scholarly journals Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ruijuan Du ◽  
Chuntian Huang ◽  
Kangdong Liu ◽  
Xiang Li ◽  
Zigang Dong
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Aurora Kinase ◽  
Interacting Proteins ◽  
Multiple Tumor ◽  
Oncogenic Pathways ◽  
Wide Range ◽  
The Family ◽  
Tumor Types ◽  
Cancer Tissues

AbstractAurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

scholarly journals Current Strategies for Identification of Glioma Stem Cells: Adequate or Unsatisfactory?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Paola Brescia ◽  
Cristina Richichi ◽  
Giuliana Pelicci
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Cell Phenotype ◽  
Multiple Tumor ◽  
Early Results ◽  
Tumorigenic Potential ◽  
Tumor Types

Cancer stem cells (CSCs) were isolated in multiple tumor types, including human glioblastomas, and although the presence of surface markers selectively expressed on CSCs can be used to isolate them, no marker/pattern of markers are sufficiently robust to definitively identify stem cells in tumors. Several markers were evaluated for their prognostic value with promising early results, however none of them was proven to be clinically useful in large-scale studies, leading to outstanding efforts to identify new markers. Given the heterogeneity of human glioblastomas further investigations are necessary to identify both cancer stem cell-specific markers and the molecular mechanisms sustaining the tumorigenic potential of these cells to develop tailored treatments. Markers for glioblastoma stem cells such as CD133, CD15, integrin-α6, L1CAM might be informative to identify these cells but cannot be conclusively linked to a stem cell phenotype. Overlap of expression, functional state and morphology of different subpopulations lead to carefully consider the techniques employed so far to isolate these cells. Due to a dearth of methods and markers reliably identifying the candidate cancer stem cells, the isolation/enrichment of cancer stem cells to be therapeutically targeted remains a major challenge.

scholarly journals Oncogenic Roles of GOLPH3 in the Physiopathology of Cancer

2020 ◽  
Vol 21 (3) ◽  
pp. 933 ◽  
Author(s):  
Stefano Sechi ◽  
Anna Frappaolo ◽  
Angela Karimpour-Ghahnavieh ◽  
Roberto Piergentili ◽  
Maria Grazia Giansanti
Keyword(s):  
Membrane Trafficking ◽  
Current Knowledge ◽  
Human Cancer ◽  
Breast Cancers ◽  
Integrative Genomics ◽  
Multiple Tumor ◽  
Cancer Breast ◽  
Oncogenic Pathways ◽  
Phosphatidylinositol 4 ◽  
Tumor Types

Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently amplified in several solid tumor types including melanoma, lung cancer, breast cancer, glioma, and colorectal cancer. Overexpression of GOLPH3 correlates with poor prognosis in multiple tumor types including 52% of breast cancers and 41% to 53% of glioblastoma. Roles of GOLPH3 in tumorigenesis may correlate with several cellular activities including: (i) regulating Golgi-to-plasma membrane trafficking and contributing to malignant secretory phenotypes; (ii) controlling the internalization and recycling of key signaling molecules or increasing the glycosylation of cancer relevant glycoproteins; and (iii) influencing the DNA damage response and maintenance of genomic stability. Here we summarize current knowledge on the oncogenic pathways involving GOLPH3 in human cancer, GOLPH3 influence on tumor metabolism and surrounding stroma, and its possible role in tumor metastasis formation.

scholarly journals Targeting microRNAs with thymoquinone: a new approach for cancer therapy

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Mina Homayoonfal ◽  
Zatollah Asemi ◽  
Bahman Yousefi
Keyword(s):  
Gene Expression ◽  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
World Health ◽  
Therapeutic Effects ◽  
Black Cumin ◽  
Small Noncoding Rnas ◽  
Wide Range ◽  
Anti Cancer ◽  
Cancer Agent

