Combination Cancer Therapy Research Articles

Engineering PD-L1 targeted liposomal canagliflozin achieves multimodal synergistic cancer therapy

Immunotherapy-involved combination cancer therapy heralds an unstoppable revolution in clinical practice. However, designing a streamlined approach to integrate immunotherapy with other therapies remains a formidable challenge. Canagliflozin, a clinical drug for type II diabetes, has gained growing interest in cancer therapy, albeit its precise mechanism remains largely elusive. Here, we delve into the multifaceted antitumor mechanisms of canagliflozin, including co-suppression of MAPK/ERK and PI3K/AKT signaling pathways, induction of PD-L1 degradation via ubiquitination and sensitization to X-ray irradiation via downregulation of DNA damage repair-related molecules, thereby offering opportunities for synergistic cancer treatment. For this purpose, we designed a universal nanoliposome coated with a PD-L1-targeting peptide to efficiently deliver canagliflozin in vivo. This simple fabricated nanodrug exhibited specific tumor-targeting ability and excellent biosafety. In vivo anti-cancer efficacy evaluation revealed synergistic pathway-targeted therapy from canagliflozin and immunotherapy facilitated by both canagliflozin and peptide. Furthermore, the introduction of radiotherapy further augmented the overall treatment performance. This study will revisit the diverse anti-tumor mechanisms of canagliflozin and its potential in cancer therapy, greatly expanding its clinical indication. In addition, the targeted delivery system of canagliflozin developed in this study will achieve multimodal synergistic cancer therapy, providing solutions to challenges in clinical cancer treatment and beyond.

Exploring the Molecular Mechanisms of Herbs in the Treatment of Hyperlipidemia Based on Network Pharmacology and Molecular Docking.

Many herbs have been shown to safely and successfully treat hyperlipidemia. However, the molecular mechanisms underlying their treatment remain unclear. In this study, 103 prescriptions for the treatment of hyperlipidemia containing 146 herbs were screened. Cluster analyses identified a core prescription comprising five herbs, namely, Crataegus pinnatifida (Shan Zha), Cassiae semen (Jue Ming Zi), Alisma orientale (Sam.) Juz. (Ze Xie), Salvia miltiorrhiza (Dan Shen), and Radix Polygoni Multiflori (He Shou Wu), in combination for the treatment of hyperlipidemia. Next, 9, 62, 5, 132, and 34 potential targets for each of the core herbs and a total of 512 hyperlipidemia-related protein targets were detected. Finally, 40 targets shared by core herbs and hyperlipidemia were identified. IL6, AKT1, IL1B, PTGS2, VEGFA, PPARG, and NOS3 were the seven proteins that were found to be most important in the treatment of hyperlipidemia. Interestingly, the Kyoto Encyclopedia of Genes and Genomes pathway indicated that these targets were mainly enriched in the lipid and atherosclerosis pathway and the cancer pathway. In addition, core target proteins such as AKT1, PTGS2, and PPARG have been demonstrated to play critical roles in hyperlipidemia and pancreatic cancer. Significant affinity between bioactive chemicals and proteins involved in cancer pathways was found by molecular docking. Molecular docking results showed that AKT1, PTGS2, and PPARG exhibited good binding ability with three bioactive chemicals, including 3-beta-hydroxymethyllenetanshiquinone, danshexinkum d, and physciondiglucoside. The treatment of hyperlipidemia by herbs may be mediated through the modulation of proteins associated with the cancer pathway. This study helps to provide a theoretical basis for future combined therapy for hyperlipidemia and cancer. [Figure: see text].

In Vivo Self-Sorting of Peptides via In Situ Assembly Evolution.

