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Cancer Biology & Medicine Nov 2020Cancer-related diseases represent the second overall cause of death worldwide. Human papilloma virus (HPV) is an infectious agent which is mainly sexually transmitted... (Review)
Review
Cancer-related diseases represent the second overall cause of death worldwide. Human papilloma virus (HPV) is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women. Almost all cervical cancers are HPV-associated, however, an increasing number of head and neck cancers (HNCs), especially oropharyngeal cancer, can be linked to HPV infection. Moreover, anogenital cancers, including vaginal, vulvar, penial, and anal cancers, represent a subset of HPV-related cancers. Whereas testing and prevention of cervical cancer have significantly improved over past decades, anogenital cancers remain more difficult to confirm. Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments. The HPV viral oncoproteins, E6 and E7, lead to degradation of, respectively, p53 and pRb resulting in entering the S phase without G1 arrest. These high-risk HPV viral oncogenes alter numerous cellular processes, including DNA repair, angiogenesis, and/or apoptosis, which eventually result in carcinogenesis. Additionally, a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks (DSB) repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers. In this review, we discuss the current knowledge regarding HPV-related cancers, current screening, and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.
Topics: Animals; Cell Transformation, Neoplastic; Cell Transformation, Viral; DNA Breaks, Double-Stranded; DNA Repair; Female; Head and Neck Neoplasms; Humans; Male; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Uterine Cervical Neoplasms
PubMed: 33299640
DOI: 10.20892/j.issn.2095-3941.2020.0370 -
Nature Reviews. Clinical Oncology Jan 2021The proto-oncogene ROS1 encodes a receptor tyrosine kinase with an unknown physiological role in humans. Somatic chromosomal fusions involving ROS1 produce chimeric... (Review)
Review
The proto-oncogene ROS1 encodes a receptor tyrosine kinase with an unknown physiological role in humans. Somatic chromosomal fusions involving ROS1 produce chimeric oncoproteins that drive a diverse range of cancers in adult and paediatric patients. ROS1-directed tyrosine kinase inhibitors (TKIs) are therapeutically active against these cancers, although only early-generation multikinase inhibitors have been granted regulatory approval, specifically for the treatment of ROS1 fusion-positive non-small-cell lung cancers; histology-agnostic approvals have yet to be granted. Intrinsic or extrinsic mechanisms of resistance to ROS1 TKIs can emerge in patients. Potential factors that influence resistance acquisition include the subcellular localization of the particular ROS1 oncoprotein and the TKI properties such as the preferential kinase conformation engaged and the spectrum of targets beyond ROS1. Importantly, the polyclonal nature of resistance remains underexplored. Higher-affinity next-generation ROS1 TKIs developed to have improved intracranial activity and to mitigate ROS1-intrinsic resistance mechanisms have demonstrated clinical efficacy in these regards, thus highlighting the utility of sequential ROS1 TKI therapy. Selective ROS1 inhibitors have yet to be developed, and thus the specific adverse effects of ROS1 inhibition cannot be deconvoluted from the toxicity profiles of the available multikinase inhibitors. Herein, we discuss the non-malignant and malignant biology of ROS1, the diagnostic challenges that ROS1 fusions present and the strategies to target ROS1 fusion proteins in both treatment-naive and acquired-resistance settings.
Topics: Animals; Humans; Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Randomized Controlled Trials as Topic
PubMed: 32760015
DOI: 10.1038/s41571-020-0408-9 -
Tumour Virus Research Jun 2022Cervical cancer is the fourth most common female cancer worldwide and results in over 300 000 deaths globally. The causative agent of cervical cancer is persistent... (Review)
Review
Cervical cancer is the fourth most common female cancer worldwide and results in over 300 000 deaths globally. The causative agent of cervical cancer is persistent infection with high-risk subtypes of the human papillomavirus and the E5, E6 and E7 viral oncoproteins cooperate with host factors to induce and maintain the malignant phenotype. Cervical cancer is a largely preventable disease and early-stage detection is associated with significantly improved survival rates. Indeed, in high-income countries with established vaccination and screening programs it is a rare disease. However, the disease is a killer for women in low- and middle-income countries who, due to limited resources, often present with advanced and untreatable disease. Treatment options include surgical interventions, chemotherapy and/or radiotherapy either alone or in combination. This review describes the initiation and progression of cervical cancer and discusses in depth the advantages and challenges faced by current cervical cancer therapies, followed by a discussion of promising and efficacious new therapies to treat cervical cancer including immunotherapies, targeted therapies, combination therapies, and genetic treatment approaches.
