scholarly journals The CIC-DUX4 fusion oncoprotein drives metastasis and tumor growth via distinct downstream regulatory programs and therapeutic targets in sarcoma

2018 ◽  
Author(s):  
Ross A. Okimoto ◽  
Wei Wu ◽  
Shigeki Nanjo ◽  
Victor Olivas ◽  
Yone K. Lin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Clinical Outcomes ◽  
Tumor Metastasis ◽  
Therapeutic Strategy ◽  
Therapeutic Targets ◽  
Treatment Strategies ◽  
Molecular Targets ◽  
Functional Diversification ◽  
Therapeutic Implications ◽  
Cdk2 Complex

AbstractTranscription factor fusion genes create oncoproteins that drive oncogenesis, and represent challenging therapeutic targets. Understanding the molecular targets by which such fusion oncoproteins promote malignancy offers an approach to develop rational treatment strategies to improve clinical outcomes. CIC-DUX4 is a transcription factor fusion that defines certain undifferentiated round cell sarcomas with high metastatic propensity and poor clinical outcomes. The molecular targets regulated by the CIC-DUX4 oncoprotein that promote this aggressive malignancy remain largely unknown. We show that increased expression of ETV4 and CCNE1 occurs via neo-morphic, direct effects of CIC-DUX4 and drives tumor metastasis and survival, respectively. We demonstrate a molecular dependence on the CCNE-CDK2 cell cycle complex that renders CIC-DUX4 tumors sensitive to inhibition of the CCNE-CDK2 complex, highlighting a therapeutic strategy for CIC-DUX4 tumors. Our findings highlight a paradigm of functional diversification of transcriptional repertoires controlled by a genetically-aberrant transcriptional regulator, with therapeutic implications.

scholarly journals Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

Oncogene ◽  
2020 ◽  
Vol 39 (39) ◽  
pp. 6139-6156 ◽  
Author(s):  
Qinyao Wei ◽  
Yun Qian ◽  
Jun Yu ◽  
Chi Chun Wong
Keyword(s):  
Cancer Cells ◽  
Tumor Metastasis ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Targets ◽  
Mesenchymal Transition ◽  
Therapeutic Implications ◽  
Metastatic Cascade ◽  
Metastatic Colonization

Abstract Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.

The Impact of Translational Research in Breast Cancer Care: Can we Improve the Therapeutic Scenario?

2018 ◽  
Vol 18 (6) ◽  
pp. 832-836
Author(s):  
Giuseppe Buono ◽  
Francesco Schettini ◽  
Francesco Perri ◽  
Grazia Arpino ◽  
Roberto Bianco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Translational Research ◽  
Cell Biology ◽  
Cancer Biology ◽  
Hormone Receptors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Molecular Heterogeneity ◽  
Therapeutic Implications ◽  
The Impact

Traditionally, breast cancer (BC) is divided into different subtypes defined by immunohistochemistry (IHC) according to the expression of hormone receptors and overexpression/amplification of human epidermal growth factor receptor 2 (HER2), with crucial therapeutic implications. In the last few years, the definition of different BC molecular subgroups within the IHC-defined subtypes and the identification of the important role that molecular heterogeneity can play in tumor progression and treatment resistance have inspired the search for personalized therapeutic approaches. In this scenario, translational research represents a key strategy to apply knowledge from cancer biology to the clinical setting, through the study of all the tumors “omics”, including genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Importantly, the introduction of new high-throughput technologies, such as next generation sequencing (NGS) for the study of cancer genome and transcriptome, greatly amplifies the potential and the applications of translational research in the oncology field. Moreover, the introduction of new experimental approaches, such as liquid biopsy, as well as new-concept clinical trials, such as biomarker-driven adaptive studies, may represent a turning point for BC translational research. </P><P> It is likely that translational research will have in the near future a significant impact on BC care, especially by giving us the possibility to dissect the complexity of tumor cell biology and develop new personalized treatment strategies.

scholarly journals Androgen and glucocorticoid receptor direct distinct transcriptional programs by receptor-specific and shared DNA binding sites

2021 ◽  
Vol 49 (7) ◽  
pp. 3856-3875
Author(s):  
Marina Kulik ◽  
Melissa Bothe ◽  
Gözde Kibar ◽  
Alisa Fuchs ◽  
Stefanie Schöne ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Transcription Factor ◽  
Dna Binding ◽  
Receptor Binding ◽  
Binding Sites ◽  
Specific Gene ◽  
Functional Diversification ◽  
Enhancer Activity ◽  
Sequence Composition

Abstract The glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied them in an equivalent cellular context. Analysis of chromatin and sequence suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the result of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (&gt;10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.

scholarly journals Tetrandrine alleviates silicosis by inhibiting canonical and non-canonical NLRP3 inflammasome activation in lung macrophages

