Synergetic Antitumor Effect Research Articles

Co-delivery of camptothecin and MiR-145 by lipid nanoparticles for MRI-visible targeted therapy of hepatocellular carcinoma

BackgroundCamptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity.MethodsLactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model.ResultsThe LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution.ConclusionsThe LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.

Versatile Thermo-Sensitive liposomes with HSP inhibition and Anti-Inflammation for synergistic Chemo-Photothermal to inhibit breast cancer metastasis

Photothermal therapy (PTT) is a prospective therapeutic method for breast cancer. However, excess inflammatory response induced by PTT may aggravate tumor metastasis. Meanwhile, the overexpressed heat shock proteins (HSPs) by cancer cells can protect them from hyperthermia during PTT. Therefore, to attenuate the PTT-induced inflammation and inhibit tumor metastasis, a folate receptor-targeted thermo-sensitive liposome (BI-FA-LP) co-loading Berberine (BBR) and Indocyanine green (ICG) was developed. BI-FA-LP utilized enhanced permeability and retention (EPR) effect and FA receptor-mediated endocytosis to selectively accumulate at tumor, reducing off-target toxicity during the treatment. After targeting to the tumor site, BBR and ICG were released from BI-FA-LP upon laser irradiation, and ICG showed good photothermal performance, while BBR inhibited HSP70 and HSP90 expression during PTT, exerting chemo-photothermal synergetic anti-tumor effect. Moreover, BBR could suppress the PTT induced inflammation, thus inhibiting tumor metastasis and ameliorating tissue injury. Thus, this versatile liposome provided a new strategy to enhance PTT and anti-inflammatory effects for breast cancer treatment.

Bacterial outer membrane vesicle-cancer cell hybrid membrane-coated nanoparticles for sonodynamic therapy in the treatment of breast cancer bone metastasis

Breast cancer bone metastasis is a terminal-stage disease and is typically treated with radiotherapy and chemotherapy, which causes severe side effects and limited effectiveness. To improve this, Sonodynamic therapy may be a more safe and effective approach in the future. Bacterial outer membrane vesicles (OMV) have excellent immune-regulating properties, including modulating macrophage polarization, promoting DC cell maturation, and enhancing anti-tumor effects. Combining OMV with Sonodynamic therapy can result in synergetic anti-tumor effects. Therefore, we constructed multifunctional nanoparticles for treating breast cancer bone metastasis. We fused breast cancer cell membranes and bacterial outer membrane vesicles to form a hybrid membrane (HM) and then encapsulated IR780-loaded PLGA with HM to produce the nanoparticles, IR780@PLGA@HM, which had tumor targeting, immune regulating, and Sonodynamic abilities. Experiments showed that the IR780@PLGA@HM nanoparticles had good biocompatibility, effectively targeted to 4T1 tumors, promoted macrophage type I polarization and DC cells activation, strengthened anti-tumor inflammatory factors expression, and presented the ability to effectively kill tumors both in vitro and in vivo, which showed a promising therapeutic effect on breast cancer bone metastasis. Therefore, the nanoparticles we constructed provided a new strategy for effectively treating breast cancer bone metastasis.Graphical

The cumulative antitumor effects of regorafenib and radiotherapy in hepatocellular carcinoma.

Regorafenib is a second-line standard treatment for hepatocellular carcinoma (HCC). However, the efficacy of regorafenib is often limited due to drug resistance, individual differences among patients, and irrational drug use. Radiotherapy (RT) is an important method of localized HCC treatment, and combining RT with other therapies may exert a synergetic antitumor effect. Platelet-derived growth factor receptor-like (PDGFRL) is a tumor suppressor in various solid tumors. However, the function of PDGFRL in HCC is still unknown. In this study, we explored whether regorafenib and RT exert a synergetic effect on the treatment of HCC.The antitumor effect and mechanisms of the combination of regorafenib and RT were verified in a xenograft mouse model in vivo and in HCC cells in vitro.The combination treatment significantly inhibited cell proliferation and promoted apoptosis both in vitro and in vivo.PDGFRL, a potential target of regorafenib, was increased after cumulative treatment in HCC cells, and PDGFRL suppressed HCC cell proliferation and promoted apoptosis by inhibiting STAT3 pathway activation. Furthermore, the cumulative antitumor effect was dependent on the upregulated expression of PDGFRL and inhibition of STAT3 signaling pathway activation in HCC cells.This study increased the understanding of the molecular mechanism underlying the effect of regorafenib plus RT on HCC and provided a theoretical basis for the clinical practice of HCC.

