Therapeutic Combinations Research Articles

Real-world efficacy and safety of combined first-line treatment with PARP inhibitors and novel hormonal therapy in mCRPC patients with HRR gene mutations

ObjectiveThis study evaluated the real-world efficacy and safety of combining PARP inhibitors with novel hormonal therapy (NHT) as a first-line treatment in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations.MethodsWe enrolled 41 mCRPC patients who received at least 1 month of combined treatment with PARP inhibitors and NHT. Patients were divided into two groups: Cohort A (mutations in BRCA1, BRCA2, or ATM genes) and Cohort B (mutations in other HRR genes). The primary endpoint was imaging-based progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), overall survival (OS), PSA50 response, and adverse events (AEs). To ensure accurate research results and control confounding factors, we will employ multivariate Cox proportional hazards models to evaluate key variables affecting mCRPC patient survival outcomes.ResultsThis study enrolled 41 patients, 22 in Cohort A and 19 in Cohort B. The median PFS for all patients was 21.8 months, and the median OS had yet to be reached. The overall ORR was 48.8%, and the DCR was 61.0%. Specifically, the median PFS for Cohort A was 21.8 months compared to 14.5 months for Cohort B. The median OS had yet to be reached for either cohort. Regarding efficacy, 81.8% of patients in Cohort A and 73.7% in Cohort B achieved a PSA50 response. Imaging assessments showed ORRs of 54.6% for Cohort A and 42.1% for Cohort B, with DCRs of 72.7% and 47.4%, respectively. 85.4% of patients experienced grade 1 or 2 adverse events, and 51.2% encountered grade 3 or 4. In the multivariate Cox regression analysis focusing on PFS, the Gleason score was identified as a significant predictor (HR = 5.8, 95% CI: 1.65–20.2, p = 0.006).ConclusionCombined first-line treatment with PARP inhibitors and NHT is effective and well-tolerated in mCRPC patients with HRR gene mutations, particularly those with BRCA1, BRCA2, or ATM mutations. These findings underscore the potential of this therapeutic combination in managing mCRPC in the Chinese population, suggesting a favorable outcome for those with specific genetic backgrounds.

Updates in novel immunotherapeutic strategies for relapsed/refractory AML

Acute myeloid leukemia (AML) is a severe hematological malignancy with poor outcomes, particularly in older adults. Traditional treatment options like high-dose chemotherapy often lead to refractory or relapsed AML, with even worse outcomes. New therapies for relapsed and refractory AML are needed, and this review explores the most recent advancements in immunotherapy in AML. Checkpoint Inhibitors utilizing innate or adaptive immune targeting have shown potential to improve AML outcomes when combined with hypomethylating agents and chemotherapy. The use of adoptive cell therapy in AML demonstrates promising early data, however, there is a need for better target selection. Although early in development, both vaccine therapy as well as stimulator of interferon genes (STING) agonists have potential to enhance the innate immune response to overcome AML’s immune evasion. Immunotherapy has become a promising approach for AML treatment, especially in refractory and relapsed AML, especially in patients who are not eligible for allogeneic stem cell transplants. Future research should focus on a deeper understanding of the immune microenvironment to identify the most critical targets for optimization, as well as personalized therapeutic combination strategies. Here we present a comprehensive overview of the recent developments in immunotherapy for relapsed and refractory AML.

Helen Lavretsky: Translational neuroscience of integrative medicine

Professor Helen Lavretsky, a pioneering force in geriatric psychiatry and integrative medicine at the University of California, Los Angeles (UCLA)'s Departments of Psychiatry and Biobehavioral Sciences, has fundamentally reshaped our understanding of brain health and aging. Her groundbreaking research connecting mind-body interventions with neurobiological mechanisms has transformed skepticism into scientific acceptance, establishing new paradigms in mental health care. As director of research for the UCLA's Integrative Medicine Collaborative and Late-life Mood, Stress and Wellness Research Program, she has led seminal studies on novel therapeutic combinations for treatment-resistant depression and cognitive disorders. Her work, recognized by “triple crown” honors from major psychiatric associations in 2020, spans from innovative psychopharmacology to pioneering investigations in yoga and Tai Chi for mental health. A dedicated mentor who has championed women and underrepresented minorities in science for over 25 years, Professor Lavretsky currently serves as President of the American Association for Geriatric Psychiatry (2022–25), and she is on the Advisory Research Council to the National Center of Complementary and Integrative Medicine. In her engaging Genomic Press Interview, Professor Lavretsky shares insights from her remarkable journey from a young medical student to becoming a leading voice in integrative psychiatry, offering a compelling glimpse into the future of personalized mental health care.

Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH).

Metabolic dysfunction-associated steatotic liver disease (MASLD)and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.

Targeting chromatin modifying complexes in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a devastating hematologic malignancy with high rates of relapse, which can, in part, be attributed to the dysregulation of chromatin modifications. These epigenetic modifications can affect the capacity of hematopoietic cells to self-renew or differentiate, which can lead to transformation. Aberrant histone modifications contribute to the derepression of self-renewal genes such as HOXA/B and MEIS1 in committed hematopoietic progenitors, which is considered a key mechanism of leukemogenesis in MLL-rearranged (MLL-r) and NPM1-mutated AML. As regulators of some of the key histone modifications in this disease, the menin-KMT2A and polycomb repressive (PRC1/2) complexes have been identified as promising targets for the treatment of AML. This review explores recent discoveries of how leukemic cells hijack these complexes and their interactions with other chromatin regulators to promote disease progression. We also discuss inhibitors targeting these complexes that have demonstrated therapeutic efficacy in preclinical and clinical studies and propose novel therapeutic combinations targeting the KMT2A and PRC1/2 broader interacting networks to overcome issues of resistance to existing monotherapies.

Neuroimmune-competent human brain organoid model of Diffuse Midline Glioma.

Pediatric high-grade gliomas, such as diffuse midline glioma (DMG), have a poor prognosis and lack curative treatments. Current research models of DMG primarily rely on human DMG cell lines cultured in vitro or xenografted into the brains of immunodeficient mice. However, these models are insufficient to recapitulate the complex cell-cell interactions between DMG and the tumor immune microenvironment (TIME), therefore fall short of accurately reflecting how efficacious therapeutic agents or combinations will be in the clinical setting. To address these challenges, we developed a neuroimmune-competent brain/tumor fusion organoid model system consisting entirely of human cells to investigate the interactions between DMG cells and the primary innate immune cells of the brain, microglia, in the TIME at both cellular and subcellular levels. We generated microglia-containing brain organoids (MiCBO) that carry morphologically mature, motile microglia and multiple subtypes of neurons to mimic the brain tumor microenvironment. These organoids were then fused with H3K27M mutant, TP53P27R/K132R DMG tumor spheroids to create the MiCBO-tumor fusion (MiCBO-TF) model. We utilized live imaging methods to simultaneously track the mobility of microglial cell bodies and the motility of their process, as well as the behavior of tumor cells within a human brain tissue environment. Our MiCBO-TF model faithfully recapitulated the diffuse infiltration pattern of DMG into brain tissue and revealed that microglial mobility and interactions with tumor cells are highly influenced by external factors and surrounding tissue environment. The MiCBO-TF model represents a powerful platform for both mechanistic investigations and the development of precision medicine approaches for DMG.

Drugs in Development to Manage Acute Pain.

Acute pain, defined as short-term pain arising from injury or other noxious stimuli, affects patient outcomes, quality of life, and healthcare costs. Safe, effective treatment of acute pain is essential in preventing increased morbidity, mortality, and the transition to chronic pain. In this review, we explore some of the latest therapeutic agents, formulations, combinations, and administration routes of drugs emerging in clinical practice in the USA for the treatment of acute pain. These agents include VX-548 (Suzetrigine), Cebranopadol, AAT-076, Combogesic intravenous (IV), sublingual ketamine, XG004 (naproxen/pregabalin conjugate), and HTX-011 (Zynrelef). We analyze the pharmacodynamics, pharmacokinetics, development status, and clinical implications of these drugs, emphasizing the importance of finding an agent that provides both a strong safety profile and effective relief from acute pain. Our findings show promise but also highlight the need for further large-scale research to allow these drugs to be utilized in a clinical context for patients experiencing acute pain.

