Combination Therapy Strategies Research Articles

Novel sodium tauroursodeoxycholate-based multifunctional liposomal delivery system for encapsulation of oleanolic acid and combination therapy of type 2 diabetes mellitus

Liposomes have demonstrated great potential for drug delivery and diabetes treatment. However, hydrolysis by enzymes and emulsification by endogenous bile salts make liposomes unstable in the gastrointestinal tract. In this study, sodium tauroursodeoxycholate (TUDCNa)-based multifunctional bilosomes were designed to address the deficiencies of conventional liposomes. In the designed bilosomes, cholesterol was replaced by TUDCNa, which served as both a membrane stabilizer and an antidiabetic drug. Oleanolic acid (OA) was encapsulated in both conventional liposomes (OA-Ch-Lip) and bilosomes (OA-Tu-Bil) to compare their properties. Firstly, OA-Tu-Bil exhibited similar encapsulation efficiency and drug loading compared to OA-Ch-Lip, but with a smaller particle size. Secondly, OA-Tu-Bil showed better stability than OA-Ch-Lip. Thirdly, bilosomes exhibited prolonged intestinal retention time and improved permeability and oral bioavailability. Fourthly, in type 2 diabetes mellitus (T2DM) mice model, TUDCNa synergized with OA to exhibit the strongest therapeutic effect. In conclusion, TUDCNa have demonstrated the ability to substitute cholesterol in conventional liposomes, it provided a new approach for oral delivery of hypoglycemic drugs, and offered an innovative strategy for combination therapy.

Abstract C032: De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer

Abstract Oncogenic KRAS, the genetic driver of 90% of PDAC, induces a metabolic rewiring characterized, in part, by dependency on de novo pyrimidine biosynthesis. Dihydroorotate dehydrogenase (DHODH) is the enzymatic ‘chokepoint’ of the de novo pyrimidine biosynthesis pathway and an in vivo metabolic liability in pancreatic ductal adenocarcinoma (PDAC). Targeting enzymes in the de novo pyrimidine synthesis pathway such as dihydroorotate dehydrogenase (DHODH) with clinically available inhibitor brequinar (BQ) starved the tumor of nucleotide synthesis and restrained growth of PDAC cells in vitro. However, therapeutic resistance limited BQ long-term effects in PDAC xenografts, which suggests compensatory pathways and that combinatorial strategies are required for enhanced efficacy. Here, we integrated a mass spectrometry (MS)-based quantitative temporal proteomics workflow, LC/MS- based metabolomics and in vitro and in vivo drug-anchored CRISPR/Cas9 genetic screens to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Combinatorial regimens with DHODH and BCL-XL inhibition synergistically induce apoptosis in PDAC cell lines and patient-derived PDAC organoids. In vivo DHODH inhibition with Brequinar and BCL-XL degradation with DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits the growth of PDAC tumors. Our data defines mechanisms of adaptation to DHODH inhibition and identifies a combination therapy strategy in PDAC. Citation Format: huan zhang, Qijia yu, Naiara Santana-Codina, Clara Poupault, Claudia Campos, Xingping Qin, Aparna Padhye, Nicole Sindoni, Miljan Kuljanin, Junning Wang, Matthew J. Dorman, Andrew J. Aguirre, Stephanie K. Dougan, Kristopher A. Sarosiek, Joseph D. Mancias. De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C032.

Modulating the Self-Assembly of a Camptothecin Prodrug with Paclitaxel for Anticancer Combination Therapy: A Molecular Dynamics Approach.

Camptothecin (CPT) and paclitaxel (PTX), derived from natural products, are recognized for their significant efficacy in clinical cancer treatments. Despite its therapeutic advantages, CPT is challenged by issues of toxicity and solubility, necessitating its use in conjugation with other compounds for enhanced compatibility. This study delves into the coassembly mechanism of Evans blue-conjugated camptothecin (EB-CPT) with PTX, aiming to elucidate their synergistic potential in combination therapy applications, employing all-atom molecular dynamics simulations. The EB-CPT prodrug is reported to form a self-aggregated cluster. Our findings suggest that increasing the PTX concentration induces a dispersion of EB-CPT clusters, thereby disrupting their inherent self-assembly. This disruption is explained to be facilitated by the coassembly of EB-CPT and PTX. With increasing concentration of PTX, a lengthening of the coassembled structures is observed, supporting the experimental findings of tube-like coassembled structures at higher weight ratios of PTX. Hydrophobic interactions and π-π stacking are the primary forces responsible for the formation of both self- and coassembled structures. Interestingly, the structural analysis reveals that the CPT moiety of EB-CPT is less involved in assemblies due to steric hindrances. Instead, the interaction and coassembly processes are predominantly mediated by the EB derivative component of the prodrug. This research underscores the critical role of the solubilizing agent, EB derivative, in mediating the flexibility and interaction of CPT in combination therapy strategies, particularly with PTX, thus emphasizing the importance of conjugates for therapeutic developments. Furthermore, the molecular insights into the interaction sites and mechanisms facilitating coassembly between EB-CPT and PTX contribute valuable knowledge to the field, highlighting the potential of these nanomedicine combinations in advancing cancer treatment modalities.