Improving cellular uptake and synergetic anti-tumor effects of magnolol and Brucea javanica oil through self-microemulsion

Objective Magnolol (MG) and Brucea javanica (L.) Merr. oil (BJO) possess synergetic anti-tumor effects, but have poor water solubility and stability, which results in low oral bioavailability. Significance The MG loaded self-microemulsion drug delivery system (MG-SMDDS) with BJO as oil phase component was utilized to improve the cellular uptake and synergetic anti-tumor effects. Methods Compatibility study and pseudoternary phase diagram (PTPD) were respectively employed to screen for the composition and proportion of oil phase in the formulation. Central composite design-effect surface method was applied to optimize proportion of each formulation condition. The droplet size, ζ-potential, colloid stability, encapsulation rate (ER) and in vitro dissolution rate of MG-SMDDS were evaluated. Furthermore, cellular uptake and cytotoxicity of the microemulsion on HepG2 cells were assessed. Results The optimal composition of MG-SMDDS was: MG (9.09%), castor oil (7.40%), BJO (2.47%), Cremophor EL 35 (54.04%) and 1, 2-propanediol (27.01%). The MG-SMDDS exhibited satisfactory droplet size, ζ-potential, colloid stability and ER, as well as faster dissolution rate than free MG. More importantly, SMEDDS containing BJO could enhance the cellular uptake and cytotoxicity of free BJO and free MG on tumor cells. Conclusions The BJO self-microemulsion delivery technique can provide an idea for design of oral delivery vehicles based on BJO.

Deformable Smart DNA Nanomachine for Synergistic Intracellular Cancer-Related miRNAs Imaging and Chemo-Gene Therapy of Drug-Resistant Tumors.

Diagnosis and treatment of tumor especially drug-resistant tumor remains a huge challenge, which requires intelligent nanomedicines with low toxic side effects and high efficacy. Herein, deformable smart DNA nanomachines are developed for synergistic intracellular cancer-related miRNAs imaging and chemo-gene therapy of drug-resistant tumors. The tetrahedral DNA framework (MA-TDNA) with fluorescence quenched component and five antennas is self-assembled first, and then DOX molecules are loaded on the MA-TDNAs followed by linking MUC1-aptamer and Mcl-1 siRNA to the antennas of MA-TDNA, so that the apt-MA-TDNA@DOX-siRNA (DNA nanomachines) is constructed. The DNA nanomachine can respond to two tumor-related miRNAs in vitro and in vivo, which can undergo intelligent miRNA-triggered opening of the framework, resulting in the "turn on" of the fluorescence for sensitively and specifically sensing intracellular miRNAs. Meanwhile, both miRNA-responded rapid release and pH-responded release of DOX are achieved for chemotherapy of tumor. In addition, the gene therapy of the DNA nanomachines is achieved due to the miRNA-specific capture and the RNase H triggered release of Mcl-1 siRNA. The DNA nanomachines intergrading both tumor imaging and chemo-gene therapy in single nanostructures realized efficient tumor-targeted, image-guided, and microenvironment-responsive tumor diagnosis and treatment, which provides a synergetic antitumor effect on drug-resistant tumor.

Sorafenib-Encapsulated Liposomes to Activate Hypoxia-Sensitive Tirapazamine for Synergistic Chemotherapy of Hepatocellular Carcinoma.