Topics: Female; Humans; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Papillomavirus Infections; Uterine Cervical Neoplasms
PubMed: 35460940
DOI: 10.1016/j.tvr.2022.200238 -
Nature Reviews. Cancer Aug 2017The term 'undruggable' was coined to describe proteins that could not be targeted pharmacologically. However, progress is being made to 'drug' many of these targets, and... (Review)
Review
The term 'undruggable' was coined to describe proteins that could not be targeted pharmacologically. However, progress is being made to 'drug' many of these targets, and therefore more appropriate terms might be 'difficult to drug' or 'yet to be drugged'. Many desirable targets in cancer fall into this category, including the RAS and MYC oncogenes, and pharmacologically targeting these intractable proteins is now a key challenge in cancer research that requires innovation and the development of new technologies. In this Viewpoint article, we asked four scientists working in this field for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research.
Topics: Antineoplastic Agents; Drug Discovery; Humans; Molecular Targeted Therapy; NF-kappa B; Neoplasms; Oncogene Proteins, Fusion; Proto-Oncogene Proteins c-myb; Proto-Oncogene Proteins c-myc; Receptors, Androgen; ras Proteins
PubMed: 28643779
DOI: 10.1038/nrc.2017.36 -
Critical Reviews in Oncology/hematology Jun 2022Cervical cancer (CC), one of the major causes of death of women throughout the world is primarily caused due to Human Papilloma Virus (HPV) 16 and 18. The early region... (Review)
Review
PURPOSE
Cervical cancer (CC), one of the major causes of death of women throughout the world is primarily caused due to Human Papilloma Virus (HPV) 16 and 18. The early region (E) oncoproteins of HPV are associated with the etiopathogenesis and contribute to the progression of cancer. The present article comprehensively discussed the structural organization and biological functions of all E proteins of HPV and their contribution to progression of CC with an intent to decipher the pathological hallmarks and their relationship. Additionally, the role of E proteins in reference to therapeutics will also be presented.
METHODS
A systematic search has been carried out for articles published in PubMed database by using combinations of different keywords with Boolean operators (AND, OR, NOT) including cervical cancer, HPV, E proteins, and signaling.
RESULTS
From the analysis of literature review, its apparent that E proteins are the major contributor to disease progression. E1, E2, and E4 forms are mainly associated with viral integration, replication, and transcription whereas E6 and E7 act as an oncoprotein and are associated with the progression of cancer. E5 regulates cell proliferation, apoptosis, and facilitates the activity of E6 and E7. Additionally, E proteins were observed associated with numerous cell signaling pathways including PI3K/AKT, Wnt, Notch and reasonably contribute to the initiation of malignancy, cell proliferation, metastasis, and drug resistance. Knowing the role and interplay of each protein in initiation to progression of CC, their therapeutic significance has been elucidated. The present study observations demonstrate that E6 and E7 are the major cause of HPV-mediated CC progression. E1, E2, and E5 also act as a backbone for E6 and E7 and most of the current approaches have targeted E6 and E7 mediated action only.
CONCLUSION
The present review illustrates the structural organization as well as function and regulation of all early proteins of HPV and their association with several cellular signaling pathways. The observations provide clue on the regulatory aspect of these proteins in initiation to progression and reasonably represent that targeting these proteins could be a novel therapeutic strategy for CC. In particular, its seemingly appears that inhibition of the activity of E6 and E7 oncoproteins may be a better selective target to delay the progression of CC. The review reaffirms the role of E proteins and encourages future studies on developing diagnostics, and most importantly therapeutics strategies targeting E6 and E7 oncoproteins to tackle CC related morbidity and mortality.
Topics: Female; Human papillomavirus 16; Humans; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Papillomavirus Infections; Phosphatidylinositol 3-Kinases; Uterine Cervical Neoplasms
PubMed: 35381343
DOI: 10.1016/j.critrevonc.2022.103675 -
Nature Reviews. Molecular Cell Biology May 2020Oncoproteins of the MYC family are major drivers of human tumorigenesis. Since a large body of evidence indicates that MYC proteins are transcription factors, studying... (Review)
Review
Oncoproteins of the MYC family are major drivers of human tumorigenesis. Since a large body of evidence indicates that MYC proteins are transcription factors, studying their function has focused on the biology of their target genes. Detailed studies of MYC-dependent changes in RNA levels have provided contrasting models of the oncogenic activity of MYC proteins through either enhancing or repressing the expression of specific target genes, or as global amplifiers of transcription. In this Review, we first summarize the biochemistry of MYC proteins and what is known (or is unclear) about the MYC target genes. We then discuss recent progress in defining the interactomes of MYC and MYCN and how this information affects central concepts of MYC biology, focusing on mechanisms by which MYC proteins modulate transcription. MYC proteins promote transcription termination upon stalling of RNA polymerase II, and we propose that this mechanism enhances the stress resilience of basal transcription. Furthermore, MYC proteins coordinate transcription elongation with DNA replication and cell cycle progression. Finally, we argue that the mechanism by which MYC proteins regulate the transcription machinery is likely to promote tumorigenesis independently of global or relative changes in the expression of their target genes.