AC099850.3 promotes HBV-HCC cell proliferation and invasion through regulating CD276: a novel strategy for sorafenib and immune checkpoint combination therapy

BackgroundThis study investigates the molecular mechanisms of CC@AC&SF@PP NPs loaded with AC099850.3 siRNA and sorafenib (SF) for improving hepatitis B virus-related hepatocellular carcinoma (HBV-HCC).MethodsA dataset of 44 HBV-HCC patients and their survival information was selected from the TCGA database. Immune genes related to survival status were identified using the ImmPort database and WGCNA analysis. A prognostic risk model was constructed and analyzed using Lasso regression. Differential analysis was performed to screen key genes, and their significance and predictive accuracy for HBV-HCC were validated using Kaplan–Meier survival curves, ROC analysis, CIBERSORT analysis, and correlation analysis. The correlation between AC099850.3 and the gene expression matrix was calculated, followed by GO and KEGG enrichment analysis using AC099850.3 and its co-expressed genes. HepG2.2.15 cells were selected for in vitro validation, and lentivirus interference, cell cycle determination, CCK-8 experiments, colony formation assays, Transwell experiments, scratch experiments, and flow cytometry were performed to investigate the effects of key genes on HepG2.2.15 cells. A subcutaneous transplanted tumor model in mice was constructed to verify the inhibitory effect of key genes on HBV-HCC tumors. Subsequently, pH-triggered drug release NPs (CC@AC&SF@PP) were prepared, and their therapeutic effects on HBV-HCC in situ tumor mice were studied.ResultsA prognostic risk model (AC012313.9, MIR210HG, AC099850.3, AL645933.2, C6orf223, GDF10) was constructed through bioinformatics analysis, showing good sensitivity and specificity in diagnostic prediction. AC099850.3 was identified as a key gene, and enrichment analysis revealed its impact on cell cycle pathways. In vitro cell experiments demonstrated that AC099850.3 promotes HepG2.2.15 cell proliferation and invasion by regulating immune checkpoint CD276 expression and cell cycle progression. In vivo, subcutaneously transplanted tumor experiments showed that AC099850.3 promotes the growth of HBV-HCC tumors in nude mice. Furthermore, pH-triggered drug release NPs (CC@AC&SF@PP) loaded with AC099850.3 siRNA and SF were successfully prepared and delivered to the in situ HBV-HCC, enhancing the effectiveness of combined therapy for HBV-HCC.ConclusionsAC099850.3 accelerates the cell cycle progression and promotes the occurrence and development of HBV-HCC by upregulating immune checkpoint CD276 expression. CC@AC&SF@PP NPs loaded with AC099850.3 siRNA and SF improve the effectiveness of combined therapy for HBV-HCC.

Bionic aggregation-induced emission photosensitizer for enhanced cancer immunotherapy

Cold exposure therapy (CE), as an inexpensive method, has shown great potential in cancer therapy. Exploring the combined anti-tumor mechanism of CE and traditional therapies (such as photodynamic therapy (PDT)) is exciting and promising. Here, a bionic aggregation-induced emission photosensitizer system (named THL) is designed for combined CE to enhance anti-tumor immunotherapy. THL inherits the homologous targeting ability of tumor derived exosomes, promoting the enrichment of THL at the tumor site. Under external illumination, THL generates hydroxyl radicals and superoxide anions through type I PDT. In addition, mice are pretreated with cold exposure, which promotes THL mediated PDT and reactive oxygen species (ROS) generation by reducing the production of ATP and GSH in tumor tissue. This combination therapy increases production of ROS within the tumor, inhibits the growth of distant tumors, recurrent and rechallenged tumors and increases the number of cytotoxic CD8+T cells and memory T cells. Compared to PDT alone, combination therapy shows greater advantages in tumor immunotherapy. The combination therapy strategy provides new ideas for cancer immunotherapy.