In vitro and patient studies with platelets to explore off-target cardiovascular effects of integrase inhibitors.

People with HIV currently face a tenfold higher risk of developing cardiovascular disease (CVD) than those without HIV. Studies have shown various off-target effects of antiretroviral treatment (ART) on the cardiovascular system, but little is known about the effects of currently used integrase strand transfer inhibitors (INSTIs) on platelets. Platelet activation is associated with increased CVD, thrombus formation, and release of proinflammatory mediators, so exploring platelet effects from currently prescribed ART may contribute to the understanding of CVD etiopathogenesis in people with HIV. We aimed to identify potential effects of INSTIs on platelet aggregation and activation markers from individuals without HIV after in vitro treatment with clinically relevant drug concentrations. We used bictegravir (BIC) and dolutegravir (DTG) individually or in the therapeutic drug combinations BIC/emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) or DTG/lamivudine (3TC). Additionally, we conducted a pilot study to compare platelet activity profiles from people with HIV on BIC/FTC/TAF and DTG/3TC. Changes to in vitro platelet aggregation responses upon exposure to different INSTIs were observed both upon individual drug application and when using therapeutic combinations. However, these effects were not reflected in flow-cytometric evaluation of platelet degranulation. A pilot study in eight people with HIV and eight without HIV revealed no significant effects but established protocols for future patient studies. There is currently no consistent evidence of an effect of INSTIs on platelet activation. Further study is warranted, focusing on models with more pathophysiological relevance, including extensive studies in people with HIV.

Macrocycle-based self-assembled amphiphiles for co-delivery of therapeutic combinations to tumor

For tumor treatment, the efficiency of single chemotherapeutic agent is generally limited and the traditional combination chemotherapies frequently result in the aggravation of side effects. Herein, an amphiphilic pillararene-based self-assembled nanoparticle (APSN) composed of hydrazide-pillar[5]arene (HP5A-6C) that achieve effective co-delivery of therapeutic combinations was reported. Through integrating multitudinous macrocyclic cavities into a single nanoparticle, the APSN could co-load two antitumor drugs, cisplatin (CP) and nitrogen mustard (NM) via host-guest interactions. A serious of safety tests preliminary demonstrated that blank carrier APSN had good biocompatibility. Cytotoxicity assay verified that co-delivery system CP+NM@APSN could exert a synergistic antitumor effect at the cellular level. In vivo studies demonstrated that CP+NM@APSN could not only improve chemotherapeutic outcomes in tumor-bearing model mouse but also alleviate two medications-related side effects. These favorable findings were attributed to the formation of ternary supramolecular assembly that benefited from an enhanced permeability and retention effect. © 2024 Elsevier Science. All rights reserved

Genetic Characterization of Multidrug-Resistant Acinetobacter baumannii and Synergy Assessment of Antimicrobial Combinations.

Background/Objectives: A. baumannii is a prominent nosocomial pathogen due to its drug-resistant phenotype, representing a public health problem. In this study, the aim was to determine the effect of different antimicrobial combinations against selected multidrug-resistant (MDR) or extensive drug-resistant (XDR) isolates of A. baumannii. Methods: MDR or XDR A. baumannii isolates were characterized by assessing genes associated with drug resistance, efflux pumps, porin expression, and biofilm formation. The activities of antimicrobial combinations including tigecycline, ampicillin/sulbactam, meropenem, levofloxacin, and colistin were evaluated using checkerboard and time-to-kill assays on isolates with different susceptibility profiles and genetic characteristics. Results: Genetic characterization of MDR/XDR strains (n = 100) included analysis of OXA-24/40 gene carbapenemase (98%), genes encoding aminoglycoside-modifying enzymes (44%), and parC gene mutations (10%). AdeIJK, AdeABC, and AdeFGH efflux pumps were overexpressed in 17-34% of isolates. Omp33-36, OmpA, and CarO membrane porins were under-expressed in 50-76% of isolates; CarO was overexpressed in 22% of isolates. Isolates showed low biofilm production (11%). Synergistic activity was observed with levofloxacin-ampicillin/sulbactam and meropenem-colistin, which were able to inhibit bacterial growth. Conclusions: Genetic characteristics of A. baumannii were highly variable among the strains. Synergistic activity was observed with meropenem-colistin and levofloxacin-ampicillin/sulbactam combinations in the checkerboard method, but not in the time-to-kill assays. These discrepancies among both methods indicate that further studies are needed to determine the best therapeutic combination for treating infections by A. baumannii.