Topics: Carcinogenesis; Cell Cycle; Cell Proliferation; DNA Replication; Humans; N-Myc Proto-Oncogene Protein; Neoplasms; Oncogene Proteins; Proto-Oncogene Proteins c-myc; Transcription Factors; Transcription, Genetic
PubMed: 32071436
DOI: 10.1038/s41580-020-0215-2 -
Blood Nov 2020Nucleoporin 98 (NUP98) fusion oncoproteins are observed in a spectrum of hematologic malignancies, particularly pediatric leukemias with poor patient outcomes. Although... (Review)
Review
Nucleoporin 98 (NUP98) fusion oncoproteins are observed in a spectrum of hematologic malignancies, particularly pediatric leukemias with poor patient outcomes. Although wild-type full-length NUP98 is a member of the nuclear pore complex, the chromosomal translocations leading to NUP98 gene fusions involve the intrinsically disordered and N-terminal region of NUP98 with over 30 partner genes. Fusion partners include several genes bearing homeodomains or having known roles in transcriptional or epigenetic regulation. Based on data in both experimental models and patient samples, NUP98 fusion oncoprotein-driven leukemogenesis is mediated by changes in chromatin structure and gene expression. Multiple cofactors associate with NUP98 fusion oncoproteins to mediate transcriptional changes possibly via phase separation, in a manner likely dependent on the fusion partner. NUP98 gene fusions co-occur with a set of additional mutations, including FLT3-internal tandem duplication and other events contributing to increased proliferation. To improve the currently dire outcomes for patients with NUP98-rearranged malignancies, therapeutic strategies have been considered that target transcriptional and epigenetic machinery, cooperating alterations, and signaling or cell-cycle pathways. With the development of more faithful experimental systems and continued study, we anticipate great strides in our understanding of the molecular mechanisms and therapeutic vulnerabilities at play in NUP98-rearranged models. Taken together, these studies should lead to improved clinical outcomes for NUP98-rearranged leukemia.
Topics: Animals; Hematologic Neoplasms; Humans; Nuclear Pore Complex Proteins; Oncogene Proteins, Fusion
PubMed: 32766874
DOI: 10.1182/blood.2020007093 -
Cancer Science Jul 2020The Mdm2 oncoprotein and its association with p53 were discovered 30 years ago, and a cornucopia of activities and regulatory pathways have been associated with it. In... (Review)
Review
The Mdm2 oncoprotein and its association with p53 were discovered 30 years ago, and a cornucopia of activities and regulatory pathways have been associated with it. In this review, we will raise questions about Mdm2 and its cousin Mdm4 that we consider worth pursuing in future research, reaching from molecular structures and intracellular activities all the way to development, evolution, and cancer therapy. We anticipate that such research will not only close a few gaps in our knowledge but could add new dimensions to our current view. This compilation of questions contributes to the preparation for the 10th Mdm2 Workshop in Tokyo.
Topics: Aging; Animals; Biological Evolution; Biomarkers, Tumor; Cell Cycle Proteins; Cell Transformation, Neoplastic; Gene Expression Regulation; Humans; Molecular Targeted Therapy; Multigene Family; Mutation; Protein Binding; Protein Transport; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Stress, Physiological; Tumor Suppressor Protein p53
PubMed: 32335977
DOI: 10.1111/cas.14433 -
Nature Reviews. Drug Discovery Nov 2014Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held... (Review)
Review
Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches.
Topics: Animals; Antineoplastic Agents; Humans; Oncogene Proteins; Signal Transduction; ras Proteins
PubMed: 25323927
DOI: 10.1038/nrd4389 -
Nature Nov 2021The majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by...
The majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes. However, most cancers have a modest mutational burden that is insufficient to generate responses using neoantigen-based therapies. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins that are essential for tumourigenesis and focus on targeting the unmutated peptide QYNPIRTTF, discovered on HLA-A*24:02, which is derived from the neuroblastoma dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (CARs) using a counter-panning strategy with predicted potentially cross-reactive peptides. We further hypothesized that peptide-centric CARs could recognize peptides on additional HLA allotypes when presented in a similar manner. Informed by computational modelling, we showed that PHOX2B peptide-centric CARs also recognize QYNPIRTTF presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we demonstrated potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.
Topics: Animals; Antigens, Neoplasm; Cell Line; Cell Line, Tumor; Cross Reactions; Cross-Priming; Female; HLA Antigens; Homeodomain Proteins; Humans; Immunotherapy; Interferon-gamma; Mice; Neoplasms; Oncogene Proteins; Receptors, Chimeric Antigen; T-Lymphocytes; Transcription Factors
PubMed: 34732890
DOI: 10.1038/s41586-021-04061-6