Despite significant progress achieved in artificial self-sorting in solution, operating self-sorting in the body remains a considerable challenge. Here, we report an in vivo self-sorting peptide system via an in situ assembly evolution for combined cancer therapy. The peptide E3C16-SS-EIY consists of two disulfide-connected segments, E3C16SH and SHEIY, capable of independent assembly into twisted or flat nanoribbons. While E3C16-SS-EIY assembles into nanorods, exposure to glutathione (GSH) leads to the conversion of the peptide into E3C16SH and SHEIY, thus promoting in situ evolution from the nanorods into self-sorted nanoribbons. Furthermore, incorporation of two ligand moieties targeting antiapoptotic protein XIAP and organellar endoplasmic reticulum (ER) into the self-sorted nanoribbons allows for simultaneous inhibition of XIAP and accumulation surrounding ER. This leads to the cytotoxicity toward the cancer cells with elevated GSH levels, through activating caspase-dependent apoptosis and inducing ER dysfunction. In vivo self-sorting of E3C16-SS-EIY decorated with ligand moieties is thoroughly validated by tissue studies. Tumor-bearing mouse experiments confirm the therapeutic efficacy of the self-sorted assemblies for inhibiting tumor growth, with excellent biosafety. Our findings demonstrate an efficient approach to develop in vivo self-sorting systems and thereby facilitating in situ formulation of biomedical agents.

A fractional-order model for optimizing combination therapy in heterogeneous lung cancer: integrating immunotherapy and targeted therapy to minimize side effects

This research presents a novel approach to address the complexities of heterogeneous lung cancer dynamics through the development of a Fractional-Order Model. Focusing on the optimization of combination therapy, the model integrates immunotherapy and targeted therapy with the specific aim of minimizing side effects. Notably, our approach incorporates a clever fusion of Proportional-Integral-Derivative (PID) feedback controls alongside the optimization process. Unlike previous studies, our model incorporates essential equations accounting for the interaction between regular and mutated cancer cells, delineates the dynamics between immune cells and mutated cancer cells, enhances immune cell cytotoxic activity, and elucidates the influence of genetic mutations on the spread of cancer cells. This refined model offers a comprehensive understanding of lung cancer progression, providing a valuable tool for the development of personalized and effective treatment strategies. the findings underscore the potential of the optimized treatment strategy in achieving key therapeutic goals, including primary tumor control, metastasis limitation, immune response enhancement, and controlled genetic mutations. The dynamic and adaptive nature of the treatment approach, coupled with economic considerations and memory effects, positions the research at the forefront of advancing precision and personalized cancer therapeutics.

Supramolecular antibody-drug conjugates for combined antibody therapy and photothermal therapy targeting HER2-positive cancers

Antibody therapy of anti-HER2 monoclonal antibody (mAb) has been an important strategy in treating HER2-positive cancers. However, the efficacy is restricted by many factors, including the level of HER2 expressed by tumor cells and antibody resistance. To overcome these and boost the efficacy, a novel nanoparticle (NP) was constructed in this study for combined antibody therapy of antibody and photothermal therapy (PTT). This novel NP was assembled from 1-pyrenecarboxylic acid (PCA) functionalized anti-HER2 mAb and indocyanine green (ICG), a photothermal transduction agents (PTA), by non-covalent interactions, which was named as Anti-HER2 mAb-pyrene-indocyanine green (H-P-I). Notably, the constructed H-P-I NP not only maintained the affinity and cytotoxicity of anti-HER2 mAb, but also exhibited high photothermal conversion efficiency mediated by ICG. Both in vitro and in vivo assessments confirmed that compared with monotherapy of antibody or ICG, H-P-I demonstrated preferable efficacy in treating HER2-positive cancers. Further biochemistry analysis and pathological analysis ensured the biosafety of H-P-I administration. Taked together, this study proposes a feasible method for constructing tumor-targeted nano PTA based on anti-HER2 mAb through supramolecular self-assembly strategy, achieving synergistic antibody photothermal anticancer treatment, which has the potential to be a promising candidate for combination therapy of HER2-positive cancers.

Enhancing cancer immunotherapy and antiangiogenic therapy by regulating gut microbes: Opportunities and challenges

AbstractAs the largest microecosystem in the human body, gut microbes (GMs) and their metabolites play an important role in regulating human health. In recent years, immune checkpoint therapy (ICT) combined with antiangiogenic agents is an emerging combination therapy for cancer. There is growing evidence that GMs can affect the effectiveness of drugs to treat cancer. GMs not only regulate angiogenesis in the tumor microenvironment, but also influence the efficacy of immune checkpoint inhibitors. Many studies show that Bifidobacterium can upregulate the anticancer function of immune checkpoint blockers. In addition, GMs have been found to be involved in the formation of blood vessels and other developmental processes. Clinically, GMs are believed to play a key role in patients receiving antiangiogenic therapy and ICT. In this perspective, we provide an overview of the composition and function of the gut microbiome, and discuss the role of the GMs against the conditioning of angiogenic therapy and ICT. We also summarize new approaches and clinical translational trials using GMs for cancer therapy, and present opportunities and challenges for targeting GMs for cancer therapy in the future.