Hyaluronic acid-coated porphyrin nanoplatform with oxygen sustained supplying and glutathione depletion for enhancing photodynamic/ion/chemo synergistic cancer treatment

Hypoxia and high concentration of glutathione (GSH) in tumor seriously hinder the role of reactive oxygen species (ROS) and oxygen-dependence strategy in tumor treatment. In this work, a self-generating oxygen and self-consuming GSH hyaluronic acid (HA)-coated porphyrin nanoplatform (TAPPP@CaO2/Pt(IV)/HA) is established for enhancing photodynamic/ion/chemo targeting synergistic therapy of tumor. During the efforts of ROS production by nanosystems, a GSH consuming strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. CaO2 in the nanosystems is decomposed into O2 and H2O2 in an acidic environment, which alleviates hypoxia and enhances the photodynamic therapy (PDT) effect. Calcium overload causes mitochondria dysfunction and induces apoptosis. Pt (IV) reacts with GSH to produce Pt (II) for chemotherapy and reduce the concentration of GSH, protecting ROS from scavenging for augmenting ROS-induced oxidative damage. In vitro and in vivo results demonstrated the self-generating oxygen and self-consuming GSH strategy can enhance ROS-dependent PDT coupled with ion/chemo synergistic therapy. The proposed strategy not only solves the long-term problem that hypoxia limits therapeutic effect of PDT, but also ameliorates the highly reducing environment of tumors. Thus the preparation of TAPPP@CaO2/Pt(IV)/HA provided a novel strategy for the effective combined therapy of cancers.

Nanodelivery Optimization of IDO1 Inhibitors in Tumor Immunotherapy: Challenges and Strategies.

Tryptophan (Trp) metabolism plays a vital role in cancer immunity. Indoleamine 2.3-dioxygenase 1 (IDO1), is a crucial enzyme in the metabolic pathway by which Trp is degraded to kynurenine (Kyn). IDO1-mediated Trp metabolites can inhibit tumor immunity and facilitate immune evasion by cancer cells; thus, targeting IDO1 is a potential tumor immunotherapy strategy. Recently, numerous IDO1 inhibitors have been introduced into clinical trials as immunotherapeutic agents for cancer treatment. However, drawbacks such as low oral bioavailability, slow onset of action, and high toxicity are associated with these drugs. With the continuous development of nanotechnology, medicine is gradually entering an era of precision healthcare. Nanodrugs carried by inorganic, lipid, and polymer nanoparticles (NPs) have shown great potential for tumor therapy, providing new ways to overcome tumor diversity and improve therapeutic efficacy. Compared to traditional drugs, nanomedicines offer numerous significant advantages, including a prolonged half-life, low toxicity, targeted delivery, and responsive release. Moreover, based on the physicochemical properties of these nanomaterials (eg, photothermal, ultrasonic response, and chemocatalytic properties), various combination therapeutic strategies have been developed to synergize the effects of IDO1 inhibitors and enhance their anticancer efficacy. This review is an overview of the mechanism by which the Trp-IDO1-Kyn pathway acts in tumor immune escape. The classification of IDO1 inhibitors, their clinical applications, and barriers for translational development are discussed, the use of IDO1 inhibitor-based nanodrug delivery systems as combination therapy strategies is summarized, and the issues faced in their clinical application are elucidated. We expect that this review will provide guidance for the development of IDO1 inhibitor-based nanoparticle nanomedicines that can overcome the limitations of current treatments, improve the efficacy of cancer immunotherapy, and lead to new breakthroughs in the field of cancer immunotherapy.

Advances in Pediatric Obsessive-Compulsive Disorder (OCD) Treatment: A Comprehensive Narrative Review.

