Conventional immunotherapy has emerged as a key option for cancer treatment. However, its efficacy has been limited in urological cancers, especially prostate cancer, because of the immunosuppressive tumor microenvironment (TME), difficulty in drug delivery, aberrant immune response, and damage to normal cells. Bispecific antibodies (BsAbs) are engineered proteins with two different antigen-binding domains, designed using different technologies and in various formats. BsAb-based tumor immunotherapy has yielded optimistic results in preclinical and clinical investigations of many tumor types, including urological cancers. However, a series of challenges, including tumor heterogeneity, TME, Ab immunogenicity, adverse effects, serum half-life, low response rates, and drug resistance, hamper the application of BsAbs. In this review, we provide insights into the most common BsAb platforms with different mechanisms of action, which are under preclinical and clinical research, along with ways to overcome the challenges in BsAb administration for treating urological cancer.
Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated cell growth. Genetic mutations can determine tumor onset by either augmenting cell division rates or restraining normal controls such as cell cycle arrest or apoptosis. As a result, tumor cells not only undergo uncontrolled cell division but also become compromised in their ability to exit the cell cycle accurately. Regulation of cell cycle progression is enabled by specific surveillance mechanisms known as cell cycle checkpoints, and aberrations in these signaling pathways often culminate in cancer. For instance, DNA damage checkpoints, which preclude the generation and augmentation of DNA damage in the G1, S, and G2 cell cycle phases, are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Notably, tumors have evolved to become dependent on checkpoints for their survival. For example, checkpoint pathways such as the DNA replication stress checkpoint and the mitotic checkpoint rarely undergo mutations and remain intact because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation leading to cell death. In this review, we initially focus on cell cycle control pathways and specific functions of checkpoint signaling involved in normal and cancer cells and then proceed to examine how cell cycle control and checkpoint mechanisms can provide new therapeutic windows that can be exploited for cancer therapy.
Significance Statement: DNA damage checkpoints are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Conversely, DNA replication stress and mitotic checkpoints rarely undergo mutations because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation, leading to cancer cell death. This review focuses on the checkpoint signaling mechanisms involved in cancer cells and how an emerging understanding of these pathways can provide new therapeutic opportunities for cancer therapy.
Vascular endothelial growth factor (VEGF) is overexpressed in nasopharyngeal carcinoma and suppresses the anti-tumour immune response. Previous studies have shown that adding anti-VEGF treatment to PD-1 inhibition treatment strategies improves tumour response. We aimed to compare the efficacy of pembrolizumab, a PD-1 inhibitor, with or without bevacizumab, a VEGF inhibitor, in nasopharyngeal carcinoma.
Methods
In this randomised, open-label, phase 2 trial done at two hospitals (National University Cancer Institute and Tan Tock Seng Hospital) in Singapore, patients with platinum-resistant recurrent or metastatic nasophayngeal carcinoma were eligible if they were aged 21 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Patients were assigned (1:1; using random permuted blocks with varying sizes of 4 and 6) to receive either intravenous pembrolizumab (200 mg) every 21 days or a combination of pembrolizumab with intravenous bevacizumab (7·5 mg/kg) administered 1 week prior to each dose, until radiographic disease progression, unacceptable toxicity, completion of 32 cycles, or withdrawal of consent. The study was open label, therefore no masking of treatment assignment was implemented. The primary endpoint was objective response rate, assessed using RECIST (version 1.1) by independent radiologists and analysed in the intention-to-treat population (ie, all randomly assigned patients). This trial is registered with ClinicalTrials.gov, NCT03813394, and enrolment has closed.
Findings
Between May 13, 2019, and Dec 6, 2023, we assessed 60 individuals for eligibility, 12 were excluded, and 48 were randomly allocated to pembrolizumab alone (n=24) or a combination of bevacizumab and pembrolizumab (n=24). The median age was 56 years (IQR 48–65), and 40 (83%) of 48 patients were male and eight (17%) were female. The median follow-up was 28·3 months (IQR 15·1–55·9). The objective response rate was significantly higher in the bevacizumab and pembrolizumab group (58·3% [95% CI 36·6–77·9] than in the pembrolizumab group (12·5% [2·7–32·4]; unadjusted RR 4·67 [95% CI 1·54–14·18]; p=0·0010). Grade 3 treatment-related adverse events occurred in two (8%) of 24 patients in the pembrolizumab group and in seven (29%) of 24 patients in the bevacizumab and pembrolizumab group; the most common severe or grade 3–4 treatment-related adverse events were thrombosis or bleeding (four [17%] of 24 patients in the bevacizumab and pembrolizumab group vs none of 24 patients in the pembrolizumab group), and others were transaminitis (none vs 1 [4%]), colitis (1 [4%] vs none]), cytopenias (none vs 1 [4%]), dermatological toxicities (1 [4%] vs none]), hypertension (1 [4%] vs none]), and proteinuria (1 [4%] vs none]). There were no grade 4 treatment-related adverse events or treatment-related deaths in either group.
