-
European Journal of Nuclear Medicine... Jul 2023FAP is a membrane-bound protease under investigation as a pan-cancer target, given its high levels in tumors but limited expression in normal tissues. FAP-2286 is a...
PURPOSE
FAP is a membrane-bound protease under investigation as a pan-cancer target, given its high levels in tumors but limited expression in normal tissues. FAP-2286 is a radiopharmaceutical in clinical development for solid tumors that consists of two functional elements: a FAP-targeting peptide and a chelator used to attach radioisotopes. Preclinically, we evaluated the immune modulation and anti-tumor efficacy of FAP-2287, a murine surrogate for FAP-2286, conjugated to the radionuclide lutetium-177 (Lu) as a monotherapy and in combination with a PD-1 targeting antibody.
METHODS
C57BL/6 mice bearing MCA205 mouse FAP-expressing tumors (MCA205-mFAP) were treated with Lu-FAP-2287, anti-PD-1, or both. Tumor uptake of Lu- FAP-2287 was assessed by SPECT/CT scanning, while therapeutic efficacy was measured by tumor volume and survival. Immune profiling of tumor infiltrates was evaluated through flow cytometry, RNA expression, and immunohistochemistry analyses.
RESULTS
Lu-FAP-2287 rapidly accumulated in MCA205-mFAP tumors leading to significant tumor growth inhibition (TGI) and longer survival time. Significant TGI was also observed from anti-PD-1 and the combination. In flow cytometry analysis of tumors, Lu-FAP-2287 increased CD8 T cell infiltration which was maintained in the combination with anti-PD-1. The increase in CD8 T cells was accompanied by an induction of STING-mediated type I interferon response and higher levels of co-stimulatory molecules such as CD86.
CONCLUSION
In a preclinical model, FAP-targeted radiotherapy enhanced anti-PD-1-mediated TGI by modulating the TME and increasing the recruitment of tumor-infiltrating CD8 T cells. These findings provide a rationale for clinical studies of combined Lu-FAP-2286 radiotherapy and immune checkpoint inhibition in FAP-positive tumors.
Topics: Animals; Mice; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; Tumor Microenvironment; Cell Line, Tumor; Mice, Inbred C57BL; Fibroblasts
PubMed: 37086273
DOI: 10.1007/s00259-023-06211-6 -
Heliyon Oct 2023Glioblastoma is an extremely lethal cancer characterized by great heterogeneity at different molecular and cellular levels. As a result, treatment options have moved far... (Review)
Review
Glioblastoma is an extremely lethal cancer characterized by great heterogeneity at different molecular and cellular levels. As a result, treatment options have moved far from systemic and universal therapies toward targeted treatments and personalized medicine. However, for successful translation from preclinical studies to clinical trials, experiments must be performed on reliable disease models. Numerous experimental models have been developed for glioblastoma, ranging from simple 2D cell cultures to study the nature of the disease to complex 3D models such as neurospheres, organoids, tissue-slice cultures, bioprinted models, and tumor on chip, as perfect prototypes to evaluate the therapeutic potential of different drugs. The presence of multiple research models is consistent with the complexity and molecular diversity of glioblastoma. The advantage of such models is the recapitulation of the tumor environment, and in some cases the preservation of immune system components as well as the creation of simple vessels. There are also two case studies translating studies on glioblastoma organoids to patients as well as four ongoing clinical trials using glioblastoma models, indicating high clinical potential of glioblastoma models.
PubMed: 37928397
DOI: 10.1016/j.heliyon.2023.e21070 -
Arteriosclerosis, Thrombosis, and... Sep 2023Therapeutic approaches to reduce atherogenic lipid and lipoprotein levels remain the most effective and assessable strategies to prevent and treat cardiovascular... (Review)
Review
Therapeutic approaches to reduce atherogenic lipid and lipoprotein levels remain the most effective and assessable strategies to prevent and treat cardiovascular disease. The discovery of novel research targets linked to pathways associated with cardiovascular disease development has enhanced our ability to decrease disease burden; however, residual cardiovascular disease risks remain. Advancements in genetics and personalized medicine are essential to understand some of the factors driving residual risk. Biological sex is among the most relevant factors affecting plasma lipid and lipoprotein profiles, playing a pivotal role in the development of cardiovascular disease. This minireview summarizes the most recent preclinical and clinical studies covering the effect of sex on plasma lipid and lipoprotein levels. We highlight the recent advances in the mechanisms regulating hepatic lipoprotein production and clearance as potential drivers of disease presentation. We focus on using sex as a biological variable in studying circulating lipid and lipoprotein levels.