Obsessive-compulsive disorder (OCD), characterized by persistent, intrusive thoughts (obsessions) and repetitive behaviors or mental acts (compulsions), can significantly impact a child's daily functioning, academic performance, and overall quality of life. As the prevalence of pediatric OCD continues to rise, there is a critical demand for evidence-based treatments that not only alleviate symptoms but also enhance the quality of life for affected children and adolescents. By identifying gaps in knowledge and suggesting directions for future research, this narrative review contributes to the ongoing discourse on pediatric OCD treatments. Ultimately, the synthesis of evidence aims to enhance our understanding and inform best practices in the compassionate and effective management of OCD in children and adolescents.The aim of this study is to provide a comprehensive overview of current trends and emerging strategies in the treatment of pediatric obsessive-compulsive disorder (OCD) and highlights the significance of tailoring treatment approaches to individual patient needs, considering factors such as symptom severity and treatment response. Concentrating on interventions supported by empirical evidence, the review delves into cognitive-behavioral therapy (CBT), pharmacotherapy, the synergistic effects of these modalities, and inventive therapeutic approaches, all while considering the distinctive developmental aspects pertinent to pediatric populations.We conducted this review by searching for titles in the PubMed database from 2013 to present. Our comprehensive literature review focused on advancements in treating pediatric OCD, using keywords like "Obsessive-compulsive disorder," "Pediatric," "treatment," "CBT," "SSRI," "Pharmacotherapy," and "combination therapy." While both pharmacotherapy and CBT show individual efficacy, the combination of these approaches appears to be more effective, especially for medication non-responders with no prior exposure to CBT, despite some mixed findings. These findings contribute significantly to the ongoing discussion on optimizing combined therapy strategies tailored to the complexities of pediatric OCD.

Lefamulin Overcomes Acquired Drug Resistance via Regulating Mitochondrial Homeostasis by Targeting ILF3 in Hepatocellular Carcinoma.

Acquired resistance represents a critical clinical challenge to molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) treatment in hepatocellular carcinoma (HCC). Therefore, it is urgent to explore new mechanisms and therapeutics that can overcome or delay resistance. Here, a US Food and Drug Administration (FDA)-approved pleuromutilin antibiotic is identified that overcomes sorafenib resistance in HCC cell lines, cell line-derived xenograft (CDX) and hydrodynamic injection mouse models. It is demonstrated that lefamulin targets interleukin enhancer-binding factor 3 (ILF3) to increase the sorafenib susceptibility of HCC via impairing mitochondrial function. Mechanistically, lefamulin directly binds to the Alanine-99 site of ILF3 protein and interferes with acetyltransferase general control non-depressible 5 (GCN5) and CREB binding protein (CBP) mediated acetylation of Lysine-100 site, which disrupts the ILF3-mediated transcription of mitochondrial ribosomal protein L12 (MRPL12) and subsequent mitochondrial biogenesis. Clinical data further confirm that high ILF3 or MRPL12 expression is associated with poor survival and targeted therapy efficacy in HCC. Conclusively, this findings suggest that ILF3 is a potential therapeutic target for overcoming resistance to TKIs, and lefamulin may be a novel combination therapy strategy for HCC treatment with sorafenib and regorafenib.

SIRT7 knockdown promotes gemcitabine sensitivity of pancreatic cancer cell via upregulation of GLUT3 expression

Gemcitabine serves as a first-line chemotherapeutic treatment for pancreatic cancer (PC), but it is prone to rapid drug resistance. Increasing the sensitivity of PC to gemcitabine has long been a focus of research. Fasting interventions may augment the effects of chemotherapy and present new options. SIRT7 is known to link metabolism with various cellular processes through post-translational modifications. We found upregulation of SIRT7 in PC cells is associated with poor prognosis and gemcitabine resistance. Cross-analysis of RNA-seq and ATAC-seq data suggested that GLUT3 might be a downstream target gene of SIRT7. Subsequent investigations demonstrated that SIRT7 directly interacts with the enhancer region of GLUT3 to desuccinylate H3K122. Our group's another study revealed that GLUT3 can transport gemcitabine in breast cancer cells. Here, we found GLUT3 KD reduces the sensitivity of PC cells to gemcitabine, and SIRT7 KD-associated gemcitabine-sensitizing could be reversed by GLUT3 KD. While fasting mimicking induced upregulation of SIRT7 expression in PC cells, knocking down SIRT7 enhanced sensitivity to gemcitabine through upregulating GLUT3 expression. We further confirmed the effect of SIRT7 deficiency on the sensitivity of gemcitabine under fasting conditions using a mouse xenograft model. In summary, our study demonstrates that SIRT7 can regulate GLUT3 expression by binding to its enhancer and altering H3K122 succinylation levels, thus affecting gemcitabine sensitivity in PC cells. Additionally, combining SIRT7 knockdown with fasting may improve the efficacy of gemcitabine. This unveils a novel mechanism by which SIRT7 influences gemcitabine sensitivity in PC and offer innovative strategies for clinical combination therapy with gemcitabine.

