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Current Opinion in Oncology Jul 2024There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA).... (Review)
Review
PURPOSE OF REVIEW
There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA). Current therapy at diagnosis involves multiagent chemotherapy and local therapy, but despite intensification of treatment, those with metastases at diagnosis and recurrent disease have poor outcomes.
RECENT FINDINGS
Improved understanding of Ewing sarcoma biology has identified novel targets with promising activity in Ewing sarcoma patients, including tyrosine kinase inhibitors that are now undergoing evaluation as combination and maintenance therapy. Other emerging therapies include those that target the EWSR1::FLI1 fusion oncoprotein, and act on DNA damage, cell cycle and apoptotic pathways. Immunotherapeutic approaches, particularly CAR-T-cell therapy directed at GD2, also hold promise. Recent collaborative clinical trials that have defined an international standard of care for patients with newly diagnosed Ewing sarcoma and novel platform studies with adaptive designs offer unique opportunities to investigate these therapies inclusive of all ages.
SUMMARY
Close international collaboration between clinicians and biologists will allow us to prioritize promising emerging therapies and develop biomarkers to facilitate their incorporation into standard of care and more rapidly translate into benefit for Ewing sarcoma patients.
Topics: Humans; Sarcoma, Ewing; Bone Neoplasms; Oncogene Proteins, Fusion; Molecular Targeted Therapy; Immunotherapy, Adoptive
PubMed: 38775200
DOI: 10.1097/CCO.0000000000001048 -
Stem Cell Research & Therapy Jul 2022RUNX1T1 (Runt-related transcription factor 1, translocated to 1), a myeloid translocation gene (MTG) family member, is usually investigated as part of the fusion protein... (Review)
Review
RUNX1T1 (Runt-related transcription factor 1, translocated to 1), a myeloid translocation gene (MTG) family member, is usually investigated as part of the fusion protein RUNX1-RUNX1T1 for its role in acute myeloid leukemia. In the main, by recruiting histone deacetylases, RUNX1T1 negatively influences transcription, enabling it to regulate the proliferation and differentiation of hematopoietic progenitors. Moreover, the formation of blood vessels, neuronal differentiation, microglial activation following injury, and intestinal development all relate closely to the expression of RUNX1T1. Furthermore, through alternative splicing of RUNX1T1, short and long isoforms have been noted to mediate adipogenesis by balancing the differentiation and proliferation of adipocytes. In addition, RUNX1T1 plays wide-ranging and diverse roles in carcinoma as a biomarker, suppressor, or positive regulator of carcinogenesis, closely correlated to specific organs and dominant signaling pathways. The aim of this work was to investigate the structure of RUNX1T1, which contains four conserved nervy homolog domains, and to demonstrate crosstalk with the Notch signaling pathway. Moreover, we endeavored to illustrate the effects of RUNX1T1 on cell fate from multiple aspects, including its influence on hematopoiesis, neuronal differentiation, microglial activation, intestinal development, adipogenesis, angiogenesis, and carcinogenesis.
Topics: Carcinogenesis; Humans; Leukemia, Myeloid, Acute; Oncogene Proteins, Fusion; RUNX1 Translocation Partner 1 Protein; Translocation, Genetic
PubMed: 35902872
DOI: 10.1186/s13287-022-03074-w -
Journal of Medical Virology Oct 2023There has been an explosion in the number of papillomaviruses that have been identified and fully sequenced. Yet only a minute fraction of these has been studied in any... (Review)
Review
There has been an explosion in the number of papillomaviruses that have been identified and fully sequenced. Yet only a minute fraction of these has been studied in any detail. Most of our molecular research efforts have focused on the E6 and E7 proteins of "high-risk," cancer-associated human papillomaviruses (HPVs). Interactions of the high-risk HPV E6 and E7 proteins with their respective cellular targets, the p53 and the retinoblastoma tumor suppressors, have been investigated in minute detail. Some have thus questioned if research on papillomaviruses remains an exciting and worthwhile area of investigation. However, fundamentally new insights on the biological activities and cellular targets of the high-risk HPV E6 and E7 proteins have been discovered and previously unstudied HPVs have been newly associated with human diseases. HPV infections continue to be an important cause of human morbidity and mortality and since there are no antivirals to combat HPV infections, research on HPVs should remain attractive to new investigators and biomedical funding agencies, alike.