Topics: Male; Female; Humans; Cardiovascular Diseases; Lipoproteins; Atherosclerosis; Triglycerides
PubMed: 37409532
DOI: 10.1161/ATVBAHA.122.318247 -
Frontiers in Cell and Developmental... 2023Angelman syndrome (AS) is an imprinted neurodevelopmental disorder that lacks a cure, characterized by developmental delay, intellectual impairment, seizures, ataxia,... (Review)
Review
Angelman syndrome (AS) is an imprinted neurodevelopmental disorder that lacks a cure, characterized by developmental delay, intellectual impairment, seizures, ataxia, and paroxysmal laughter. The condition arises due to the loss of the maternally inherited copy of the gene in neurons. The paternally inherited allele is unable to compensate because it is silenced by the expression of an antisense transcript () on the paternal chromosome. , encoding enigmatic E3 ubiquitin ligase variants, regulates target proteins by either modifying their properties/functions or leading them to degradation through the proteasome. Over time, animal models, particularly the Knock-Out (KO) mice, have significantly contributed to our understanding of the molecular mechanisms underlying AS. However, a shift toward human pluripotent stem cell models (PSCs), such as human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), has gained momentum. These stem cell models accurately capture human genetic and cellular characteristics, offering an alternative or a complement to animal experimentation. Human stem cells possess the remarkable ability to recapitulate neurogenesis and generate "brain-in-a-dish" models, making them valuable tools for studying neurodevelopmental disorders like AS. In this review, we provide an overview of the current state-of-the-art human stem cell models of AS and explore their potential to become the preclinical models of choice for drug screening and development, thus propelling AS therapeutic advancements and improving the lives of affected individuals.
PubMed: 37928900
DOI: 10.3389/fcell.2023.1274040 -
The Journal of Heart and Lung... Mar 2024Several reports have highlighted the dichotomous nature of the Interleukin-33 (IL-33) system in cardiac and lung disease, where this cytokine can exert both protective... (Review)
Review
Several reports have highlighted the dichotomous nature of the Interleukin-33 (IL-33) system in cardiac and lung disease, where this cytokine can exert both protective effects and drive pro-inflammatory responses in a context-specific manner. This State-of-the-Art review focuses on preclinical mechanistic studies of the IL-33 system in development of allograft rejection in heart and lung transplantation. We address the scope of potential cellular sources of IL-33 and pathways for cellular release that may impact the study of this cytokine system in transplant models. We then highlight soluble IL-33 receptor as a biomarker in cardiac allograft rejection and detail preclinical models that collectively demonstrate a role for this cytokine in driving type-2 immune programs to protect cardiac allografts. We contrast this with investigation of IL-33 in lung transplantation, which has yielded mixed and somewhat conflicting results when comparing human studies with preclinical models, which have implicated the IL-33 system in both allograft tolerance and acceleration of chronic rejection. We summarize and interpret these results in aggregate and provide future directions for study of IL-33 in heart and lung transplantation.
PubMed: 38452960
DOI: 10.1016/j.healun.2024.02.1459 -
Cells Aug 2023Infectious diseases, particularly Tuberculosis (TB) caused by , pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most... (Review)
Review
Infectious diseases, particularly Tuberculosis (TB) caused by , pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases.
Topics: Humans; Communicable Diseases; Biological Therapy; Mycobacterium tuberculosis; Drug Delivery Systems; Oligonucleotides, Antisense; RNA, Messenger
PubMed: 37626929
DOI: 10.3390/cells12162119 -
Cellular and Molecular Life Sciences :... Oct 2023Our current knowledge regarding the development of the human brain mostly derives from experimental studies on non-human primates, sheep, and rodents. However, these... (Review)
Review
Our current knowledge regarding the development of the human brain mostly derives from experimental studies on non-human primates, sheep, and rodents. However, these studies may not completely simulate all the features of human brain development as a result of species differences and variations in pre- and postnatal brain maturation. Therefore, it is important to supplement the in vivo animal models to increase the possibility that preclinical studies have appropriate relevance for potential future human trials. Three-dimensional brain organoid culture technology could complement in vivo animal studies to enhance the translatability of the preclinical animal studies and the understanding of brain-related disorders. In this review, we focus on the development of a model of hypoxic-ischemic (HI) brain injury using human brain organoids to complement the translation from animal experiments to human pathophysiology. We also discuss how the development of these tools provides potential opportunities to study fundamental aspects of the pathophysiology of HI-related brain injury including differences in the responses between males and females.