AbstractCancer is a global disease involving transformation of normal cells into tumor types via numerous mechanisms, with mortality among all generations, in spite of the breakthroughs in chemotherapy, radiotherapy and/or surgery for cancer treatment. Since one in six deaths is due to cancer, it is one of the overriding priorities of world health. Recently, bioactive natural compounds have been widely recognized due to their therapeutic effects for treatment of various chronic disorders, notably cancer. Thymoquinone (TQ), the most valuable constituent of black cumin seeds, has shown anti-cancer characteristics in a wide range of animal models. The revolutionary findings have revealed TQ’s ability to regulate microRNA (miRNA) expression, offering a promising approach for cancer therapy. MiRNAs are small noncoding RNAs that modulate gene expression by means of variation in features of mRNA. MiRNAs manage several biological processes including gene expression and cellular signaling pathways. Accordingly, miRNAs can be considered as hallmarks for cancer diagnosis, prognosis and therapy. The purpose of this study was to review the various molecular mechanisms by which TQ exerts its potential as an anti-cancer agent through modulating miRNAs.

scholarly journals 2 Quantitation of CD137 and Nectin-4 expression across multiple tumor types to support indication selection for BT7480, a Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A2-A2
Author(s):  
Heather Cohen ◽  
Carly Campbell ◽  
Kristen Hurov ◽  
Johanna Lahdenranta ◽  
Tara Gelb ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Unmet Need ◽  
Human Tumor ◽  
Immunofluorescence Assay ◽  
Breast Cancers ◽  
Multiple Tumor ◽  
Wide Range ◽  
Tumor Types

BackgroundBicycles are fully synthetic constrained peptides with antibody-like affinities that target selectively, readily penetrate tumor tissue, have relatively short half-lives, and can be chemically linked together to generate multifunctional molecules. BT7480 is a Bicycle TICA™ that binds both CD137 on immune cells and Nectin-4 on cancer cells to deliver a potent anti-tumor immune signal in Nectin-4 expressing tumors. Nectin-4 has been reported to be highly expressed in a wide range of human solid tumors, however the expression of CD137, abundance and localization of CD137+ immune cells in Nectin-4+ tumors are unknowns. A translational and informatics pipeline was established to interrogate the human tumor microenvironment to identify patient populations most likely to benefit from BT7480, which is being developed as a potential first-in-class molecule for the treatment of high unmet need cancers associated with Nectin-4 expression.MethodsTCGA RNAseq data for Nectin-4 and CD137 were analyzed from ~10,000 samples across 36 human cancers. Using a proprietary Nectin-4 mAb and MultiOmyx™ technology, a 19-plexed immunofluorescence assay was developed to simultaneously quantify the presence of Nectin-4+ and CD137+ cells, identify immune cell subsets and their spatial topography in 43 human tumor FFPE samples from HNSCC, lung, bladder, and breast cancers. Each FFPE slide was presented to a pathologist for tissue annotation and selection of regions of interest for image analysis. Proprietary deep learning-based workflows were applied to identify stroma and tumor regions, individual cells and perform cell classification for phenotypes of interest.ResultsRNA expression analysis indicated co-expression of Nectin-4 and CD137 in several tumor types with >50% tumors within NSCLC, HNSCC, breast, esophageal, and ovarian cancers expressing high levels of both targets. Spatial proteomic studies in HNSCC, lung, breast and bladder cancer samples demonstrated that Nectin-4 and CD137 co-expression at the protein level (>1% positive cells) was detected in 74% samples tested. CD137+ cells in Nectin-4+ tumors were identified as CD4+ T cells (37.6%), CD8+ T cells (16.8%) and CD68+ macrophages (5.9%). A subset of CD137+ cells (32.7%) were found to be deeply tumor penetrant and within close proximity of Nectin-4+ tumor cells across all indications tested.ConclusionsResults from this study support prioritization of indications for BT7480 clinical development and the utility of the MultiOmyx™ assay to monitor Nectin-4 and CD137 expression and to demonstrate proof-of-mechanism for the BT7480 FIH clinical trial expected to start in 2H-2021.

TMOD-30. NTRK2 SPLICE VARIANT, TRKB.T1, LINKS NEUROBIOLOGY, EMBRYONIC DEVELOPMENT, AND ONCOGENESIS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi222-vi222
Author(s):  
Siobhan Pattwell ◽  
Sonali Arora ◽  
Nicholas Nuechterlein ◽  
Michael Zager ◽  
Keith Loeb ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splice Variant ◽  
Transcript Level ◽  
Neurotrophin Receptor ◽  
Unique Role ◽  
Multiple Tumor ◽  
Oncology Research ◽  
Level Data ◽  
Wide Range ◽  
Tumor Types

Abstract Temporally regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and is highly expressed in a wide range of adult and pediatric tumors. Further, forced expression of TrkB.T1 causes multiple solid and non-solid tumors in mice in the context of tumor suppressor loss. These results highlight a unique role for the neurotrophin receptor splicing in development and oncogenesis and underscore the need for considering alternative splicing and transcript level data in neuroscience, developmental biology, and oncology research.