Combination therapy with the synergistic effect is an effective way in cancer chemotherapy. Herein, an antiangiogenic sorafenib (SOR) and hypoxia-activated prodrug tirapazamine (TPZ)-coencapsulated liposome (LipTPZ/SOR) is prepared for chemotherapy of hepatocellular carcinoma (HCC). SOR is a multi-target tyrosine kinase inhibitor that can inhibit tumor cell proliferation and angiogenesis. The antiangiogenesis effect of SOR can reduce oxygen supply and aggravate tumor hypoxia, which is able to activate hypoxia-sensitive prodrug TPZ, exhibiting the synergistic antitumor effect. LipTPZ/SOR at different molar ratios of TPZ and SOR can significantly inhibit the proliferation of hepatocellular carcinoma cells. The mole ratio of TPZ and SOR was optimized to 2:1, which exhibited the best synergetic antitumor effect. The synergistic antitumor mechanism of SOR and TPZ was also investigated in vivo. After treated with SOR, the number of vessels was decreased, and the degree of hypoxia was aggravated in tumor tissues. What is more, in the presence of SOR, TPZ could be activated to inhibit tumor growth. The combination of TPZ and SOR exhibited an excellent synergistic antitumor effect. This research not only provides an innovative strategy to aggravate tumor hypoxia to promote TPZ activation but also paints a blueprint about a new nanochemotherapy regimen for the synergistic chemotherapy of HCC, which has excellent biosafety and bright clinical application prospects.

Cell Membrane Hybrid Lipid Nanovesicles Enhance Innate Immunity for Synergistic Immunotherapy by Promoting Immunogenic Cell Death and cGAS Activation.

Immunotherapy shows great therapeutic potential for long-term protection against tumor relapse and metastasis. Innate immune sensors, such as cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), dissolve DNA and induce type I interferon. Through activation of the cGAS/STING pathway, chemotherapy drugs and reversine (REV) may provide synergetic anti-tumor effects. Here, we prepared drug-loaded cell membrane hybrid lipid nanovesicles (LEVs) (designated LEV@DOX@REV) by fusion of cell membranes, phospholipids, doxorubicin (DOX), and REV, to realize accurate delivery to tumors and chemo-immunotherapy. The cell membranes of LEVs confer "homing" abilities. DOX can induce immunogenic cell death as a result of its specific immunomodulatory effects, which promotes the maturation of immune cells and improves the microenvironment of the immune system. REV is proven to efficiently activate cGAS/STING signaling, thereby enhancing the immune system. The antitumor efficacy of LEV@DOX@REV was evaluated in a 4T1 subcutaneous tumor xenograft model, a distant metastatic tumor model, and a liver metastatic tumor model. LEV@DOX@REV facilitated the infiltration of cytotoxic T lymphocytes within tumors, increased the secretion of proinflammatory cytokines, and modified the tumor microenvironment. In conclusion, LEV@DOX@REV displayed favorable antitumor effects and extended the survival of tumor-bearing mice. We therefore successfully developed nanoparticles capable of enhancing immune activation that have potential therapeutic applications for cancer immunotherapy.

3D-printed scaffold harboring copper ions combined with near-infrared irradiation for local therapy of cancer

Cancer is a major health threat and a leading cause of human death worldwide. Surgical resection is the primary treatment for most cancers; however, some patients develop locoregional recurrence. Here, we developed an in situ cancer therapeutic system aimed to locally treat cancer and prevent postoperative recurrence. A functional scaffold, based on alginate/gelatin and crosslinked with copper ions, was fabricated by 3D printing and showed an excellent photothermal effect under near-infrared (NIR) irradiation. The combination of copper ions and NIR effectively killed thyroid cancer cells and patient-derived organoids, indicating a synergetic and broad-spectrum antitumor effect on thyroid cancer through the chemo-photothermal therapy. This implantable stent is designed to provide effective treatment in the vicinity of the tumor site and can be degraded without secondary surgery. The copper-loaded hydrogel scaffold may be a potential candidate for local cancer treatment and pave the way for precise and effective cancer therapy.

Amplifying "eat me signal" by immunogenic cell death for potentiating cancer immunotherapy.

Immunogenic cell death (ICD) is a unique mode of cell death, which can release immunogenic damage-associated molecular patterns (DAMPs) and tumor-associated antigens to trigger long-term protective antitumor immune responses. Thus, amplifying "eat me signal" during tumor ICD cascade is critical for cancer immunotherapy. Some therapies (radiotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), etc.) and inducers (chemotherapeutic agents, etc.) have enabled to initiate and/or facilitate ICD and activate antitumor immune responses. Recently, nanostructure-based drug delivery systems have been synthesized for inducing ICD through combining treatment of chemotherapeutic agents, photosensitizers for PDT, photothermal transformation agents for PTT, radiosensitizers for radiotherapy, etc., which can release loaded agents at an appropriate dosage in the designated place at the appropriate time, contributing to higher efficiency and lower toxicity. Also, immunotherapeutic agents in combination with nanostructure-based drug delivery systems can produce synergetic antitumor effects, thus potentiating immunotherapy. Overall, our review outlines the emerging ICD inducers, and nanostructure drug delivery systems loading diverse agents to evoke ICD through chemoradiotherapy, PDT, and PTT or combining immunotherapeutic agents. Moreover, we discuss the prospects and challenges of harnessing ICD induction-based immunotherapy, and highlight the significance of multidisciplinary and interprofessional collaboration to promote the optimal translation of this treatment strategy.