Topics: Male; Female; Animals; Humans; Sheep; Disease Models, Animal; Brain; Hypoxia-Ischemia, Brain; Rodentia; Organoids; Brain Injuries
PubMed: 37804439
DOI: 10.1007/s00018-023-04951-0 -
International Journal of Molecular... Nov 2023Neuromuscular diseases (NMDs) are a genetically or clinically heterogeneous group of diseases that involve injury or dysfunction of neuromuscular tissue components,... (Review)
Review
Neuromuscular diseases (NMDs) are a genetically or clinically heterogeneous group of diseases that involve injury or dysfunction of neuromuscular tissue components, including peripheral motor neurons, skeletal muscles, and neuromuscular junctions. To study NMDs and develop potential therapies, remarkable progress has been made in generating in vitro neuromuscular models using engineering approaches to recapitulate the complex physical and biochemical microenvironments of 3D human neuromuscular tissues. In this review, we discuss recent studies focusing on the development of in vitro co-culture models of human motor neurons and skeletal muscles, with the pros and cons of each approach. Furthermore, we explain how neuromuscular in vitro models recapitulate certain aspects of specific NMDs, including amyotrophic lateral sclerosis and muscular dystrophy. Research on neuromuscular organoids (NMO) will continue to co-develop to better mimic tissues in vivo and will provide a better understanding of the development of the neuromuscular tissue, mechanisms of NMD action, and tools applicable to preclinical studies, including drug screening and toxicity tests.
Topics: Humans; Neuromuscular Diseases; Muscle, Skeletal; Neuromuscular Junction; Motor Neurons; Organoids
PubMed: 38069329
DOI: 10.3390/ijms242317006 -
Molecular Oncology Jul 2023Cancer immunotherapy has revolutionized the treatment of some malignancies. Yet, many tumors do not unfortunately respond to immune-based therapies. Deeper insights into...
Cancer immunotherapy has revolutionized the treatment of some malignancies. Yet, many tumors do not unfortunately respond to immune-based therapies. Deeper insights into the biology of the immune response to cancer are required to identify novel therapeutic targets and advance immuno-oncology. To do so, we need to study cancer in patient-derived models that can faithfully recapitulate and capture the complexity and heterogeneity of the tumor immune ecosystem. Platforms facilitating the analysis of the human tumor immune microenvironment of individual patients are crucial. Patient-derived models are fundamental not only to better understand the biology of the cancer immune system but also to discern the mechanism of action of therapeutic compounds and perform preclinical studies toward improving the success of subsequent clinical testing. In this viewpoint, I present a brief review of patient-derived models for cancer immunotherapy.
Topics: Humans; Ecosystem; Neoplasms; Medical Oncology; Immunotherapy; Immune System; Tumor Microenvironment
PubMed: 37278114
DOI: 10.1002/1878-0261.13470 -
Cureus Jan 2024The knees are the most frequently affected weight-bearing joints in osteoarthritis (OA), impacting millions of people globally. With increasing life spans and obesity... (Review)
Review
The knees are the most frequently affected weight-bearing joints in osteoarthritis (OA), impacting millions of people globally. With increasing life spans and obesity rates, the prevalence of knee OA will further mount, leading to a significant increase in the economic burden. The usual treatment modalities utilized to manage knee OA have shortcomings. Over the last decade, the field of regenerative medicine involving the use of biologics, such as autologous peripheral blood-derived orthobiologics, including hyperacute serum (HS), has evolved and shown potential for managing knee OA. In this manuscript, we qualitatively present the in vitro, pre-clinical, clinical, and ongoing studies investigating the applications of HS in the context of knee OA. Seven in vitro studies and one clinical study fit the scope of our manuscript. The results demonstrated that the administration of HS is potentially safe and efficacious in terms of increasing the viability of osteoarthritic chondrocytes, reducing pain and inflammation, and improving function in patients with knee OA. However, due to insufficient literature, pre-clinical studies to better understand the mechanism of action are required. In addition, adequately powered, multi-center, non-randomized, and randomized controlled trials with longer follow-up are warranted to establish the safety and efficacy of HS for the management of knee OA and to justify its clinical use.
PubMed: 38420081
DOI: 10.7759/cureus.53118