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Recent Patents on Anti-cancer Drug... 2021Epidermal growth factor receptor and anaplastic lymphoma kinase play key roles in tumorigenesis and disease progression. Currently, targeted therapy is a better approach... (Review)
Review
BACKGROUND
Epidermal growth factor receptor and anaplastic lymphoma kinase play key roles in tumorigenesis and disease progression. Currently, targeted therapy is a better approach for cancer therapy compared with traditional chemotherapy. EGFR-based/ALK-based target therapies are key targets for drug development in cancer therapy.
OBJECTIVE
The objective of this study was to show a recent trend in research and development of EGFR-based/ALK-based targets and to better understand the Intellectual Property surrounding EGFR-based and ALK-based targets.
METHODS
EGFR-based and ALK-based targets were analyzed by comprehensive US patent analysis. US patents of EGFR-based/ALK-based targets were analyzed from September 2001 to September 2020.
RESULTS
The results indicated that the key technologies and methods of EGFR-based/ALK-based targets were developed by large global pharmaceutical companies or American companies/universities. Small molecular inhibitors showed a higher percentage in the number of patents of EGFRbased targets. In addition, the present study also showed recent small molecular targeted drugs approved by FDA.
CONCLUSION
Global large pharmaceutical companies and American companies/universities have obvious advantages in the research and development of targeted drugs. EGFR-based target was still an attractive target for research and drug development in the past 10 years. Also, large global pharmaceutical companies prefer to complete key technology research and development by independent innovation instead of collaboration.
Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Genes, erbB-1; Humans; Molecular Targeted Therapy; Patents as Topic; Protein Kinase Inhibitors; United States
PubMed: 33847258
DOI: 10.2174/1574892816666210413151906 -
Parasites & Vectors May 2021The proliferative stage (tachyzoite) of Toxoplasma gondii (T. gondii) is critical for its transmission and pathogenesis, and a proto-oncogene eukaryotic translation...
BACKGROUND
The proliferative stage (tachyzoite) of Toxoplasma gondii (T. gondii) is critical for its transmission and pathogenesis, and a proto-oncogene eukaryotic translation initiation factor (eIF-5A) plays an important role in various cellular processes such as cell multiplication.
METHODS
We performed a proteomic study to evaluate the specific roles of eIF-5A involved in invasion and replication of T. gondii, and both in vivo and in vitro trials using eIF-5A-interfered and wild tachyzoites were performed to verify the proteomic results.
RESULTS
The results of our study showed that T. gondii eIF-5A affected tachyzoite growth and also participated in the synthesis of proteins through regulation of both ribosomal and splicing pathways. Inhibition of eIF-5A in T. gondii resulted in the downregulated expression of soluble adhesions, such as microneme protein 1 (MIC1) and MIC4, which in turn decreased the parasite population that adhered to the surface of host cells. The reduced attachment, combined with lower expression of some rhoptry proteins (ROPs) and dense granule antigens (GRAs) involved in different stages of T. gondii invasion such as ROP4 and GRA3, ultimately reduce the invasion efficiency. These processes regulated by eIF-5A eventually affect the replication of tachyzoites.
CONCLUSIONS
Our findings showed that eIF-5A influenced tachyzoite survival and was also involved in the process of parasite invasion and replication. These results will provide new clues for further development of targeted drugs to control T. gondii infection.
Topics: Animals; CRISPR-Cas Systems; DNA Replication; Female; Gene Deletion; Mice, Inbred BALB C; Peptide Initiation Factors; Protein Interaction Maps; Proteomics; Proto-Oncogenes; Protozoan Proteins; RNA-Binding Proteins; Rats; Rats, Sprague-Dawley; Toxoplasma; Toxoplasmosis; Virulence; Eukaryotic Translation Initiation Factor 5A; Mice
PubMed: 34039408
DOI: 10.1186/s13071-021-04791-6 -
Nature Cell Biology Jan 2023Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to...
Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRAS-driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS paralogue imbalance in oncogenic KRAS-driven lung cancer.
Topics: Mice; Animals; Humans; Proto-Oncogene Proteins p21(ras); Cell Transformation, Neoplastic; Signal Transduction; Lung Neoplasms; Genes, ras; Mutation; Membrane Proteins; GTP Phosphohydrolases
PubMed: 36635501
DOI: 10.1038/s41556-022-01049-w -
Molecular Oncology Mar 2023Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has a high prevalence of up to 15% and accounts for 90-95% of prostatitis diagnoses, and yet its...