Mathematical Modeling of Tumor Immune Interactions: The Role of Anti-FGFR and Anti-PD-1 in the Combination Therapy.

Bladder cancer poses a significant global health burden with high incidence and recurrence rates. This study addresses the therapeutic challenges in advanced bladder cancer, focusing on the competitive mechanisms of ligand or drug binding to receptors. We developed a refined mathematical model that integrates the dynamics of tumor cells and immune responses, particularly targeting fibroblast growth factor receptor 3 (FGFR3) and immune checkpoint inhibitors (ICIs). This study contributes to understanding combination therapies by elucidating the competitive binding dynamics and quantifying the synergistic effects. The findings highlight the importance of personalized immunotherapeutic strategies, considering factors such as drug dosage, dosing schedules, and patient-specific parameters. Our model further reveals that ligand-independent activated-state receptors are the most essential drivers of tumor proliferation. Moreover, we found that PD-L1 expression rate was more important than PD-1 in driving the dynamic evolution of tumor and immune cells. The proposed mathematical model provides a comprehensive framework for unraveling the complexities of combination therapies in advanced bladder cancer. As research progresses, this multidisciplinary approach contributes valuable insights toward optimizing therapeutic strategies and advancing cancer treatment paradigms.

Efficacy and safety of camrelizumab, apatinib, and capecitabine combination therapy in advanced biliary tract cancer: a phase 2, nonrandomized, prospective study.

Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. In this phase 2, nonrandomized,prospective study, eligible patients received camrelizumab (200mg, d1, Q3W), apatinib (250mg, qd, d1-d21, Q3W), and capecitabine (1000mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in thefirst-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in thefirst-line setting. NCT04720131.

Advances in Light-Responsive Smart Multifunctional Nanofibers: Implications for Targeted Drug Delivery and Cancer Therapy.

Over the last decade, scientists have shifted their focus to the development of smart carriers for the delivery of chemotherapeutics in order to overcome the problems associated with traditional chemotherapy, such as poor aqueous solubility and bioavailability, low selectivity and targeting specificity, off-target drug side effects, and damage to surrounding healthy tissues. Nanofiber-based drug delivery systems have recently emerged as a promising drug delivery system in cancer therapy owing to their unique structural and functional properties, including tunable interconnected porosity, a high surface-to-volume ratio associated with high entrapment efficiency and drug loading capacity, and high mass transport properties, which allow for controlled and targeted drug delivery. In addition, they are biocompatible, biodegradable, and capable of surface functionalization, allowing for target-specific delivery and drug release. One of the most common fiber production methods is electrospinning, even though the relatively two-dimensional (2D) tightly packed fiber structures and low production rates have limited its performance. Forcespinning is an alternative spinning technology that generates high-throughput, continuous polymeric nanofibers with 3D structures. Unlike electrospinning, forcespinning generates fibers by centrifugal forces rather than electrostatic forces, resulting in significantly higher fiber production. The functionalization of nanocarriers on nanofibers can result in smart nanofibers with anticancer capabilities that can be activated by external stimuli, such as light. This review addresses current trends and potential applications of light-responsive and dual-stimuli-responsive electro- and forcespun smart nanofibers in cancer therapy, with a particular emphasis on functionalizing nanofiber surfaces and developing nano-in-nanofiber emerging delivery systems for dual-controlled drug release and high-precision tumor targeting. In addition, the progress and prospective diagnostic and therapeutic applications of light-responsive and dual-stimuli-responsive smart nanofibers are discussed in the context of combination cancer therapy.

Cisplatin Encapsulated Plasmonic Blackbodies for NIR Light Activatable Chemo-Phototherapy and Reduction of 4-Nitrophenol.

