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Trends in Molecular Medicine Aug 2023Ubiquitin-proteasome system (UPS) is a selective proteolytic system that is associated with the expression or function of target proteins and participates in various... (Review)
Review
Ubiquitin-proteasome system (UPS) is a selective proteolytic system that is associated with the expression or function of target proteins and participates in various physiological and pathological processes of breast cancer. Inhibitors targeting the 26S proteasome in combination with other drugs have shown promising therapeutic effects in the clinical treatment of breast cancer. Moreover, several inhibitors/stimulators targeting other UPS components are also effective in preclinical studies, but have not yet been applied in the clinical treatment of breast cancer. Therefore, it is vital to comprehensively understand the functions of ubiquitination in breast cancer and to identify potential tumor promoters or tumor suppressors among UPS family members, with the aim of developing more effective and specific inhibitors/stimulators targeting specific components of this system.
Topics: Humans; Female; Ubiquitin; Proteasome Endopeptidase Complex; Breast Neoplasms; Ubiquitination
PubMed: 37328395
DOI: 10.1016/j.molmed.2023.05.006 -
Journal of the National Comprehensive... Dec 2023The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome...
The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Medical Oncology; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 38081133
DOI: 10.6004/jnccn.2023.0061 -
Annual Review of Medicine Jan 2024Multiple myeloma is a cancer of bone marrow plasma cells that represents approximately 10% of hematologic malignancies. Though it is typically incurable, a remarkable... (Review)
Review
Multiple myeloma is a cancer of bone marrow plasma cells that represents approximately 10% of hematologic malignancies. Though it is typically incurable, a remarkable suite of new therapies developed over the last 25 years has enabled durable disease control in most patients. This article briefly introduces the clinical features of multiple myeloma and aspects of multiple myeloma biology that modern therapies exploit. Key current and emerging treatment modalities are then reviewed, including cereblon-modulating agents, proteasome inhibitors, monoclonal antibodies, other molecularly targeted therapies (selinexor, venetoclax), chimeric antigen receptor T cells, T cell-engaging bispecific antibodies, and antibody-drug conjugates. For each modality, mechanism of action and clinical considerations are discussed. These therapies are combined and sequenced in modern treatment pathways, discussed at the conclusion of the article, which have led to substantial improvements in outcomes for multiple myeloma patients in recent years.
Topics: Humans; Multiple Myeloma; Immunotherapy; Proteasome Inhibitors; Antibodies, Monoclonal; Biological Therapy
PubMed: 37729027
DOI: 10.1146/annurev-med-050522-033815 -
Drugs Nov 2023Elranatamab (elranatamab-bcmm; ELREXFIO™) is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T cell engager being developed by Pfizer for the treatment of... (Review)
Review
Elranatamab (elranatamab-bcmm; ELREXFIO™) is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T cell engager being developed by Pfizer for the treatment of multiple myeloma (MM). Elranatamab bridges CD3 on T cells with BCMA expressed on multiple myeloma cells, thereby activating T cells to induce T cell-mediated cytotoxicity against myeloma cells. In August 2023, elranatamab received its first approval in the USA for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. Elranatamab received accelerated approval for this indication based on response rate and durability of response, and continued approval may be contingent on the demonstration of clinical benefit in a confirmatory trial(s). Elranatamab has also received a positive opinion in the EU for RRMM and is under regulatory review in Japan and several other countries worldwide. Clinical studies of elranatamab are also underway in countries around the world. This article summarizes the milestones in the development of elranatamab leading to this first approval for the treatment of RRMM.
Topics: Adult; Humans; Multiple Myeloma; B-Cell Maturation Antigen; Antineoplastic Agents; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 37924427
DOI: 10.1007/s40265-023-01954-w -
Signal Transduction and Targeted Therapy Mar 2024NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However,... (Review)
Review
NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.
Topics: Humans; Immunotherapy; NF-kappa B; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 38433280
DOI: 10.1038/s41392-024-01757-9 -
Molecular Diagnosis & Therapy Nov 2023Equecabtagene autoleucel (Fucaso), an autologous anti-B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy that uses lentivirus as a... (Review)
Review
Equecabtagene autoleucel (Fucaso), an autologous anti-B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy that uses lentivirus as a gene vector to transfect autologous T cells, is being developed by IASO Biotechnology and Innovent Biologics, Inc. for the treatment of multiple myeloma (MM) and autoimmune diseases of the nervous system, including neuromyelitis optica spectrum disorder (NMOSD). Equecabtagene autoleucel was granted conditional approval in China in June 2023 for the treatment of adults with relapsed or refractory MM (RRMM) who have progressed after ≥ 3 lines of therapy (≥ 1 proteasome inhibitor and an immunomodulator). This article summarizes the milestones in the development of equecabtagene autoleucel leading to this first approval in patients with RRMM who have progressed after multiple lines of therapy.