EXTH-09. GENE MODIFICATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS FOR IMPROVEMENT OF IMMUNOTHERAPIES FOR MALIGNANT GLIOMAS

Abstract Patients living with high-grade gliomas have a poor survival prognosis. Furthermore, standard of care treatment for these malignant gliomas has not significantly improved in the past decades. Our laboratory previously demonstrated that the combination of two different immunotherapies with HSPCs provided a significant survival benefit in preclinical brain tumor models, however, this therapeutic combination is still not 100% curative. We hypothesized that gene modification of HSPCs could add additional therapeutic benefit to immunotherapies for the treatment of resistant gliomas. Hematopoietic stem and progenitor cells (HSPCs) have been widely used in different clinical settings due to their ability to self-renew and differentiate into all immune cell lineages. In recent years, HSPCs have been the target of a variety of gene editing research efforts to decipher the most effective method for gene modification to use for therapeutic purposes. After comparison with previously established methods, we optimized a protocol for the successful editing of murine HSPCs and human CD34+ cells. Using Cas9 mRNA and sgRNAs in HSPCs, we achieved up to 80% reduction in gene expression. This method is superior to others due to its efficient, quick, inexpensive, and reliable nature. We also showed that, by knocking-down IL-6R in HSPCs, we can drive their differentiation into dendritic cells, while decreasing MDSCs and macrophages. Furthermore, gene-modified HSPCs are also capable of bone marrow reconstitution of lethally irradiated mice. Currently, we are testing whether the combination of gene-modified HSPCs with immunotherapy provides additional survival benefit to unmodified HSPCs with immunotherapy in a resistant murine glioma model.

DDEL-16. MICROMESH FOR REVAMPING THE ‘COLD’ TUMOR MICROENVIRONMENT IN GLIOBLASTOMA IMMUNOTHERAPY

Abstract High-grade gliomas have poor prognoses with limited treatment options, typically maximal safe resection and adjuvant radiochemotherapy. Novel therapies often face challenges due to low brain penetrance and poor bioavailability. To address these issues, a conformable, compartmentalized polymeric implant called microMESH has been developed. microMESH provides localized, sustained release of drugs, small inhibitors, antibodies, and nanomedicines, enabling novel therapeutic combinations. When applied to the tumor margins, microMESH adheres to the tissue, releasing its therapeutic cargo over weeks and reducing systemic toxicity. Its biocompatibility, cytotoxicity, and anti-tumor efficacy were tested on murine cancer cells (CT-2A) and orthotopic glioblastoma syngeneic models. Exposing primary bone marrow-derived monocytes (BMDM) to CT-2A conditioned medium increased the expression of anti-inflammatory cytokines (IL-10 and IL-4) by 2 times without significantly affecting the pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), indicating that CT-2A cells tend to establish an immunosuppressive ‘cold’ tumor microenvironment. Next, the co-incubation of CT-2A cells with BMDM followed by the administration of the immune checkpoint inhibitor aCD47 resulted in a cancer cell viability drop by 50% already at 50 μg/ml aCD47 after 1 day. Additionally, pre-treatment with docetaxel (DTXL) further decreased cell viability, suggesting a synergism between aCD47 and the chemotherapeutic drug. Flow cytometry showed that 50 nM DTXL at 3 days post-incubation was responsible for a strong translocation of the ‘immunogenic dell death’ protein calreticulin on the cell membrane, potentially explaining the synergism. Over 2 months, the intracranially deployed microMESH biodegraded without inducing any toxic effect. In orthotopic CT-2A tumors, aCD47/DTXL–microMESH (0.75 mg/kg, single intracranial application) showed a 40-day survival compared to 22 days for iv DTXL (3 mg/kg qod), 24 days for ip aCD47 (5 mg/kg qod), and 18 days for untreated mice. microMESH helped identify and enabled novel combination therapies directly at the tumor bed, demonstrating superior efficacy over systemic therapies.