Cisplatin (CDDP) is an FDA-approved chemotherapeutic drug used for treating various solid tumors. Despite of its effectiveness towards chemotherapy, it faces several challenges, such as multi-drug resistance (MDR) and significant damage to the normal tissues. To address these challenges, various nanoformulations were developed to improve the delivery and safety of CDDP. One of the limitation in these CDDP loaded nanoformulations is that the effective CDDP loading concentrations are very poor. Therefore, this leaves a grand challenge to develop an effective strategy to carry higher concentrations of CDDP molecules, and also simultaneously exhibit very unique properties. Herein, we have developed an one-pot synthesis of Cisplatin encapsulated Plasmonic blackbody (CiP), which offers a double play for near infrared (NIR) light activatable chemo-photothermal therapy in destructing cancer cells as well as mediate catalytic reduction of 4-nitrophenol (4-NP). The CiP nanoformulation exhibits superior light absorbing capabilities in the NIR region with an appreciable photothermal conversion efficiency of 41 %. Further, NIR light activatable combinatorial therapeutic approach of CiP was demonstrated against ovarian cancer cells and as a catalyst for the reduction of model pollutant 4-nitrophenol. Our findings highlight the potential of CiP as a versatile platform for light-activated combinatorial cancer therapy and environmental pollutant remediation.

Exploring the potential of cryptochlorogenic acid as a dietary adjuvant for multi-target combined lung cancer treatment

BackgroundLung cancer is a highly malignant disease with limited treatment options and significant adverse effects. It is urgent to develop novel treatment strategies for lung cancer. In recent years, TMEM16A has been confirmed as a specific drug target for lung cancer. The development of TMEM16A-targeting drugs and combined administration for the treatment of lung cancer has become a research hotspot. MethodsFluorescence screening and electrophysiological experiments were conducted to confirm the inhibitory effect of CCA on TMEM16A. Molecular dynamics simulation and site-directed mutagenesis were employed to analyze the binding mode of CCA and TMEM16A. CCK-8, colony formation, wound healing, transwell, and annexin-V experiments were conducted to explore the regulatory effects and mechanisms of CCA on the proliferation, migration, and apoptosis of lung cancer cells. Tumor model mice and pharmacokinetic experiments were used to examine the efficacy and safety of CCA and cisplatin in vivo. ResultsThis study firstly confirmed that CCA effectively inhibits TMEM16A to exert anticancer effects and analyzed the pharmacological mechanism. CCA bound to S517/N546/E623/E633/Q637 of TMEM16A through hydrogen bonding and electrostatic interactions. It inhibited the proliferation and migration, and induced apoptosis of lung cancer cells by targeting TMEM16A. In addition, the combined administration of CCA and cisplatin exhibited a synergistic effect, enhancing the efficacy of lung cancer treatment while reducing side effects. ConclusionCCA is an effective novel inhibitor of TMEM16A, and it synergizes with cisplatin in anticancer treatment. These findings will provide new research ideas and lead compound for the combination therapy of lung cancer.

Naphthalene Diimide-Based Polycyclic Conjugated Molecule Composite CoFe2O4 Nanohybrids for Photoacoustic Imaging-Mediated Photo-/Sonic Therapy.

The complex and harsh tumor microenvironment imped the efficacy of single-modality tumor therapy. With the advantages of biosafety, organic/inorganic nanohybrids have attracted more and more interest of researchers, and it is critical to investigate the development of highly efficient nanohybrids for multimodality combination therapy of cancers. Herein, a naphthalene diimide-based polycyclic conjugated molecule (NDI-S) is designed and synthesized, which has broader light absorption in the near infrared (NIR) region, outstanding photothermal conversion ability, and excellent photostability. Inorganic CoFe2O4 is synthesized via a solvothermal technique, which can produce much more reactive oxygen species (ROS) as a sonosensitizer when activated by ultrasonic (US). NDI-S and CoFe2O4 are then nanoprecipitated to create the organic/inorganic nanohybrids, NDI-S@CoFe2O4. According to the results of in vitro and in vivo experiments, NDI-S@CoFe2O4 can serve as a multifunctional nanoplatform for multimodal treatment of tumors in combination with photothermal/photodynamic/sonodynamic- therapy under the guidance of photoacoustic imaging, which provides a new vision of the development of organic/inorganic nanohybrids for cancer theranostics.

Nanoparticles Based on Polydopamine and Honokiol for Combination Therapy of Colorectal Cancer

Nanoparticles Based on Polydopamine and Honokiol for Combination Therapy of Colorectal Cancer

Rational Design of Targeted Gold Nanoclusters with High Affinity to Integrin αvβ3 for Combination Cancer Therapy.