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation.

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Redox-responsive hyaluronic acid-celastrol prodrug micelles with glycyrrhetinic acid co-delivery for tumor combination therapy

Combining cytotoxic drugs with tumor microenvironment (TME) modulator agents is an effective strategy to enhance anti-tumor effects. In this study, two natural anti-tumor active ingredients celastrol (CEL) and glycyrrhetinic acid (GA) were combined for tumor treatment. In order to ensure the precise co-delivery and controllable synchronous release of combined drugs to tumors, it is necessary to construct a suitable nano-drug delivery platform. Based on this, we coupled hyaluronic acid (HA) with CEL by amide reaction to obtain an amphiphilic polymer prodrug HA-SS-CEL, and GA was spontaneously loaded into polymer micelles by self-assembly to obtain G/HSSC-M. G/HSSC-M has ideal size distribution, redox-responsive synchronous drug release, enhanced tumor cell internalization and in vivo tumor targeting. Compared with free drugs, the construction of multifunctional polymer micelles makes G/HSSC-M show better anticancer effect at the same concentration, and can significantly inhibit the proliferation and migration of HepG2 and 4T1 cells. In the in vivo experiments, G/HSSC-M inhibited tumor as high as 75.12% in H22 tumor-bearing mice. The mechanism included regulation of M1/M2 macrophage polarization, inhibition of Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signaling pathway, and remodeling of tumor blood vessels. Therefore, the development of prodrug micelles co-loaded with CEL and GA provides a promising drug co-delivery strategy for combined cancer therapy.

The role of dysregulated metabolism and associated genes in gastric cancer initiation and development.

The review delves into the intricate interplay between metabolic dysregulation and the onset and progression of gastric cancer (GC), shedding light on a pivotal aspect of this prevalent malignancy. GC stands as one of the leading causes of cancer-related mortality worldwide, its trajectory influenced by a multitude of factors, among which metabolic dysregulation and aberrant gene expression play significant roles. The article navigates through the fundamental roles of metabolic dysregulation in the genesis of GC, unveiling phenomena such as aberrant glycolysis, epitomized by the Warburg effect, alongside anomalies in lipid and amino acid metabolism. It delineates how these disruptions fuel the cancerous process, facilitating uncontrolled cell proliferation and survival. Furthermore, the intricate nexus between metabolism and the vitality of GC cells is elucidated, underscoring the profound influence of metabolic reprogramming on tumor energy dynamics and the accrual of metabolic by-products, which further perpetuate malignant growth. A pivotal segment of the review entails an exploration of key metabolic-related genes implicated in GC pathogenesis. MYC and TP53 are spotlighted among others, delineating their pivotal roles in driving tumorigenesis through metabolic pathway modulation. These genetic pathways serve as critical nodes in the intricate network orchestrating GC development, providing valuable targets for therapeutic intervention. This review embarks on a forward-looking trajectory, delineating the potential therapeutic avenues stemming from insights into metabolic dysregulation in GC. It underscores the promise of targeted therapies directed towards specific metabolic pathways implicated in tumor progression, alongside the burgeoning potential of combination therapy strategies leveraging both metabolic and conventional anti-cancer modalities. In essence, this comprehensive review serves as a beacon, illuminating the intricate landscape of metabolic dysregulation in GC pathogenesis. Through its nuanced exploration of metabolic aberrations and their genetic underpinnings, it not only enriches our understanding of GC biology but also unveils novel therapeutic vistas poised to revolutionize its clinical management.

Dynamic modeling of the glucose–insulin system with inhibitors impulsive control

Pulse injection of insulin analogues is an important strategy to control glucose concentrations and can be combined with ‐glucosidase inhibitors to reduce adverse effects to improve glucose control. To elucidate this combination therapy strategy, we assumed dietary intake in the form of pulse glucose injection and proposed a novel mathematical model incorporating pulse injection insulin and ‐glucosidase inhibitors. In type 1 diabetes, the existence and uniqueness of the positive periodic solution is confirmed utilizing the Lambert W function. The global asymptotic stability of the positive periodic solution is achieved through the application of Floquet multiplier theory and the comparison principle. Furthermore, in type 2 diabetes, the permanence of the system is also confirmed through the comparison theorem. Numerical analysis validated the theoretical calculations, highlighting the significance of insulin injection dosage and frequency, as well as ‐glucosidase inhibitor therapy. Additionally, we systematically assessed a rational approach for diabetes treatment combined with ‐glucosidase inhibitors, providing more practical clinical strategies. This facilitates the extension of our model to encompass other drugs that may be utilized in future clinical interventions.