CTNI-43. MULTI-CENTER PHASE I STUDY OF CONCURRENT PAXALISIB AND RADIATION THERAPY (RT) IN PATIENTS WITH SOLID TUMOR BRAIN METASTASES (BM) OR LEPTOMENINGEAL METASTASES (LM) HARBORING PI3K PATHWAY ALTERATIONS

Abstract INTRODUCTION Partial or whole brain RT is a standard treatment for solid tumor BM and LM. However, tumors harboring PI3K pathway mutations have poorer CNS control after RT alone. Combining RT with paxalisib, a CNS-penetrant PI3K/mTOR inhibitor, may overcome radioresistance. METHODS This multi-center, phase I trial (NCT04192981) studied concurrent paxalisib with cranial RT (30Gy in 10 fractions) for PI3K pathway-altered BM/LM. Part A was a 3 + 3 dose escalation cohort of paxalisib at 45, 60 or 75mg to establish maximum tolerated dose (MTD). Part B was an expansion at MTD to further validate safety and early efficacy. CNS response was assessed using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. RESULTS From 3/2020-2/2024, 21 patients (median age 58y, n=18 with BM, n=10 with breast cancer) were enrolled. PIK3CA mutations were the most common pathway alteration (n=15, 71%) followed by PTEN deletion (n=3, 14%). Part A enrolled 12 patients of which 9 were evaluable (3 did not complete protocol therapy). There were no dose-limiting toxicities (DLTs) at 45mg, and 2 DLTs at 60mg: grade 3 nausea and grade 4 neutropenic enterocolitis. Subsequently, 9 additional patients were enrolled during Part B at MTD of 45mg, of which 1 withdrew consent prior to completion of study interventions. No additional DLTs were observed during Part B. In total, there were 14 evaluable patients who received 45mg/day paxalisib concurrently with RT, two of whom died of intercurrent extracranial progression prior to CNS restaging. Of the remaining 12, there was robust response signal. At 1-month post-treatment, 6/12 (50%) had partial response (PR) and the remaining had stable disease (SD). To date, best CNS response is 67% PR (8/12) and 33% SD (4/12). CONCLUSIONS A MTD of 45 mg/day has been confirmed for paxalisib with concurrent brain RT for PI3K pathway-altered BM/LM. Given significant unmet need, this novel therapeutic combination warrants further investigation given promising activity signal.

Preclinical Activity of RAS(ON) Multi-Selective Inhibitor RMC-7977 and Therapeutic Combinations in AML with Signaling Mutations

Preclinical Activity of RAS(ON) Multi-Selective Inhibitor RMC-7977 and Therapeutic Combinations in AML with Signaling Mutations

Antifungal Associations with a Polyelectrolyte Promote Significant Reduction of Minimum Inhibitory Concentrations against Opportunistic Candida spp. Strains.

The current global scenario presents us with a growing increase in infections caused by fungi, referred to by specialists in the field as a "silent epidemic", aggravated by the limited pharmacological arsenal and increasing resistance to this therapy. For this reason, drug repositioning and therapeutic compound combinations are promising strategies to mitigate this serious problem. In this context, this study investigates the antifungal activity of the non-toxic, low-cost and widely available cationic polyelectrolyte Poly(diallyldimethylammonium chloride) (PDDA), in combination with different antifungal drugs: systemic (amphotericin B, AMB), topical (clioquinol, CLIO) and oral (nitroxoline, NTX). For each combination, different drug:PDDA ratios were tested and, through the broth microdilution technique, the minimum inhibitory concentration (MIC) of these drugs in the different ratios against clinically important Candida species strains was determined. Overall, PDDA combinations with the studied drugs demonstrated a significant increase in drug activity against most strains, reaching MIC reductions of up to 512 fold for the fluconazole resistant Candida krusei (Pichia kudriavzevii). In particular, the AMB-PDDA combination 1:99 was highly effective against AMB-resistant strains, demonstrating the excellent profile of PDDA as an adjuvant/association in novel antifungal formulations with outdated conventional drugs.

