scholarly journals Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2983
Author(s):  
Ruth M. Urbantat ◽  
Peter Vajkoczy ◽  
Susan Brandenburg
Keyword(s):  
Targeted Therapies ◽  
Clinical Studies ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
The Novel ◽  
Therapeutic Approaches ◽  
Antiangiogenic Treatment ◽  
Chemokine Signaling ◽  
Preclinical And Clinical Studies

With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment.

scholarly journals Understanding the Evolutionary Games in NSCLC Microenvironment

2020 ◽  
Author(s):  
Ranjini Bhattacharya ◽  
Robert Vander Velde ◽  
Viktoriya Marusyk ◽  
Bina Desai ◽  
Artem Kaznatcheev ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Targeted Therapies ◽  
Evolutionary Dynamics ◽  
Fusion Gene ◽  
Evolutionary Game ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Intrinsic Resistance ◽  
Frequency Changes

AbstractWhile initially highly successful, targeted therapies eventually fail as populations of tumor cells evolve mechanisms of resistance, leading to resumption of tumor growth. Historically, cell-intrinsic mutational changes have been the major focus of experimental and clinical studies to decipher origins of therapy resistance. While the importance of these mutational changes is undeniable, a growing body of evidence suggests that non-cell autonomous interactions between sub-populations of tumor cells, as well as with non-tumor cells within tumor microenvironment, might have a profound impact on both short term sensitivity of cancer cells to therapies, as well as on the evolutionary dynamics of emergent resistance. In contrast to well established tools to interrogate the functional impact of cell-intrinsic mutational changes, methodologies to understand non-cell autonomous interactions are largely lacking.Evolutionary Game Theory (EGT) is one of the main frameworks to understand the dynamics that drive frequency changes in interacting competing populations with different phenotypic strategies. However, despite a few notable exceptions, the use of EGT to understand evolutionary dynamics in the context of evolving tumors has been largely confined to theoretical studies. In order to apply EGT towards advancing our understanding of evolving tumor populations, we decided to focus on the context of the emergence of resistance to targeted therapies, directed against EML4-ALK fusion gene in lung cancers, as clinical responses to ALK inhibitors represent a poster child of limitations, posed by evolving resistance. To this end, we have examined competitive dynamics between differentially labelled therapy-naïve tumor cells, cells with cell-intrinsic resistance mechanisms, and cells with cell-extrinsic resistance, mediated by paracrine action of hepatocyte growth factor (HGF), within in vitro game assays in the presence or absence of front-line ALK inhibitor alectinib. We found that producers of HGF were the fittest in every pairwise game, while also supporting the proliferation of therapy-naïve cells. Both selective advantage of these producer cells and their impact on total population growth was a linearly increasing function of the initial frequency of producers until eventually reaching a plateau. Resistant cells did not significantly interact with the other two phenotypes. These results provide insights on reconciling selection driven emergence of subpopulations with cell non-cell autonomous resistance mechanisms, with lack of evidence of clonal dominance of these subpopulations. Further, our studies elucidate mechanisms for co-existence of multiple resistance strategies within evolving tumors. This manuscript serves as a technical report and will be followed up with a research paper in a different journal.

scholarly journals Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers

2021 ◽  
Author(s):  
Antonella Montinaro ◽  
Itziar Areso Zubiaur ◽  
Julia Saggau ◽  
Anna-Laura Kretz ◽  
Rute M. M. Ferreira ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Cancer Cells ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Treatment Modalities ◽  
Cancer Resistance ◽  
Therapeutic Approaches ◽  
Highly Effective ◽  
Drastic Increase ◽  
New Treatment

AbstractPrimary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from a broad range of cancers, importantly without inducing detectable adverse events. Remarkably, the combination of TRAIL with CDK9 inhibition was also highly effective on cancers resistant to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Dynamic BH3 profiling revealed that, mechanistically, combining TRAIL with CDK9 inhibition induced a drastic increase in the mitochondrial priming of cancer cells. Intriguingly, this increase occurred irrespective of whether the cancer cells were sensitive or resistant to chemo- or targeted therapy. We conclude that this pro-apoptotic combination therapy has the potential to serve as a highly effective new treatment option for a variety of different cancers. Notably, this includes cancers that are resistant to currently available treatment modalities.

scholarly journals The role of interleukin-18 in the development and progression of atherosclerosis

2020 ◽  
Vol 27 ◽  
Author(s):  
Afsane Bahrami ◽  
Thozhukat Sathyapalan ◽  
Amirhossein Sahebkar
Keyword(s):  
Plaque Rupture ◽  
Inflammatory Disorder ◽  
The Novel ◽  
Interleukin 18 ◽  
Therapeutic Approaches ◽  
Innate And Adaptive Immunity ◽  
Plaque Instability ◽  
Chronic Inflammatory Disorder ◽  
Preclinical And Clinical Studies

