Review
Abstract
The pursuit of a vaccine against the human cytomegalovirus (HCMV) has been ongoing for more than 50 years. HCMV is the leading infectious cause of birth defects, including damage to the brain, and is a common cause of complications in organ transplantation. The complex biology of HCMV has made vaccine development difficult, but a recent meeting sponsored by the National Institute of Allergy and Infectious Diseases in September of 2023 brought together experts from academia, industry, and federal agencies to discuss progress in the field. The meeting reviewed the status of candidate HCMV vaccines under study and the challenges in clinical trial design in demonstrating efficacy against congenital CMV infection or the reduction of HCMV disease following solid organ transplantation or hematopoietic stem cell transplantation. Discussion in the meeting revealed that, with the numerous candidate vaccines that are under study, it is clear that a safe and effective HCMV vaccine is within reach. Meeting attendees achieved a consensus opinion that even a partially effective vaccine would have a major effect on the global health consequences of HCMV infection.
Authors
Sallie R. Permar, Mark R. Schleiss, Stanley A. Plotkin
Abstract
Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a “drug cocktail” approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.
Authors
Yusuf Mastoor, Elizabeth Murphy, Barbara Roman
Abstract
As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation and the enzyme complexes represent a major frontier for therapeutic development. Clinically viable therapies targeting the activities of histone lysine methyltransferases (HKMT) and demethylases (HKDMs) have only recently begun to emerge following FDA approval of the EZH2 inhibitor tazemetostat in 2020 and remain limited to compounds targeting the well-studied SET domain–containing HKMTs and their opposing HKDMs. These include the H3K27 methyltransferases EZH2/EZH1, the singular H3K79 methyltransferase DOT1L, and the H3K4 methyltransferase MLL1/COMPASS as well as H3K9 and H3K36 methyltransferases. They additionally include the H3K4/9-preferential demethylase LSD1 and the H3K4-, H3K27-, and H3K36-preferential KDM5, KDM6, and KDM2 demethylase subfamilies, respectively. This Review discusses the results of recent clinical and preclinical studies relevant to all of these existing and potential therapies. It provides an update on advancements in therapeutic development, as well as more basic molecular understanding, within the past 5 years approximately. It also offers a perspective on histone lysine methylation that departs from the long-predominant “histone code” metaphor, emphasizing complex-disrupting inhibitors and proximity-based approaches rather than catalytic domain inhibitors in the outlook for future therapeutic development.
Authors
Sarah Gold, Ali Shilatifard
Abstract
Salivary gland dysfunction is a common side effect of cancer treatments. Salivary function plays key roles in critical daily activities. Consequently, changes in salivary function can profoundly impair quality of life for cancer patients. We discuss salivary gland anatomy and physiology to understand how anticancer therapies such as chemotherapy, bone marrow transplantation, immunotherapy, and radiation therapy impair salivary function. We discuss approaches to quantify xerostomia in the clinic, including the advantages and limitations of validated quality-of-life instruments and approaches to directly measuring salivary function. Current and emerging approaches to treat cancer therapy–induced dry mouth are presented using radiation-induced salivary dysfunction as a model. Limitations of current sialagogues and salivary analogues are presented. Emerging approaches, including cellular and gene therapy and novel pharmacologic approaches, are described.
Authors
Cristina Paz, Annemarie Glassey, Abigail Frick, Sarah Sattar, Nicholas G. Zaorsky, Grace C. Blitzer, Randall J. Kimple
Abstract
Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting in BRCA1/2 deficiency are frequently identified in breast, ovarian, prostate, pancreatic, and other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted cancer therapy. However, a substantial fraction of cancer patients carrying BRCA1/2 mutations do not respond to PARPis, and most patients develop resistance to PARPis over time, highlighting a major obstacle to PARPi therapy in the clinic. Recent studies have revealed that changes of specific functional defects of BRCA1/2-deficient cells, particularly their defects in suppressing and protecting single-stranded DNA gaps, contribute to the gain or loss of PARPi-induced synthetic lethality. These findings not only shed light on the mechanism of action of PARPis, but also lead to revised models that explain how PARPis selectively kill BRCA-deficient cancer cells. Furthermore, new mechanistic principles of PARPi sensitivity and resistance have emerged from these studies, generating potentially useful guidelines for predicting the PARPi response and design therapies for overcoming PARPi resistance. In this Review, we will discuss these recent studies and put them in context with the classic views of PARPi-induced synthetic lethality, aiming to stimulate the development of new therapeutic strategies to overcome PARPi resistance and improve PARPi therapy.
Authors
Xin Li, Lee Zou
Abstract
Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.
Authors
Xiaobing Tian, Praveen R. Srinivasan, Vida Tajiknia, Ashley F. Sanchez Sevilla Uruchurtu, Attila A. Seyhan, Benedito A. Carneiro, Arielle De La Cruz, Maximilian Pinho-Schwermann, Andrew George, Shuai Zhao, Jillian Strandberg, Francesca Di Cristofano, Shengliang Zhang, Lanlan Zhou, Alexander G. Raufi, Arunasalam Navaraj, Yiqun Zhang, Nataliia Verovkina, Maryam Ghandali, Dinara Ryspayeva, Wafik S. El-Deiry
Abstract
A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health–related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.
Authors
Lauren A. Schrader, Sean M. Ronnekleiv-Kelly, John B. Hogenesch, Christopher A. Bradfield, Kristen M.C. Malecki
Abstract
Psilocybin, MDMA, and ketamine have emerged as potentially effective treatments for rapid amelioration of the symptoms of mood and related psychiatric disorders. All clinical data collected so far with regard to psilocybin or MDMA, which have reported positive outcomes for treating depression, anxiety, posttraumatic stress disorder, and drug or alcohol use disorders, have involved clinician-assisted intervention. While the case for ketamine is assumed to be different, the first report of the successful use of ketamine in psychiatry for treating depression was in combination with psychotherapy, and an emerging literature suggests that the subjective state of individual experiences with ketamine predicts clinical outcome. This Review will focus on (a) a brief review of the literature, showing that the context or the process of drug administration has been an integrative component of published work; (b) the importance of clinical trials to compare the efficacy of the drug (“pill”) as a stand-alone treatment versus drug in combination with clinician-assisted psychological support (“process”); and (c) suggestions for future approaches in animal models that take into account the role of systems and behavioral neuroscience in explaining a potential role for context, experience, and expectancy in drug effect.
Authors
Alejandro Torrado Pacheco, Bita Moghaddam
Abstract
Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor–induced MG. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.
Authors
Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, Linda L. Kusner
Abstract
Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play a crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome in cancer cells reprograms the immune landscape within the tumor microenvironment, thereby hindering antitumor immunity, promoting tumor progression, and inducing immunotherapy resistance. Targeting epigenetically mediated tumor-immune crosstalk is an emerging strategy to inhibit tumor progression and circumvent the limitations of current immunotherapies, including immune checkpoint inhibitors. In this Review, we discuss the mechanisms by which epigenetic aberrations regulate tumor-immune interactions and how epigenetically targeted therapies inhibit tumor progression and synergize with immunotherapy.
Authors
Lizhi Pang, Fei Zhou, Yang Liu, Heba Ali, Fatima Khan, Amy B. Heimberger, Peiwen Chen
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