Topics: Humans; Oncogene Proteins, Viral; Human Papillomavirus Viruses; Papillomavirus E7 Proteins; Papillomavirus Infections; Neoplasms; Papillomaviridae
PubMed: 37861365
DOI: 10.1002/jmv.29191 -
Biochemical Society Transactions Jun 2023RAS proteins are small GTPases that transduce signals from membrane receptors to signaling pathways that regulate growth and differentiation. Four RAS proteins are... (Review)
Review
RAS proteins are small GTPases that transduce signals from membrane receptors to signaling pathways that regulate growth and differentiation. Four RAS proteins are encoded by three genes - HRAS, KRAS, NRAS. Among them, KRAS is mutated in human cancer more frequently than any other oncogene. The KRAS pre-mRNA is alternatively spliced to generate two transcripts, KRAS4A and KRAS4B, that encode distinct proto-oncoproteins that differ almost exclusively in their C-terminal hypervariable regions (HVRs) that controls subcellular trafficking and membrane association. The KRAS4A isoform arose 475 million years ago in jawed vertebrates and has persisted in all vertebrates ever since, strongly suggesting non-overlapping functions of the splice variants. Because KRAS4B is expressed at higher levels in most tissues, it has been considered the principal KRAS isoform. However, emerging evidence for KRAS4A expression in tumors and splice variant-specific interactions and functions have sparked interest in this gene product. Among these findings, the KRAS4A-specific regulation of hexokinase I is a stark example. The aim of this mini-review is to provide an overview of the origin and differential functions of the two splice variants of KRAS.
Topics: Animals; Humans; Proto-Oncogene Proteins p21(ras); Neoplasms; Protein Isoforms; Signal Transduction; ras Proteins; Mutation
PubMed: 37222266
DOI: 10.1042/BST20221347 -
Cancer Discovery Dec 2023PML nuclear bodies (NB) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA...
UNLABELLED
PML nuclear bodies (NB) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid-liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB assembly, PML sumoylation, and PML-RARA degradation, mechanistically explaining clinical ATO resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML that could pave the way to novel cancer drugs.
SIGNIFICANCE
Arsenic curative effects in APL rely on PML targeting. We report a PML B-box-2 structure that drives trimer assembly, positioning a cysteine trio to form an arsenic-binding pocket, which is disrupted in resistant patients. Identification of this ROS-sensitive triad controlling PML dynamics and functions could yield novel drugs. See related commentary by Salomoni, p. 2505. This article is featured in Selected Articles from This Issue, p. 2489.
Topics: Humans; Arsenic; Promyelocytic Leukemia Nuclear Bodies; Cysteine; Arsenicals; Oxides; Arsenic Trioxide; Leukemia, Promyelocytic, Acute; Oncogene Proteins; Oncogene Proteins, Fusion
PubMed: 37655965
DOI: 10.1158/2159-8290.CD-23-0453 -
Viruses Oct 2021Papillomaviruses dysregulate the G1/S cell cycle transition in order to promote DNA synthesis in S phase, which is a requirement for viral replication. The human... (Review)
Review
Papillomaviruses dysregulate the G1/S cell cycle transition in order to promote DNA synthesis in S phase, which is a requirement for viral replication. The human papillomaviruses (HPV) E6 and E7 oncoproteins mediate degradation of the cell cycle regulators p53 and Rb, which are two of the most universally disrupted tumor-suppressor genes in all of cancer. The G1/S checkpoint is activated in normal cells to allow sufficient time for DNA repair in G1 before proceeding to replicate DNA and risk propagating unrepaired errors. The TP53 pathway suppresses a variety of such errors, including translocation, copy number alterations, and aneuploidy, which are thus found in HPV-associated tumors similarly to HPV-negative tumors with other mechanisms of TP53 disruption. However, E6 and E7 maintain a variety of other virus-host interactions that directly disrupt a growing list of other DNA repair and chromatin remodeling factors, implying HPV-specific repair deficiencies. In addition, HPV-associated squamous cell carcinomas tumors clinically respond differently to DNA damaging agents compared to their HPV negative counterparts. The focus of this review is to integrate three categories of observations: (1) pre-clinical understanding as to the effect of HPV on DNA repair, (2) genomic signatures of DNA repair in HPV-associated tumor genomes, and (3) clinical responses of HPV-associated tumors to DNA damaging agents. The goals are to try to explain why HPV-associated tumors respond so well to DNA damaging agents, identify missing pieces, and suggest clinical strategies could be used to further improve treatment of these cancers.