: Atherosclerosis (AS) as a chronic inflammatory disorder of the cardiovascular system, is one of the leading cause of ischemic heart disease, stroke and peripheral vascular disease. There is growing evidence on the role of innate and adaptive immunity in the pathogenesis of atherosclerosis. Interleukin-18 is one of the novel proinflammatory cytokines involved in the atherogenesis, atherosclerotic plaque instability and plaque rupture. In this review, we overview the findings of the preclinical and clinical studies about the role and mechanism of action of IL-18 in the pathogenesis of AS, which could offer novel prognostic and therapeutic approaches.

scholarly journals Bridging Tumorigenesis and Therapy Resistance With a Non-Darwinian and Non-Lamarckian Mechanism of Adaptive Evolution

2021 ◽  
Vol 11 ◽  
Author(s):  
Francesco Catania ◽  
Beata Ujvari ◽  
Benjamin Roche ◽  
Jean-Pascal Capp ◽  
Frédéric Thomas
Keyword(s):  
Purifying Selection ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Evolution ◽  
Therapeutic Approaches ◽  
Genetic Changes ◽  
Modern Times ◽  
Simple Rules ◽  
Rules Of Thumb ◽  
And Shifts

Although neo-Darwinian (and less often Lamarckian) dynamics are regularly invoked to interpret cancer’s multifarious molecular profiles, they shine little light on how tumorigenesis unfolds and often fail to fully capture the frequency and breadth of resistance mechanisms. This uncertainty frames one of the most problematic gaps between science and practice in modern times. Here, we offer a theory of adaptive cancer evolution, which builds on a molecular mechanism that lies outside neo-Darwinian and Lamarckian schemes. This mechanism coherently integrates non-genetic and genetic changes, ecological and evolutionary time scales, and shifts the spotlight away from positive selection towards purifying selection, genetic drift, and the creative-disruptive power of environmental change. The surprisingly simple use-it or lose-it rationale of the proposed theory can help predict molecular dynamics during tumorigenesis. It also provides simple rules of thumb that should help improve therapeutic approaches in cancer.

scholarly journals Antibody Conjugates for Sarcoma Therapy: How Far along Are We?

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 978
Author(s):  
Letizia Polito ◽  
Giulia Calafato ◽  
Massimo Bortolotti ◽  
Cecilia Chiarelli Olivari ◽  
Stefania Maiello ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Surface Antigens ◽  
Therapeutic Agents ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Antibody Conjugates ◽  
Hematological Tumors ◽  
Preclinical And Clinical Studies ◽  
Patients Experience ◽  
Sarcoma Treatment

Sarcomas are one of the most difficult type of cancer to manage and treat because of their extremely heterogeneous molecular and morphological features. Despite the progress made over the years in the establishment of standard protocols for high and low grading/staging sarcoma patients, mostly with chemotherapy and/or radiotherapy, 50% of treated patients experience relapse episodes. Because of this, in the last 20 years, new therapeutic approaches for sarcoma treatment have been evaluated in preclinical and clinical studies. Among them, antibody-based therapies have been the most studied. Immunoconjugates consist of a carrier portion, frequently represented by an antibody, linked to a toxic moiety, i.e., a drug, toxin, or radionuclide. While the efficacy of immunoconjugates is well demonstrated in the therapy of hematological tumors and more recently also of epithelial ones, their potential as therapeutic agents against sarcomas is still not completely explored. In this paper, we summarize the results obtained with immunoconjugates targeting sarcoma surface antigens, considering both preclinical and clinical studies. To date, the encouraging results obtained in preclinical studies allowed nine immunoconjugates to enter clinical trials, demonstrating the validity of immunotherapy as a promising pharmacological tool also for sarcoma therapy.

scholarly journals NF-κB Dependent Chemokine Signaling in Pancreatic Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1445 ◽  
Author(s):  
Geismann ◽  
Schäfer ◽  
Gundlach ◽  
Hauser ◽  
Egberts ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Target Genes ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Resistance ◽  
Intrinsic Resistance ◽  
Chemokine Signaling

Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes. These genes are involved in nearly all scenarios described as the hallmarks of cancer. In addition to classical regulators of apoptosis, NF-κB regulates the expression of chemokines and their receptors, both in the tumor cells and in cells of the microenvironment. These chemokines mediate autocrine and paracrine loops among tumor cells but also cross-signaling between tumor cells and the stroma. In this review, we will focus on NF-κB-mediated chemokine signaling, with an emphasis on therapy resistance in pancreatic cancer.

scholarly journals Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

2016 ◽  
Vol 23 (12) ◽  
pp. T179-T197 ◽  
Author(s):  
Isabel Coutinho ◽  
Tanya K Day ◽  
Wayne D Tilley ◽  
Luke A Selth
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
The Novel ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Signaling Axis ◽  
Novel Therapeutic Strategies

The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in theARgene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

scholarly journals PTEN Tumor-Suppressor: The Dam of Stemness in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1076 ◽  
Author(s):  
Francesca Luongo ◽  
Francesca Colonna ◽  
Federica Calapà ◽  
Sara Vitale ◽  
Micol E. Fiori ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Epithelial To Mesenchymal Transition ◽  
Critical Role ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Pten Gene ◽  
Therapeutic Approaches ◽  
Mesenchymal Transition ◽  
Increased Risk

PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.

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