Cytotoxic T-lymphocyte-associated Protein 4 and Cancer Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-7-SCI-7
Author(s):  
James Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Therapy ◽  
Mouse Models ◽  
Late Stage ◽  
Cd4 T Cells ◽  
Controlled Trial ◽  
Immune Checkpoints ◽  
Multiple Tumor ◽  
Tumor Types

Abstract The existence of multiple non-redundant l inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits CD28 mediated costimulation. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (>4.5 years) survival benefit in about 23% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease. A recent retrospective study of almost 5,000 patients showed an inflection point at about 2.5 years with essentially no deaths of about 20% of patients for 10 years following treatment. The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. We have recently uncovered a mechanism whereby anti-CTLA-4 antibodies expand Treg in lymph nodes but cause their depletion in the tumor microenvironment. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms. We have also shown that CTLA-4 blockade results in a 2-5 fold increase in the frequency of CD4 T cells expression ICOS (inducible costimulator) in both tumor tissues and blood. This population contains that vast majority of tumor antigen specific cells that produce IFNg and TNFa. The appearance of the ICOS+ CD4 cells serves as a pharmacodynamic marker of a biological effect of anti-CTLA-4 activity. Using mouse models, we have shown that the ICOS/ICOSL pathway is critical for optimal anti-tumor activity of anti-CTLA-4. Furthermore, we have shown that agonist stimulation of ICOS coupled with CTLA-4 blockade results in enhanced anti-tumor efficacy in mouse models, suggest that ICOS is a compelling molecule to develop as a target for agonistic targeting of costimulatory checkpoints. PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25% . A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients. Our studies indicate that the mechanisms of anti-PD-1 mediated tumor immunity are distinct from those of anti-CTLA-4, at least as for the role of ICOS+ CD4 T cells. These studies and their implications for cancer therapy will be discussed. Disclosures Allison: Jounce Therapeutics: Consultancy, Equity Ownership, Patents & Royalties: Licensed patent.; Bristol Meyers-Squibb: Patents & Royalties: Licensed patent owned by the University of California. Previously received royalties.

Oncogenic pathways as the basis of primary immune ignorance

2017 ◽  
Vol 1 (5) ◽  
pp. 421-428
Author(s):  
Maulik Patel
Keyword(s):  
Molecular Mechanisms ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Single Agent ◽  
Small Cell ◽  
Small Cell Lung ◽  
Oncogenic Pathways ◽  
Clinical Responses ◽  
Prostate Cancers ◽  
Tumor Types

The success of immune checkpoint inhibitor therapies (ICTs) to bring about durable clinical responses in a subset of patients with different cancer histologies is transforming cancer care. However, many patients do not benefit from single-agent ICT, including patients with melanoma and non-small cell lung cancer, which are often considered to be immunogenic tumor types. In addition, several other common solid tumors, such as breast, colon, and prostate cancers, have reported very low response rates. A growing body of evidence suggests that the majority of tumors may be categorized as being primary immune-ignorant tumors, hence precluding response to single-agent ICTs. The molecular mechanisms that govern the immune-ignorant phenotype are under intense investigation. This review focuses on how oncogenic pathways can promote the development of a primary immune-ignorant tumor.

scholarly journals Oncogenic role of a developmentally regulated NTRK2 splice variant

2022 ◽  
Author(s):  
Siobhan S Pattwell ◽  
Sonali Arora ◽  
Nicholas Nuechterlein ◽  
Michael Zager ◽  
Keith R Loeb ◽  
...  
Keyword(s):  
Splice Variant ◽  
Affinity Purification ◽  
Neurotrophin Receptor ◽  
Oncogenic Signaling ◽  
Developmentally Regulated ◽  
Multiple Tumor ◽  
Wide Range ◽  
Tumor Types ◽  
Affinity Purification Mass Spectrometry ◽  
Oncogenic Signaling Pathways

Temporally-regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and forced over-expression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring TRK fusions. Affinity purification-mass spectrometry (AP-MS) proteomic analysis reveals TrkB.T1 has distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, TGF-β, Hedgehog, and Ras. From alterations in splicing factors to changes in gene expression, the discovery of isoform specific oncogenes with embryonic ancestry has the potential to shape the way we think about developmental systems and oncology.