CL4-modified exosomes deliver lncRNA DARS-AS1 siRNA to suppress triple-negative breast cancer progression and attenuate doxorubicin resistance by inhibiting autophagy

Triple-negative breast cancer (TNBC) is a fatal disease. Drug resistance and the lack of effective drugs are the leading causes of death in patients with TNBC. Recently, long non-coding RNAs have been proven to be effective drug design targets owing to their high tissue specificity; however, an effective drug delivery system is necessary for their clinical application. In this study, we constructed a novel nanodrug delivery system based on the epidermal growth factor receptor (EGFR)-targeted aptamer CL4-modified exosomes (EXOs-CL4) for the targeted delivery of aspartyl-tRNA synthetase-antisense RNA 1 (DARS-AS1) small interfering RNA (siRNA) and doxorubicin (DOX) to TNBC cells in vitro and in vivo. This delivery system exerted potent anti-proliferation, anti-migration, and pro-apoptotic effects on TNBC cells. Silencing DARS-AS1 increased the sensitivity of TNBC cells to DOX by suppressing the transforming growth factor-β (TGF-β)/Smad3 signaling pathway-induced autophagy, thereby enhancing the synergetic antitumor effects. Collectively, our findings revealed that EXOs-CL4-mediated delivery of DARS-AS1 siRNA can be used as a new treatment strategy for DOX-resistant TNBC. Moreover, EXOs-CL4 can be used as effective drug delivery systems for targeted TNBC therapy.

Carboxymethylcellulose based self-healing hydrogel with coupled DOX as Camptothecin loading carrier for synergetic colon cancer treatment

The self-healing hydrogels have important applications in biomedication as drug release carrier. In this research, the Doxorubicin (DOX) was coupled onto oxidized carboxymethylcellulose (CMC) (CMC-Ald) to fabricate self-healing hydrogel with intrinsic antitumor property and loaded with Camptothecin (CPT) for synergetic antitumor treatment. The DOX coupled CMC-Ald (CMC-AD) was reacted with poly(aspartic hydrazide) (PAH) to fabricate injectable self-healing hydrogel. The coupled DOX avoided the burst release of the drug and the 100 % CPT loaded hydrogel could take the advantages of both drugs to enhance the synergetic antitumor therapeutic effect. The in vitro and in vivo results revealed the CPT loaded CMC-AD/PAH hydrogel showed enhanced antitumor property and reduced biotoxicity of the drugs. These properties demonstrate that the CMC-AD/PAH hydrogel has great application prospects in biomedication.

PARP1 controls the transcription of CD24 by ADP-ribosylating the RNA helicase DDX5 in pancreatic cancer.

The PARP1 protein plays a key role in DNA damage repair and ADP-ribosylation to regulate gene expression. Strategies to target PARP1 have rapidly been developed for cancer treatment. However, the role of the innate immune response in targeted anti-PARP1 therapy remains poorly understood. In this work, we aimed to elucidate the regulatory mechanism underlying the immunogenicity of PARP1 and explore efficient therapeutic strategies to enhance the antitumor effect of PARP inhibitors. The relationships between PARP1 expression and immunosuppressive factors were examined by qRTPCR and immunoblot analysis. DNA pull-down, chromatin immunoprecipitation-quantitative PCR (ChIPqPCR) and luciferase reporter assays were employed to reveal the mechanism by which the expression of the immune checkpoint regulator CD24 is regulated by PARP1. Phagocytosis assays and pancreatic cancer animal models were applied to evaluate the therapeutic effect of simultaneous disruption of PARP1 and the antiphagocytic factor CD24. Upregulation of the innate immunosuppressive factor CD24 was observed in pancreatic cancer during PARP1 inhibition. The activating effect of targeting CD24 on macrophage phagocytosis was verified. Then, we showed that PARP1 attenuated the transcription of CD24 by ADP-ribosylating the transcription factor DDX5 in pancreatic cancer. Combined blockade of PARP1 and the antiphagocytic factor CD24 elicited a synergetic antitumor effect in pancreatic cancer. Our research provided evidence that combination treatment with PARP inhibitors and CD24 blocking monoclonal antibodies (mAbs) could be an effective strategy to improve the clinical therapeutic response in pancreatic cancer.