The unique attributes of targeted nano-drug delivery systems (TNDDSs) over conventional cancer therapies in suppressing off-target effects make them one of the most promising options for cancer treatment. There is evidence that the density of surface-conjugated ligands is a crucial factor in achieving the desired therapeutic efficacy of TNDDSs, but this is hardly manageable in conventional nanomaterials. In this context, ligand-protected gold nanoclusters (AuNCs) are excellent candidates for developing new TNDDSs with a unique control on their surface functionalities, thus helping to achieve enhanced delivery performance. Here, we study the interactions and binding free energies between ten different functionalized Au144(SR)60 (SR = thiolate ligand) nanoclusters and integrin αvβ3 using molecular dynamics simulations and the umbrella sampling method to obtain the optimal formulations. The AuNCs were functionalized with anticancer drugs (5-fluorouracil or signaling pathways inhibitors, such as capivasertib, linifanib, tanespimycin, and taselisib) and integrin-targeting peptides (RGD4C or QS13), and we identified the optimal mixed ligand layer to enhance their binding affinity to the cancer cell receptor. The results showed that changing the proportions of the same type of ligands on the surface of AuNCs led to differences of up to 38 kcal/mol in computed binding free energies. RGD4C as the targeting peptide resulted in greater affinity for αvβ3, and in most formulations studied, a higher amount of drug than peptide was needed. Polar and charged residues, such as Ser123, Asp150, Tyr178, Arg214, and Asp251 were found to play a significant role in AuNC binding. Our simulations also revealed that Mn2+ cations are crucial for stabilizing the αvβ3-AuNC complex. These findings demonstrate the potential of carefully designing the surface composition of TNDDSs to optimize their target affinity and specificity.

Survival of patients with lymph node versusbone versus visceral metastases according to CHAARTED/LATITUDE criteria in the era of intensified combination therapies for metastatic hormone-sensitive prostate cancer.

The first approvals of novel systemic therapies within recent years for metastatic hormone-sensitive (mHSPC) were mainly based on improved overall survival (OS) and time to castration resistance (ttCRPC) in mHSPC patients stratified according to CHAARTED low (LV) versus high volume (HV) and LATITUDE low (LR) versus high-risk (HR) disease. Relying on our institutional tertiary-care database we identified all mHSPC stratified according to CHAARTED LV versus HV, LATITUDE LR versus HR and the location of the metastatic spread (lymph nodes (M1a) versus bone (M1b) versus visceral/others (M1c) metastases. OS and ttCRPC analyses, as well as Cox regression models were performed according to different metastatic categories. Of 451 mHSPC, 14% versus 27% versus 48% versus 12% were classified as M1a LV versus M1b LV versus M1b HV versus M1c HV with significant differences in median OS: 95 versus 64 versus 50 versus 46 months (p < 0.001). In multivariable Cox regression models HV M1b (Hazard Ratio: 2.4, p = 0.03) and HV M1c (Hazard Ratio: 3.3, p < 0.01) harbored significant worse than M1a LV mHSPC. After stratification according to LATITUDE criteria, also significant differences between M1a LR versus M1b LR versus M1b HR versus M1c HR mHSPC patients were observed (p < 0.01) with M1b HR (Hazard Ratio: 2.7, p = 0.03) and M1c HR (Hazard Ratio: 3.5, p < 0.01), as predictor for worse OS. In comparison between HV M1b and HV M1c, as well as HR M1b versus HR M1c no differences in ttCRPC or OS were observed. Significant differences exist between different metastatic patterns of HV and LV and HR and LR criteria. Best prognosis is observed within M1a LV and LR mHSPC patients.

All-in-One Alkaline Phosphatase-Response Aggregation-Induced Emission Probe for Cancer Discriminative Imaging and Combinational Chemodynamic-Photodynamic Therapy.