Quantitative and Qualitative Methods of Studying the Processes of Socialization of a Modern Teenager

2020 ◽  
pp. 102-109
Author(s):  
Svetlana Alekseevna Raschetina ◽  
Keyword(s):  
Research Methods ◽  
Interpersonal Relations ◽  
Internet Communication ◽  
Socialization Process ◽  
Wide Range ◽  
The Family ◽  
Modern Family ◽  
Making Friends ◽  
Main Support

Relevance and problem statement. Modern unstable society is characterized by narrowing the boundaries of controlled socialization and expanding the boundaries of spontaneous socialization of a teenager based on his immersion in the question arises about the importance of the family in the process of socialization of a teenager in the conditions of expanding the space of socialization. There is a need to study the role of the family in this process, to search, develop and test research methods that allow us to reveal the phenomenon of socialization from the side of its value characteristics. The purpose and methodology of the study: to identify the possibilities of a systematic and anthropological methodology for studying the role of the family in the process of socialization of adolescents in modern conditions, testing research methods: photo research on the topic “Ego – I” (author of the German sociologist H. Abels), profile update reflexive processes (by S. A. Raschetina). Materials and results of the study. The study showed that for all the problems that exist in the family of the perestroika era and in the modern family, it acts for a teenager as a value and the first (main) support in the processes of socialization. The positions well known in psychology about the importance of interpersonal relations in adolescence for the formation of attitudes towards oneself as the basis of socialization are confirmed. Today, the frontiers of making friends have expanded enormously on the basis of Internet communication. The types of activities of interest to a teenager (traditional and new ones related to digitalization) are the third pillar of socialization. Conclusion. The “Ego – I” method of photo research has a wide range of possibilities for quantitative and qualitative analysis of the socialization process to identify the value Pillars of this process.

THE VALUE OF LOVE IN THE SYSTEM OF FORMATION OF THE PROFESSIONAL MATURITY OF THE EDUCATOR

2020 ◽  
Vol 1 (10(79)) ◽  
pp. 12-18
Author(s):  
G. Bubyreva
Keyword(s):  
Russian Federation ◽  
The State ◽  
Educational Process ◽  
Wide Range ◽  
The Family ◽  
The Russian Federation ◽  
The Government ◽  
The Individual ◽  
The Right

The existing legislation determines the education as "an integral and focused process of teaching and upbringing, which represents a socially important value and shall be implemented so as to meet the interests of the individual, the family, the society and the state". However, even in this part, the meaning of the notion ‘socially significant benefit is not specified and allows for a wide range of interpretation [2]. Yet the more inconcrete is the answer to the question – "who and how should determine the interests of the individual, the family and even the state?" The national doctrine of education in the Russian Federation, which determined the goals of teaching and upbringing, the ways to attain them by means of the state policy regulating the field of education, the target achievements of the development of the educational system for the period up to 2025, approved by the Decree of the Government of the Russian Federation of October 4, 2000 #751, was abrogated by the Decree of the Government of the Russian Federation of March 29, 2014 #245 [7]. The new doctrine has not been developed so far. The RAE Academician A.B. Khutorsky believes that the absence of the national doctrine of education presents a threat to national security and a violation of the right of citizens to quality education. Accordingly, the teacher has to solve the problem of achieving the harmony of interests of the individual, the family, the society and the government on their own, which, however, judging by the officially published results, is the task that exceeds the abilities of the participants of the educational process.  The particular concern about the results of the patriotic upbringing served as a basis for the legislative initiative of the RF President V. V. Putin, who introduced the project of an amendment to the Law of RF "About Education of the Russian Federation" to the State Duma in 2020, regarding the quality of patriotic upbringing [3]. Patriotism, considered by the President of RF V. V. Putin as the only possible idea to unite the nation is "THE FEELING OF LOVE OF THE MOTHERLAND" and the readiness for every sacrifice and heroic deed for the sake of the interests of your Motherland. However, the practicing educators experience shortfalls in efficient methodologies of patriotic upbringing, which should let them bring up citizens, loving their Motherland more than themselves. The article is dedicated to solution to this problem based on the Value-sense paradigm of upbringing educational dynasty of the Kurbatovs [15].

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