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has a high prevalence of up to 15% and accounts for 90-95% of prostatitis diagnoses, and yet its etiopathogenesis and link to prostate cancer (PCa) are still unclear. Here, we investigated microRNAs in exosomes isolated from blood and post-prostatic-massage urine of CP/CPPS type IIIb patients and healthy men. THP-1 monocytes (human leukemia monocytic cell line) were treated with exosomes and subjected to mRNA arrays "Cancer Inflammation and Immunity Crosstalk" and "Transcription Factors." Using The Cancer Genome Atlas, the expression of CP/CPPS-associated microRNAs was analyzed in PCa and normal prostate tissue. In silico functional studies were carried out to explore the disease ontology of CP/CPPS. In CP/CPPS, urine exosomes exhibited significant upregulation of eight PCa-specific microRNAs (e.g., hsa-miR-501, hsa-miR-20a, and hsa-miR-106), whose target genes were significantly enriched for GO terms, hallmark gene sets, and pathways specific for carcinogenesis. In THP-1 monocytes, CP/CPPS-derived urine exosomes induced upregulation of PCa-associated proinflammatory genes (e.g., CCR2 and TLR2) and proto-oncogene transcription factors (e.g., MYB and JUNB). In contrast, CP/CPPS-derived blood exosomes exhibited molecular properties similar to those of healthy men. Thus, CP/CPPS exhibits molecular changes that constitute a risk for PCa and should be considered in the development of PCa biomarkers and cancer screening programs.
Topics: Male; Humans; Prostatitis; Chronic Disease; Prostate; Exosomes; Pelvic Pain; Prostatic Neoplasms; MicroRNAs; Proto-Oncogenes; Massage
PubMed: 36321189
DOI: 10.1002/1878-0261.13329 -
Acta Neuropathologica Jun 2023Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan...
Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes.
Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.
Topics: Humans; Epilepsy; Ganglioglioma; Mutation; Phenotype; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins p21(ras); Genes, ras; MAP Kinase Signaling System
PubMed: 36973520
DOI: 10.1007/s00401-023-02561-5 -
Biomolecules Sep 2022Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early-onset colorectal cancer (EOCRC), or those occurring in individuals before the age...
Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early-onset colorectal cancer (EOCRC), or those occurring in individuals before the age of 50, has steadily increased over the past several decades. When compared to later onset colorectal cancer (LOCRC) in individuals over 50, our understanding of the genetic and molecular underpinnings of EOCRCs is limited. Here, we conducted transcriptomic analyses of patient-matched normal colonic segments and tumors to identify gene expression programs involved in carcinogenesis. Amongst differentially expressed genes, we found increased expression of the proto-oncogene () and its downstream targets in tumor samples. We identified tumors with high and low differential expression and found patients with high- tumors were older and overweight or obese. We also detected elevated expression of the long-non-coding RNA (lncRNA) in most tumors and found gains in copy number for both and gene loci in 35% of tumors evaluated. Our transcriptome analyses indicate that EOCRC can be sub-classified into groups based on differential expression and suggest that deregulated contributes to CRCs that develop in younger patients.
Topics: Carcinogenesis; Colorectal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; RNA, Long Noncoding
PubMed: 36139061
DOI: 10.3390/biom12091223 -
Methods in Molecular Biology (Clifton,... 2021Detection of post-translational modifications in c-Myc is an invaluable tool in assessing Myc status, particularly in cancer. However, it can be challenging to detect...
Detection of post-translational modifications in c-Myc is an invaluable tool in assessing Myc status, particularly in cancer. However, it can be challenging to detect these modifications. The evaluation of phosphorylation status of c-Myc can also be challenging with the current commercially available phosphorylation sensitive antibodies. Here, we describe protocols for the immunoprecipitation of endogenous c-Myc to probe for phosphorylation status, as well as the detection of ubiquitination and SUMOylation on c-Myc. We will also discuss the challenges of detecting phosphorylated c-Myc in formalin-fixed paraffin-embedded tissues by immunofluorescence and describe a protocol using a new rat monoclonal antibody we have generated suitable for this purpose.