Currently, specific cancer-responsive fluorogenic probes with activatable imaging and therapeutic functionalities are in great demand in the accurate diagnostics and efficient therapy of malignancies. Herein, an all-in-one strategy is presented to realize fluorescence (FL) imaging-guided and synergetic chemodynamic-photodynamic cancer therapy by using a multifunctional alkaline phosphatase (ALP)-response aggregation-induced emission (AIE) probe, TPE-APP. By responding to the abnormal expression levels of an ALP biomarker in cancer cells, the phosphate groups on the AIE probe are selectively hydrolyzed, accompanied by in situ formation of strong emissive AIE aggregates for discriminative cancer cell imaging over normal cells and highly active quinone methide species with robust chemodynamic-photodynamic activities. Consequently, the activated AIE probes can efficiently destroy cancer cell membranes and lead to the death of cancer cells within 30 min. A superior efficacy in cancer cell ablation is demonstrated in vitro and in vivo. The cancer-associated biomarker response-derived discriminative FL imaging and synergistic chemodynamic-photodynamic therapy are expected to provide a promising avenue for precise image-guided cancer therapy.

Combination therapy for advanced urothelial cancer: LEAP-011 trial.

Combination therapy for advanced urothelial cancer: LEAP-011 trial.

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.

Contemporary Treatment Patterns and Oncological Outcomes of Metastatic Hormone-sensitive Prostate Cancer and First- to Sixth- line Metastatic Castration-resistant Prostate Cancer Patients

Background and objectiveWith approval of novel systemic therapies within the past decade for metastatic hormone-sensitive (mHSPC) and castration-resistant (mCRPC) prostate cancer, patients may receive several therapy lines. However, the use of these treatments is under an ongoing change. We investigated contemporary treatment trends and progression-free (PFS) and overall (OS) survival of different therapy lines. MethodsRelying on our institutional tertiary-care database, we identified mHSPC and mCRPC patients. The main outcome consisted of treatment changes (estimated annual percentage change [EAPC]) within the past decade, as well as PFS and OS for different mHSPC and mCRPC treatment lines. Key findings and limitationsIn 1098 metastatic patients, the median age was 70 yr with a median of two systemic therapy lines. For first-line mCRPC between 2013 and 2023, androgen deprivation monotherapy (ADT) monotherapy usage decreased significantly from 31% to 0% (EAPC −38.3%, p < 0.001), while the administration of chemotherapy increased from 16.7% to 33.3% (EAPC: +10.1%, p < 0.001). The PFS/OS rates of mHSPC patients was 21/67 mo, and those for first-, second-, third-, fourth-, fifth-, and sixth-line mCRPC patients were 11/47, eight of 30, seven of 24, six of 19, seven of 17, and seven of 13 mo, respectively. With an increased number of new combination therapy lines received, the median OS in mCRPC improved from 26 mo (one systemic treatment) to 52 mo (two or more lines of systemic treatment). Conclusions and clinical implicationsSignificant changes in treatment patterns could be observed for mHSPC and mCRPC patients within the past decade, and usage of ADT monotherapy has decreased rapidly in real-world practice. Moreover, PFS decreases significantly with every therapy line, and OS increases with the implementation of new therapies. Patient summaryImprovements in the real-world setting regarding the usage of combination therapies for metastatic hormone-sensitive and castration-resistant prostate cancer were made, which is reflected in contemporary survival outcomes.

Efficacy of Cisplatin-CXCR4 Antagonist Combination Therapy in Oral Cancer.

Cisplatin is a platinum-based compound that is widely used for treating inoperable oral squamous cell carcinoma (OSCC) in Japan; however, resistance to cisplatin presents a challenge and innovative approaches are required. We aimed to investigate the therapeutic potential of targeting the chemokine receptor CXCR4, which is involved in angiogenesis and tumor progression, using the CXCR4 inhibitor AMD3100, in combination with cisplatin. AMD3100 induced necrosis and bleeding in OSCC xenografts by inhibiting angiogenesis. We investigated the combined ability of AMD3100 plus cisplatin to enhance the antitumor effect in cisplatin-resistant OSCC. An MTS assay identified HSC-2 cells as cisplatin-resistant cells in vitro. Mice treated with the cisplatin-AMD combination exhibited the most significant reduction in tumor volume, accompanied by extensive hemorrhage and necrosis. Histological examination indicated thin and short tumor vessels in the AMD and cisplatin-AMD groups. These results indicated that cisplatin and AMD3100 had synergistic antitumor effects, highlighting their potential for vascular therapy of refractory OSCC. Antitumor vascular therapy using cisplatin combined with a CXCR4 inhibitor provides a novel strategy for addressing cisplatin-resistant OSCC.