Topics: Alphapapillomavirus; Carcinoma, Squamous Cell; Cell Cycle; DNA Repair; DNA, Viral; Female; Genomics; Humans; Neoplasms; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Papillomavirus Infections; Repressor Proteins; Retinoblastoma Protein; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms
PubMed: 34696429
DOI: 10.3390/v13101998 -
Seminars in Diagnostic Pathology Sep 2021NUT carcinoma of the thorax is a rare and very aggressive tumor, whose definition is based on the demonstration of a nuclear protein in testis (NUTM1; also known as NUT)... (Review)
Review
NUT carcinoma of the thorax is a rare and very aggressive tumor, whose definition is based on the demonstration of a nuclear protein in testis (NUTM1; also known as NUT) gene fusion on 15q14 with different partners from the bromodomain-containing proteins gene family. This fusion results in an activation of MYC oncoprotein responsible for the tumor's aggressivity. NUT carcinoma arises preferentially in young adults, presenting a large thoracic mass frequently associated with lymph nodes, bone or pleural metastases. At histology, this tumor is often poorly differentiated, mainly composed of sheets of small cells with scant cytoplasm, a round nucleus with a central nucleolus. Focal areas of squamous differentiation can be observed. Mitoses and necrosis are frequent, as well as neutrophilic infiltrate. The diagnosis is based on the detection of NUT protein expression by immunohistochemistry using the rabbit monoclonal antibody C52B1 in more than 50% of the tumor nuclei. This technique offers 87% sensitivity and nearly 100% specificity with reference to FISH or RT-PCR, which confirm the NUTM1 rearrangement. The differential diagnoses include basaloid carcinoma of the lung, small cell carcinoma, thymic carcinoma (basaloid variant), SMARCA4_deficient thoracic sarcoma, other NUTM1 rearranged undifferentiated tumors, small round cell tumors, non-Hodgkin lymphoma/leukemia, and melanoma. The prognosis of NUT carcinoma remains very poor, with a median survival of 6.7 months, and 1- and 2-year overall survival rates of 30% and 19%, respectively. NUT carcinoma is often refractory to conventional chemotherapy, but ifosfamide-based regimens or BET inhibitors could represent promising therapies.
Topics: Carcinoma; DNA Helicases; Humans; Lung; Male; Nuclear Proteins; Oncogene Proteins; Oncogene Proteins, Fusion; Sarcoma; Transcription Factors
PubMed: 34176698
DOI: 10.1053/j.semdp.2021.06.005 -
Current Oncology Reports Apr 2023During the past few years there has been an expansion in our understanding of gene fusions and translocations involved in cancer of the sinonasal tract. Here we review... (Review)
Review
PURPOSE OF REVIEW
During the past few years there has been an expansion in our understanding of gene fusions and translocations involved in cancer of the sinonasal tract. Here we review the downstream biologic effects, clinical characteristics, and pathologic features of these tumors. The molecular consequences and neo-antigens resulting from these chromosomal aberrations are considered and targets for current and future clinical trials discussed.
RECENT FINDINGS
Several new, clinically relevant, chromosomal aberrations have been discovered and evaluated to varying degrees in sinonasal tumors including DEK::AFF2, BRD4::NUT, ADCK4::NUMBL, and ETV6::NTRK3. Sinonasal malignancies demonstrate a diverse genetic landscape and varying clinical courses. Recent studies illustrate that gene fusions and translocations may play a role in carcinogenesis in certain sinonasal tumor subtypes and may be used to develop new biomarker-driven and patient-centered treatments.