The present and future of the Cancer Dependency Map.

Despite tremendous progress in the past decade, the complex and heterogeneous nature of cancer complicates efforts to identify new therapies and therapeutic combinations that achieve durable responses in most patients. Further advances in cancer therapy will rely, in part, on the development of targeted therapeutics matched with the genetic and molecular characteristics of cancer. The Cancer Dependency Map (DepMap) is a large-scale data repository and research platform, aiming to systematically reveal the landscape of cancer vulnerabilities in thousands of genetically and molecularly annotated cancer models. DepMap is used routinely by cancer researchers and translational scientists and has facilitated the identification of several novel and selective therapeutic strategies for multiple cancer types that are being tested in the clinic. However, it is also clear that the current version of DepMap is not yet comprehensive. In this Perspective, we review (1) the impact and current uses of DepMap, (2) the opportunities to enhance DepMap to overcome its current limitations, and (3) the ongoing efforts to further improve and expand DepMap.

A Comprehensive Pan-Cancer Analysis of the Mitochondrial Uncoupling Protein UCP2, with a Focus on Sex and Gender-Related Aspects.

Mitochondrial uncoupling protein 2 (UCP2) plays a crucial role in regulating oxidative stress and cellular metabolism, positioning it as an important subject in oncological research. The involvement of UCP2 in cancer is complex and context-dependent, suggesting it as a potential therapeutic target. In this study, we aimed to perform a comprehensive pan-cancer analysis of UCP2, with a particular focus on gender-related malignancies such as breast (BRCA), prostate (PRAD), ovarian (OV), and testicular tumors (TGCT). We analyzed UCP2 expression in The Cancer Genome Atlas (TCGA), examining correlations with prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), immune cell infiltration, immune checkpoint genes, genes involved in steroidogenesis, sex hormone receptor genes, and drug sensitivity. Significant variability in UCP2 expression was observed across cancer types. UCP2 levels were elevated in BRCA and OV but reduced in PRAD and TGCT. High UCP2 expression was associated with a better prognosis in OV and poorer overall survival in PRAD. Furthermore, UCP2 correlated with TMB and MSI in OV, TGCT, and BRCA. UCP2 expression was also linked to immune cell infiltration, immune checkpoint genes, steroidogenic genes, and sex hormone receptor genes, with variable effects depending on cancer type and gender. Additionally, UCP2 also demonstrated sensitivity to specific anticancer drugs. Our findings highlight the interplay between UCP2, immune and hormonal pathways, and drug responseand reveal potential opportunities for new therapeutic combinations, especially in gender-related cancers.

High-resolution subtyping of fibroblasts in gastric cancer reveals diversity among fibroblast subsets and an association between the MFAP5-fibroblast subset and immunotherapy.

Gastric cancer (GC) remains a global health threat due to frequent treatment failures caused by primary or acquired resistance. Although cancer-associated fibroblasts (CAFs) have been implicated in this process, it is still unclear which specific subtype(s) of CAFs hinder T-cell infiltration and promote resistance to immunotherapy. We analyzed the GC fibroblast atlas in detail by combining 63,955 single cells from 14 scRNA-seq datasets. We also performed RNA-seq data in a local GC cohort and examined 13 bulk RNA-seq datasets to understand the biological and clinical roles of different CAF subsets. Additionally, we conducted in vitro experiments to study the role of specific proteins in GC development. We identified a total of 17 fibroblast subsets in gastric cancer, nine of which did not fit into the existing CAFs classification. These subsets exhibited significant heterogeneity in distribution and biological characteristics (metabolism, cell-cell interactions, differentiation state), as well as clinical functions such as prognosis and response to immunotherapy. In particular, cluster 6 stood out for its high expression of MFAP5, CFD, and PI16; it was found to be negatively associated with both overall survival and response to immunotherapy in GC. This association was linked to an immunosuppressive microenvironment characterized by an increase in M2 macrophages but higher levels of T cell dysfunction and exclusion-a feature shared by tumors expressing MFAP5. Furthermore, the addition of human recombinant MFAP5 promoted proliferation and migration of HGC-27 cells by inducing the MFAP5/NOTCH1/HEY1 signaling pathway. We introduce a high-resolution GC fibroblast atlas. The 17 identified fibroblast clusters provide valuable opportunities for gaining deeper biological insights into the relationship between fibroblasts and GC development. Particularly, cluster 6 and its specific marker MFAP5 could serve as prognostic factors in GC and form a foundation for personalized therapeutic combinations to address primary resistance to ICIs.