2021 ◽  
Author(s):  
Mei-yue Song ◽  
Jia-xin Wang ◽  
You-liang Sun ◽  
Zhi-fa Han ◽  
Yi-tian Zhou ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Therapeutic Strategy ◽  
Molecular Targets ◽  
Mechanisms Of Action ◽  
Inflammasome Activation ◽  
Lung Macrophages ◽  
Nlrp3 Inflammasome Activation ◽  
Function Test ◽  
And Control ◽  
Therapeutic Administration

AbstractSilicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.

scholarly journals Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2878
Author(s):  
Claudia Maria Hattinger ◽  
Maria Pia Patrizio ◽  
Leonardo Fantoni ◽  
Chiara Casotti ◽  
Chiara Riganti ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Therapeutic Targets ◽  
Treatment Strategies ◽  
Cure Rate ◽  
Acquired Drug Resistance ◽  
Unselected Patient ◽  
Dismal Prognosis ◽  
Non Coding Rnas ◽  
High Grade Osteosarcoma

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.

Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation

2021 ◽  
pp. 107815522110055
Author(s):  
Clement Chung
Keyword(s):  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Tumor Location ◽  
Prognostic Biomarkers ◽  
Her2 Gene ◽  
Braf Mutations ◽  
Therapeutic Implications ◽  
Molecular Alterations

Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [ NTRK] fusion genes, and human epidermal growth factor receptor type II [ HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.

scholarly journals Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1548
Author(s):  
Mustafa N. Mithaiwala ◽  
Danielle Santana-Coelho ◽  
Grace A. Porter ◽  
Jason C. O’Connor
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Kynurenine Pathway ◽  
Economic Problem ◽  
Cns Disease ◽  
Therapeutic Implications ◽  
Efficacious Treatment ◽  
The Central Nervous System ◽  
Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

scholarly journals Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Vol 10 (9) ◽  
pp. 1926
Author(s):  
Hiroto Inaba ◽  
Ching-Hon Pui
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Detailed Analysis ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Chemotherapeutic Agents ◽  
Response To Treatment ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Therapeutic Implications

The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved remarkably during the last five decades. Such improvements were made possible by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents, and the provision of better supportive care. With the 5-year survival rates now exceeding 90% in high-income countries, the goal for the next decade is to improve survival further toward 100% and to minimize treatment-related adverse effects. Based on genome-wide analyses, especially RNA-sequencing analyses, ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy.

scholarly journals Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 607
Author(s):  
Alice Indini ◽  
Francesco Grossi ◽  
Mario Mandalà ◽  
Daniela Taverna ◽  
Valentina Audrito
Keyword(s):  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Treatment Resistance ◽  
Metastatic Potential ◽  
Biological Behavior ◽  
Therapeutic Implications ◽  
Systemic Treatments

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.

scholarly journals EPEN-30. C11ORF95-RELA FUSION PROTEIN ENGAGES NOVEL GENOMIC LOCI TO DRIVE MURINE EPENDYMOMA GROWTH

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii314-iii314
Author(s):  
Amir Arabzade ◽  
Yanhua Zhao ◽  
Srinidhi Varadharajan ◽  
Hsiao-Chi Chen ◽  
Austin Stuckert ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Molecular Targets ◽  
Lead Target ◽  
Open Chromatin ◽  
Rna Seq ◽  
In Utero Electroporation ◽  
Pathway Activation ◽  
Mouse Cells ◽  
Shed Light

Abstract RATIONALE Over 70% of supratentorial (ST) ependymoma are characterized by an oncogenic fusion between C11ORF95 and RELA. C11ORF95-RELA fusion is frequently the sole genetic driver detected in ST ependymoma, thus ranking this genomic event as a lead target for therapeutic investigation. RELA is a transcription factor (TF) central to mediating NF-kB pathway activation in processes such as inflammation, cellular metabolism, and chemotaxis. HYPOTHESIS: We posited that C11ORF95-RELA acts as an oncogenic TF that aberrantly shapes the tumor epigenome to drive aberrant transcription. Approach: To this end we developed an in utero electroporation (IUE) mouse model of ependymoma to express C11ORF95-RELA during embryonic development. Our IUE approach allowed us to develop C11ORF95-RELA driven tumor models and cell lines. We comprehensively characterized the epigenome and transcriptome of C11ORF95-RELA fusion driven mouse cells by H3K27ac ChIP-seq, ATAC-seq, and RNA-seq. RESULTS This data revealed that: 1) C11ORF95-RELA directly engages ‘open’ chromatin and is enriched at regions with known RELA TF binding sites as well as novel genomic loci/motifs, 2) C11ORF95-RELA preferentially binds to both H3K27ac (active) enhancers and promoters, and 3) Bound C11ORF95-RELA promoter loci are associated with increased transcription of genes shared with human ependymoma. CONCLUSION Our findings shed light on the transcriptional mechanisms of C11ORF95-RELA, and reveal downstream targets that may represent cancer dependency genes and molecular targets.

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