Topics: Humans; Transcription Factors; Nuclear Proteins; Neoplasms; Translocation, Genetic; Gene Fusion; Oncogene Proteins, Fusion; Poly-ADP-Ribose Binding Proteins; Chromosomal Proteins, Non-Histone; Oncogene Proteins; Cell Cycle Proteins
PubMed: 36753024
DOI: 10.1007/s11912-023-01364-x -
Journal of Medical Virology Dec 2023Human papillomavirus (HPV) infections are a leading cause of viral-induced malignancies worldwide, with a prominent association with cervical and head and neck cancers.... (Review)
Review
Human papillomavirus (HPV) infections are a leading cause of viral-induced malignancies worldwide, with a prominent association with cervical and head and neck cancers. The pivotal role of HPV oncoproteins, E5, E6, and E7, in manipulating cellular events, which contribute to viral pathogenesis in various ways, has been extensively documented. This article reviews the influence of HPV oncoproteins on cellular signaling pathways within the host cell, shedding light on the underlying molecular mechanisms. A comprehensive understanding of these molecular alterations is essential for the development of targeted therapies and strategies to combat HPV-induced premalignancies and prevent their progress to cancer. Furthermore, this review underscores the intricate interplay between HPV oncoproteins and some of the most important cellular signaling pathways: Notch, Wnt/β-catenin, MAPK, JAK/STAT, and PI3K AKT/mTOR. The treatment efficacies of the currently available inhibitors on these pathways in an HPV-positive context are also discussed. This review also highlights the importance of continued research to advance our knowledge and enhance therapeutic interventions for HPV-associated diseases.
Topics: Humans; Female; Oncogene Proteins, Viral; Signal Transduction; Phosphatidylinositol 3-Kinases; Papillomavirus Infections; Papillomavirus E7 Proteins; Uterine Cervical Neoplasms
PubMed: 38115222
DOI: 10.1002/jmv.29315 -
Biochimica Et Biophysica Acta.... Oct 2022Since their discovery nearly 25 years ago, the BCL-2 family members BNIP3 and BNIP3L (aka Nix) have been labelled 'atypical'. Originally, this was because BNIP3 and Nix... (Review)
Review
Since their discovery nearly 25 years ago, the BCL-2 family members BNIP3 and BNIP3L (aka Nix) have been labelled 'atypical'. Originally, this was because BNIP3 and Nix have divergent BH3 domains compared to other BCL-2 proteins. In addition, this atypical BH3 domain is dispensable for inducing cell death, which is also unusual for a 'death gene'. Instead, BNIP3 and Nix utilize a transmembrane domain, which allows for dimerization and insertion into and through organelle membranes to elicit cell death. Much has been learned regarding the biological function of these two atypical death genes, including their role in metabolic stress, where BNIP3 is responsive to hypoxia, while Nix responds variably to hypoxia and is also down-stream of PKC signaling and lipotoxic stress. Interestingly, both BNIP3 and Nix respond to signals related to cell atrophy. In addition, our current view of regulated cell death has expanded to include forms of necrosis such as necroptosis, pyroptosis, ferroptosis, and permeability transition-mediated cell death where BNIP3 and Nix have been shown to play context- and cell-type specific roles. Perhaps the most intriguing discoveries in recent years are the results demonstrating roles for BNIP3 and Nix outside of the purview of death genes, such as regulation of proliferation, differentiation/maturation, mitochondrial dynamics, macro- and selective-autophagy. We provide a historical and unbiased overview of these 'death genes', including new information related to alternative splicing and post-translational modification. In addition, we propose to redefine these two atypical members of the BCL-2 family as versatile regulators of cell fate.
Topics: Autophagy; Humans; Hypoxia; Membrane Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Proteins
PubMed: 35863652
DOI: 10.1016/j.bbamcr.2022.119325