tropical Areas ◽  
Cancer Activity

Nowadays, cancer treatment has been a big challenge to healthcare systems. Most of clinical anti-cancer therapies are toxic and cause adverse effects to human body. Therefore, current trend in science is seeking and screening of natural compounds which possess antineoplastic activities to utilize in treatment. Uvaria L. - Annonaceae includes approximately 175 species spreading over tropical areas of Asia, Australia, Africa and America. Studies on chemical compositions and pharmacological effects of Uvaria showed that several compound classes in this genus such as alkaloid, flavonoid, cyclohexen derivaties, acetogenin, steroid, terpenoid, etc. indicate considerable biological activities, for example anti-tumor, anti-cancer, antibacterial, antifungal, antioxidant, etc. Specifically, anti-cancer activity of fractions of extract and pure isolated compounds stands out for cytotoxicity against many cancer cell lines. This study provides an overview of anti-cancer activity of Uvaria and suggests a potential for further studies on seeking and developing novel anti-cancer compounds. Key words: Anti-cancer, Uvaria.

Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

2020 ◽  
Vol 15 (6) ◽  
pp. 482-491 ◽  
Author(s):  
Milena Kostadinova ◽  
Milena Mourdjeva
Keyword(s):  
Cancer Cells ◽  
Small Population ◽  
Tumor Formation ◽  
Bioactive Molecules ◽  
Cancer Therapies ◽  
New Methods ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

Kinase Inhibitors Targeting Anti-angiogenesis as Anti-cancer Therapies

2012 ◽  
Vol 1 (4) ◽  
pp. 335-346 ◽  
Author(s):  
Jing Liu ◽  
Feiyang Liu ◽  
David L. Waller ◽  
Junfeng Wang ◽  
Qingsong Liu
Keyword(s):  
Kinase Inhibitors ◽  
Cancer Therapies ◽  
Anti Cancer

scholarly journals Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1627 ◽  
Author(s):  
Anita Thyagarajan ◽  
Mamdouh Salman A. Alshehri ◽  
Kelly L.R. Miller ◽  
Catherine M. Sherwin ◽  
Jeffrey B. Travers ◽  
...  
Keyword(s):  
Survival Rates ◽  
Suppressor Cells ◽  
Cell Types ◽  
Therapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Cancer Therapies ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Resistance ◽  
Cellular Mechanisms ◽  
Immunosuppressive Cell

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

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