Analysis of methotrexate use practice in patients with rheumatoid arthritis and psoriatic arthritis

Background. Pharmacoepidemiological studies play a key role in optimizing pharmacotherapy for various diseases. In particular, significant progress in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) necessitates a detailed analysis of the consumption of disease-modifying antirheumatic drugs. The modern therapeutic concept for these conditions focuses on achieving and maintaining long-term remission, which positions methotrexate (MTX) as a first-line agent, characterized by high effectiveness, safety and advantageous pharmacoeconomic profiles.Objective: to investigate the characteristics of MTX use in real clinical practice among patients with RA and PsA during outpatient medical care.Material and methods. The study comprised two parts: a retrospective cross-sectional analysis of MTX consumption dynamics in 2018, 2020, and 2023 via ATC/DDD (Anatomical Therapeutic Chemical classification, ATC; defined daily dose, DDD) methodology, and a longitudinal non-interventional pharmacoepidemiological study conducted in 2023 using the medical information system “BARS. Healthcare”.Results. The ATC/DDD analysis demonstrated a significant increase in MTX consumption among patients with RA and PsA: from 302,428.6 to 319,114.3 DDDs per 1,000 patients per year for RA, and from 28,157.1 to 310,771.6 DDDs per 1,000 patients per year for PsA in 2018 and 2023, respectively. The most frequently prescribed dose of MT was 15 mg/week. The primary therapeutic combination for 55.8% of patients was “MT + nonsteroidal anti-inflammatory drugs”, with 32.7% of patients also receiving glucocorticoids (GCs) as part of this combination. The study identified a high frequency of prescriptions for proton pump inhibitors, GCs, and cholecalciferol, highlighting the activity of diseases under consideration, potential complications, and the necessity for the prevention of clinically significant drug interactions.Conclusions. The conducted study confirmed that MTX remains the main drug for the treatment of RA and PsA. The ATC/DDD analysis demonstrated a significant increase in MTX consumption in recent years, correlating with its therapeutic effectiveness and accessibility. The high frequency of concomitant prescriptions underscores the complexity of treating RA and PsA and the need for an interdisciplinary approach to ensure safety and efficacy of the therapy.

Anti-MET Antibody Therapies in Non-Small-Cell Lung Cancer: Current Progress and Future Directions.

Background/Objectives: Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer mortality globally, though advances in targeted therapies have improved treatment outcomes. The mesenchymal-epithelial transition (MET) gene plays a significant role in NSCLC, often through protein overexpression, exon 14 skipping mutations, and gene amplification, many of which arise as resistance mechanisms to other oncogenic drivers like epidermal growth factor receptor (EGFR) mutations. This review examines the development and clinical efficacy of anti-MET antibody therapies. Methods: A comprehensive literature search was conducted using major medical databases looking at key relevant studies on anti-MET antibody studies. Both authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Amivantamab, a bispecific EGFR/MET antibody was approved to treat EGFR exon 20 insertion and now has recently been extended to target classical EGFR mutations with progression on osimertinib. Other important anti-MET targeted therapies in development include antibody drug conjugates such as telisotuzumab vedotin, REGN5093-M114, and AZD9592 and emibetuzumab, which is a humanized immunoglobulin G4 monoclonal bivalent MET antibody. Conclusions: MET plays a significant role in NSCLC and amivantamab along with other anti-MET targeted therapies play a role in directly targeting MET and addressing acquired resistance to oncogenic drivers. Future research should focus on developing novel MET antibody drugs and exploring new therapeutic combinations to enhance treatment efficacy and overcome resistance in NSCLC. Refining biomarker-driven approaches to ensure precise patient selection is also critical to optimizing treatment outcomes.