Topics: Fluorescent Antibody Technique; Genes, myc; Humans; Immunoprecipitation; Phosphorylation; Protein Processing, Post-Translational; Proteins; Proto-Oncogene Proteins c-myc; Sumoylation; Ubiquitination
PubMed: 34019287
DOI: 10.1007/978-1-0716-1476-1_5 -
Zhonghua Zhong Liu Za Zhi [Chinese... Feb 2023Lung cancer remains the leading cause of cancer-related deaths in men and women worldwide, and 85% of these patients have non-small cell lung cancer. In recent years,... (Review)
Review
Lung cancer remains the leading cause of cancer-related deaths in men and women worldwide, and 85% of these patients have non-small cell lung cancer. In recent years, the clinical use of targeted drug therapy and immune checkpoint inhibitors has dramatically changed the treatment landscape for advanced NSCLC. The mechanism and the value of targeted therapies have been a hot topic of research, as is one of the earliest discovered and most frequently mutated oncogenes, which is activated by binding to GTP and triggers a series of cascade reactions in cell proliferation and mitosis. The protein acts as a molecular switch and is activated by binding to GTP, triggering a series of cascade responses in cell proliferation and mitosis. Clinically, patients with mutated NSCLC have poor response to systemic medical therapy and poor prognosis. Since the first report of gene in 1982, research on targeted therapeutics has been slow, and previous studies such as farnesyltransferase inhibitors and downstream protein inhibitors of signaling pathway have not achieved the expected results, making long defined as a "non-druggable target". The deeper understanding of the crystal structure of has led to the discovery of potential therapeutic sites for and the development of several drugs directly targeting especially G12C inhibitors such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have shown encouraging results in clinical trials. In recent years, studies on the therapeutic efficacy of immune checkpoint inhibitors for -mutated NSCLC have made some progress. In this review, we systematically introduce the basic understanding of gene and clinical characteristics of mutated NSCLC patients, summarize the medical treatments for mutated NSCLC, including chemotherapy, anti-vascular drug therapy and tumor immunotherapy, and focus on the review and outlook of the research progress of targeted therapy.
Topics: Male; Humans; Female; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Genes, ras; Immune Checkpoint Inhibitors; Guanosine Triphosphate; Mutation
PubMed: 36781231
DOI: 10.3760/cma.j.cn112152-20220310-00167 -
Cell Death and Differentiation Jun 2023Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have...
Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered and their functions characterised, DNA sequence data of primary patient samples suggest that many more do exist. However, the nature of their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo [1]. CRISPR deletion of TFAP4 in Eµ-MYC transgenic haematopoietic stem and progenitor cells (HSPCs) and transplantation of these manipulated HSPCs into lethally irradiated animals significantly accelerated c-MYC-driven lymphoma development. Interestingly, TFAP4 deficient Eµ-MYC lymphomas all arose at the pre-B cell stage of B cell development. This observation prompted us to characterise the transcriptional profile of pre-B cells from pre-leukaemic mice transplanted with Eµ-MYC/Cas9 HSPCs that had been transduced with sgRNAs targeting TFAP4. This analysis revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such as Spi1, SpiB and Pax5, which are direct target genes of both TFAP4 and MYC. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, thereby accelerating c-MYC-driven lymphoma development.
Topics: Mice; Animals; Proto-Oncogene Proteins c-myc; Genes, myc; Lymphoma; Precursor Cells, B-Lymphoid; Mice, Transgenic
PubMed: 36894688
DOI: 10.1038/s41418-023-01145-w -
Methods in Molecular Biology (Clifton,... 2021Although many oncoproteins promote cell growth and proliferation, some also possess the potential to induce cell cycle arrest or cell death by apoptosis. Elevated and...
Although many oncoproteins promote cell growth and proliferation, some also possess the potential to induce cell cycle arrest or cell death by apoptosis. Elevated and deregulated expression of the Myc protein promotes apoptosis in both cultured cells and in some tissues in vivo. Here we describe techniques to detect Myc-induced apoptosis in vitro using flow cytometry, microscopy, and immunoblotting, and in vivo using immunohistochemical staining, immunoblotting, and analysis of RNA expression.
Topics: Animals; Annexin A5; Apoptosis; Cell Cycle; Cell Cycle Checkpoints; Cell Death; Cell Proliferation; DNA; Flow Cytometry; Genes, myc; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Proto-Oncogene Proteins c-myc
PubMed: 34019292
DOI: 10.1007/978-1-0716-1476-1_10