Topics: Adult; Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Multiple Myeloma; China
PubMed: 37658205
DOI: 10.1007/s40291-023-00673-y -
Journal of Clinical Medicine Jul 2023Despite significant advancements in immunosuppressive therapies, kidney transplant rejection continues to pose a substantial challenge, impacting the long-term survival... (Review)
Review
Despite significant advancements in immunosuppressive therapies, kidney transplant rejection continues to pose a substantial challenge, impacting the long-term survival of grafts. This article provides an overview of the diagnosis, current therapies, and management strategies for acute T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). TCMR is diagnosed through histological examination of kidney biopsy samples, which reveal the infiltration of mononuclear cells into the allograft tissue. Corticosteroids serve as the primary treatment for TCMR, while severe or steroid-resistant cases may require T-cell-depleting agents, like Thymoglobulin. ABMR occurs due to the binding of antibodies to graft endothelial cells. The most common treatment for ABMR is plasmapheresis, although its efficacy is still a subject of debate. Other current therapies, such as intravenous immunoglobulins, anti-CD20 antibodies, complement inhibitors, and proteasome inhibitors, are also utilized to varying degrees, but their efficacy remains questionable. Management decisions for ABMR depend on the timing of the rejection episode and the presence of chronic changes. In managing both TCMR and ABMR, it is crucial to optimize immunosuppression and address adherence. However, further research is needed to explore newer therapeutics and evaluate their efficacy.
PubMed: 37568328
DOI: 10.3390/jcm12154927 -
Genes & Diseases Jul 2024Protein homeostasis is the basis of normal life activities, and the proteasome family plays an extremely important function in this process. The proteasome 20S is a... (Review)
Review
Protein homeostasis is the basis of normal life activities, and the proteasome family plays an extremely important function in this process. The proteasome 20S is a concentric circle structure with two α rings and two β rings overlapped. The proteasome 20S can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits (such as 19S, 11S, and 200 PA), which is performed by its active subunit β1, β2, and β5. The proteasome can degrade misfolded, excess proteins to maintain homeostasis. At the same time, it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth. Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-κB and p53, cell cycle, immune regulation, and drug resistance. Proteasome-encoding genes have been found to be overexpressed in a variety of tumors, providing a potential novel target for cancer therapy. In addition, proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma. More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma, non-small cell lung cancer, glioblastoma, and neuroblastoma. However, proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors. Therefore, further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.
PubMed: 38523673
DOI: 10.1016/j.gendis.2023.06.037 -
Expert Opinion on Therapeutic Patents Nov 2023The therapeutic targeting of the ubiquitin-proteasome pathway (UPP) through inhibitors of the 20S proteasome core proteolytic activities has revolutionized the treatment... (Review)
Review
INTRODUCTION
The therapeutic targeting of the ubiquitin-proteasome pathway (UPP) through inhibitors of the 20S proteasome core proteolytic activities has revolutionized the treatment of hematological malignancies and is paving the way for its extension to solid tumors.
AREAS COVERED
This review covers the progress made in the field of proteasome inhibitors, ranging from the first-generation bortezomib to the latest second-generation inhibitors such as carfilzomib and ixazomib as well as the proteasome inhibitors in clinical phase such as oprozomib and marizomib. The development of selective and potent proteasome inhibitors with improved pharmacological properties is described from the synthesis to their basic biological, and clinical validation.
EXPERT OPINION
Proteasome inhibitors have transformed the treatment landscape for hematological malignancies and hold great promise for cancer therapy. Combination therapies targeting multiple pathways, the development of novel inhibitors or 'hybrid-inhibitors,' and the optimization of treatment protocols are key areas for future exploration. The extension of proteasome inhibitors for the treatment of solid tumors, and their ability to pass the blood-brain barrier open new possibilities for treating central nervous system cancers. However, managing adverse effects, particularly those affecting the central nervous system, remains a critical consideration and a strategic 'working on' aspect for the near future.
Topics: Humans; Proteasome Inhibitors; Patents as Topic; Antineoplastic Agents; Neoplasms; Hematologic Neoplasms; Multiple Myeloma
PubMed: 37847492
DOI: 10.1080/13543776.2023.2272648