Interpretation
Pembrolizumab in combination with bevacizumab was more efficacious than pembrolizumab monotherapy, with manageable toxicities in platinum-resistant nasopharyngeal carcinoma. If validated in a phase 3 trial, the combination therapy could be a new standard of care in this population of patients.
INTRODUCTION: Using an Asian cohort with high prevalence of concomitant cerebrovascular disease (CeVD), we evaluated the performance of a plasma immunoassay for tau phosphorylated at threonine 217 (p-tau217) in detecting amyloid beta positivity (Aβ+) on positron emission tomography and cognitive decline, based on a three-range reference, which stratified patients into low-, intermediate-, and high-risk groups for Aβ+.
METHODS: Brain amyloid status (Aβ– [n = 142] vs Aβ+ [n = 73]) on amyloid PET scans was assessed along with the plasma ALZpath p-tau217 assay to derive three-range reference points for PET Aβ+ based on 90% sensitivity (lower threshold) and 90% specificity (upper threshold).
RESULTS: Plasma p-tau217 (area under the curve [AUC] = 0.923) outperformed routine clinical assessments (AUC=0.760–0.819; p≤0.003) and other plasma biomarkers (AUC = 0.817–0.834; p < 0.001). The high-risk group showed significantly higher rates of cognitive decline than the low-risk group.
DISCUSSION: Risk stratification for PET Aβ+ based on a plasma p-tau217 assay demonstrated potential diagnostic and prognostic utility in an Asian cohort with concomitant CeVD.
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME’s contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME’s contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME’s implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.
Interleukin-6 (IL-6) is a pro-inflammatory cytokine playing a pivotal role during inflammation and immune responses. In the recent years, the function of IL-6 in the tumor microenvironment (TME) for affecting tumorigenesis and immunotherapy response has been investigated. The genetic mutations are mainly responsible for the development of cancer, while interactions in TME are also important, involving both cancers and non-cancerous cells. IL-6 plays a significant role in these interactions, enhancing the proliferation, survival and metastasis of tumor cells through inflammatory pathways, highlighting its carcinogenic function. Multiple immune cells including macrophages, T cells, myeloid-derived suppressor cells, dendritic cells and natural killer cells can be affected by IL-6 to develop immunosuppressive TME. IL-6 can also participate in the immune evasion through increasing levels of PD-L1, compromising the efficacy of therapeutics. Notably, IL-6 exerts a double-edge sword function and it can dually increase or decrease cancer immunotherapy, providing a challenge for targeting this cytokine in cancer therapy. Highlighting the complicated function of IL-6 in TME can lead to the development of effective therapeutics for cancer immunity.
Introduction: Collagen is essential for maintaining lung structure and function and its remodeling has been associated with respiratory diseases including chronic obstructive pulmonary disease (COPD). However, the cellular mechanisms driving collagen remodeling and the functional implications of this process in the pathophysiology of pulmonary diseases remain poorly understood.
Methods: To address this question, we employed Lyve1wt/cre; Csf1rflox/flox mice with specific depletion of Lyve-1+ macrophages and assessed the content, types and organization of collagen in lung compartments at steady state and after chronic exposure to cigarette smoke (CS).
Results: Using this mouse model, we found that the absence of this subpopulation of tissue resident macrophage led to the deposition of type I collagen fibers around the alveoli and bronchi at steady state. Further analysis by polarized light microscopy and Sircol collagen assay revealed that the collagen fibers accumulating in the lungs depleted of Lyve-1+ macrophages were thicker and crosslinked. A decrease in MMP-9 gene expression and proteolytic activity together with an increase in Col1a1, Timp-3 and Lox expression accompanied the collagen alterations. Next, we investigated the effect of the collagen remodeling on the pathophysiology of COPD and airway function in mice lacking Lyve-1+ macrophages exposed chronically to cigarette smoke (CS), a well-established animal model of COPD. We found that deposition of collagen prior CS exposure protected these mice against destruction of alveoli (emphysema), and bronchi thickening and prevented loss of airway function.