Clinical Exploration of Immunosuppressants Combined with Abiraterone in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is a malignant tumor with a high incidence in elderly men. In recent years, with the improvement of people’s living standards and the advancement of detection technology, the incidence of prostate cancer has been increasing year by year. Castration-resistant prostate cancer (CRPC) is a highly challenging type of advanced prostate cancer treatment, which clinically shows resistance to hormonal deprivation therapy. The overall treatment efficacy of CRPC is currently poor and further relevant therapeutic studies are needed to improve patient survival and quality of life. Immunosuppressants can play a role in combating the immune system of tumors, and abiraterone has also achieved remarkable results in prostate cancer treatment. This study will investigate the possible clinical effects and safety of immunosuppressants combined with abiraterone in the treatment of metastatic CRPC. The population-based study will provide clinicians with more effective treatment options, as well as enhance the understanding of novel combination therapy strategies to be implemented in the future for such patients.

Reactive oxygen species responsive chitooligosaccharides based nanoplatform for sonodynamic therapy in mammary cancer

Sonodynamic therapy (SDT) has been extensively studied as a new type of non-invasive treatment for mammary cancer. However, the poor water solubility and defective biocompatibility of sonosensitizers during SDT hinder the sonodynamic efficacy. Herein, a nanoplatform has been developed to achieve high efficient SDT against mammary cancer through the host-guest interaction of β-cyclodextrin/5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (β-CD-TPP) and ferrocenecarboxylic acid/chitooligosaccharides (FC-COS). Moreover, the glucose oxidase (GOx) was loaded through electrostatic adsorption, which efficiently restricts the energy supply in tumor tissues, thus enhancing the therapeutic efficacy of SDT for tumors. Under optimal conditions, the entire system exhibited favorable water solubility, suitable particle size and viable biocompatibility. This facilitated the integration of the characteristics of starvation therapy and sonodynamic therapy, resulting in efficient inhibition of tumor growth with minimal side effects in vivo. This work may provide new insights into the application of natural oligosaccharides for construct multifunctional nanocarrier systems, which could optimize the design and development of sonodynamic therapy strategies and even combination therapy strategies.

Efficacy and tolerability of initial triple combination therapy with metformin, dapagliflozin and saxagliptin compared with stepwise add-on therapy in drug-naïve patients with type 2 diabetes (TRIPLE-AXEL study): A multicentre, randomized, 104-week, open-label, active-controlled trial.

To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.

FADS2 confers SCD1 inhibition resistance to cancer cells by modulating the ER stress response

Stearoyl-CoA desaturase 1 (SCD1) is an attractive target for cancer therapy. However, the clinical efficacy of SCD1 inhibitor monotherapy is limited. There is thus a need to elucidate the mechanisms of resistance to SCD1 inhibition and develop new therapeutic strategies for combination therapy. In this study, we investigated the molecular mechanisms by which cancer cells acquire resistance to endoplasmic reticulum (ER) stress-dependent cancer cell death induced by SCD1 inhibition. SCD1 inhibitor-sensitive and -resistant cancer cells were treated with SCD1 inhibitors in vitro, and SCD1 inhibitor-sensitive cancer cells accumulated palmitic acid and underwent ER stress response-induced cell death. Conversely, SCD1-resistant cancer cells did not undergo ER stress response-induced cell death because fatty acid desaturase 2 (FADS2) eliminated the accumulation of palmitic acid. Furthermore, genetic depletion using siRNA showed that FADS2 is a key determinant of sensitivity/resistance of cancer cells to SCD1 inhibitor. A549 cells, an SCD1 inhibitor-resistant cancer cell line, underwent ER stress-dependent cancer cell death upon dual inhibition of SCD1 and FADS2. Thus, combination therapy with SCD1 inhibition and FADS2 inhibition is potentially a new cancer therapeutic strategy targeting fatty acid metabolism.