Discussion: Thus, we uncover that interstitial Lyve-1+ macrophages regulate the composition, amount, and architecture of collagen network in the lungs at steady state and that such collagen remodeling functionally impacts the development of COPD. This study further supports the potential of targeting collagen as promising approaches to treat respiratory diseases.
The increasing prevalence of chronic diseases and their associated morbidities demands a deeper understanding of underlying mechanism and causative factors, with the hope of developing novel therapeutic strategies. Autophagy, a conserved biological process, involves the degradation of damaged organelles or protein aggregates to maintain cellular homeostasis. Disruption of this crucial process leads to increased genomic instability, accumulation of reactive oxygen species (ROS), decreased mitochondrial functions, and suppression of ubiquitination, leading to overall decline in quality of intracellular components. Such deregulation has been implicated in a wide range of pathological conditions such as cancer, cardiovascular, inflammatory, and neurological disorders. This review explores the role of long non-coding RNAs (lncRNAs) as modulators of transcriptional and post-transcriptional gene expression, regulating diverse physiological process like proliferation, development, immunity, and metabolism. Moreover, lncRNAs are known to sequester autophagy related microRNAs by functioning as competing endogenous RNAs (ceRNAs), thereby regulating this vital process. In the present review, we delineate the multitiered regulation of lncRNAs in the autophagic dysfunction of various pathological diseases. Moreover, by highlighting recent findings on the modulation of lncRNAs in different stages of autophagy, and the emerging clinical landscape that recognizes lncRNAs in disease diagnosis and therapy, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in clinical settings of different stages of autophagic process by regulating ATG and its target genes. This focus on lncRNAs could lead to breakthroughs in personalized medicine, offering new avenues for diagnosis and treatment of complex diseases.
The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer (TNBC). Recent research indicates the aberrant expression of diverse tyrosine kinases (TKs) within this cancer, contributing significantly to tumor cell proliferation, survival, invasion, and migration. The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies, given their pivotal roles in tumor initiation, progression, and advancement. Intensive investigations have focused on various monoclonal antibodies (mAbs) and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), cellular mesenchymal-epithelial transition factor (c-MET), human epidermal growth factor receptor 2 (HER2), among others, for combating TNBC. These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents. Despite these advances, a substantial terrain of unexplored potential lies within the realm of TK targeted therapeutics, which hold promise in reshaping the therapeutic landscape. This review summarizes the various TK targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC, dissecting the outcomes and revelations stemming from diverse clinical investigations. A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBCs for the maximum efficiency of TK targeted therapeutics, either as standalone treatments or a combination. Moreover, our observation highlights that the outcomes of TK targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort, emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.
This review summarizes findings presented at the 19th World Congress of Basic & Clinical Pharmacology 2023 (Glasgow, Scotland, July 3rd to 7th, 2023) from 8 speakers in the field of resolution of inflammation, resolution pharmacology and resolution biology. It is now accepted that the acute inflammatory response is protective to defend the host against infection or tissue injury. Acute inflammation is self-limited and programmed to be lim-ited in space and time: this is achieved through endogenous resolution processes that ensure return to homeo-stasis. Resolution is brought about by agonist mediators that include specialized pro-resolving lipid mediators (SPMs) and pro-resolving proteins and peptides such as annexin A1 and angiotensin-(1–7), all acting to initiate anti-inflammatory and pro-resolving processes. If the inflammatory reaction remains unchecked through dys-functional resolution mechanism, it can become chronic and contribute to a plethora of human diseases, includ-ing respiratory, cardiovascular, metabolic, allergic diseases, and arthritis. Herein, we discuss how non-resolving inflammation plays a role in the pathogenesis of these diseases. In addition to SPMs, we highlight the discovery, biosynthesis, biofunctions, and latest research updates on innovative therapeutics (including annexin-A1 peptide-mimetic RTP-026, small molecule FPR2 agonist BM-986235/LAR-1219, biased agonist for FPR1/FPR2 Cmpd17b, lipoxin mimetics AT-01-KG and AT-02-CT, melanocortin receptor agonist AP1189, gold nanoparticles, angiotensin-(1–7), and CD300a) that can promote resolution of inflammation directly or through modulation of SPMs production. Drug development strategies based on the biology of the resolution of inflammation can offer novel therapeutic means and/or add-on therapies for the treatment of chronic diseases.