Targeting 4-1BB and PD-L1 induces potent and durable antitumor immunity in B-cell lymphoma

Although PD-1/L1 mAb has demonstrated clinical benefits in certain cancer types, low response rate and resistance remain the main challenges for the application of these immune checkpoint inhibitors (ICIs). 4-1BB is a co-stimulator molecule expressed in T cells, which could enhance T cell proliferation and activation. Herein, the synergetic antitumor effect and underlying mechanism of 4-1BB agonist combined with PD-1/PD-L1 blockade were determined in B-cell lymphoma (BCL). Subcutaneous transplantation BCL tumor models and metastasis models were established to evaluate the therapeutic effect of PD-L1 antibody and/or 4-1BB agonist in vivo. For the mechanistic study, RNA-seq was applied to analyze the tumor microenvironment and immune-related signal pathway after combination treatment. The level of IFN-γ, perforin, and granzyme B were determined by ELISA and Real-time PCR assays, while tumor-infiltrating T cells were measured by flow cytometry and immunohistochemical analysis. CD4/CD8 specific antibodies were employed to deplete the related T cells to investigate the role CD4+ and CD8+ T cells played in combination treatment. Our results showed that combining anti-PD-L1 ICI and 4-1BB agonists elicited regression of BCL and significantly extended the survival of mice compared to either monotherapy. Co-targeting PD-L1 and 4-1BB preferentially promoted intratumoral cytotoxic lymphocyte infiltration and remodeled their function. RNA-sequence analysis uncovered a series of up-regulated genes related to the activation and proliferation of cytotoxic T lymphocytes, further characterized by increased cytokines including IFN-γ, granzyme B, and perforin. Furthermore, depleting CD8+ T cells not CD4+ T cells totally abrogated the antitumor efficacy, indicating the crucial function of the CD8+ T cell subset in the combination therapy. In summary, our findings demonstrated that 4-1BB agonistic antibody intensified the antitumor immunity of anti-PD-1/PD-L1 ICI via promoting CD8+ T cell infiltration and activation, providing a novel therapeutic strategy to BCL.

EXTH-57. IDENTIFICATION OF NOVEL IMMUNE CHECKPOINT MOLECULE IN GLIOMA, LAIR1

Abstract BACKGROUND In recent years, emerging evidence indicates that tumor-associated myeloid cells (TAMCs) affect cancer progression. But the molecular mechanisms and signaling pathways involved in the TAMCs’ interaction with extracellular matrix (ECM) and tumor stroma are incompletely understood. Checkpoint inhibition therapy targets immune inhibitory receptors, such as CTLA-4 and PD-1, which have become a major weapon in fighting cancer. These antibodies demonstrate apparent advantages such as being easy to use, broad applicability, and durable clinical response. Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR1), also called CD305, a collagen-binding immunoreceptor tyrosine-based inhibition motifs (ITIM)-bearing inhibitory receptor, was identified to present on almost all immune cell populations and overexpressed in cancers of human patients. However, LAIR1’s role and regulation in solid cancers are poorly defined. OBJECTIVE To identify LAIR1 as a new class of immune checkpoints in cancers that impacts TAMCs-associated tumor immunity. Further functional investigation warrants understanding the crosstalk between LAIR1-related immune checkpoint blocking agent(s), immune micro-environment, and its underlying mechanisms for targeted therapy development. METHODS Murine GBM cell line KR158-Luciferase cell line was used to set up the mouse model. Tumor-bearing mice were administered the Anti-LAIR1 blockade and IgG, followed by IVIS imaging for tumor growth and survival were recorded. The presentation and phenotype of immune cell populations in tumors and spleens were measured through scRNA-Seq. RESULTS GBM is one of these tumors that overexpress LAIR1 based on the TCGA analysis. LAIR1 molecules express highly on macrophages, monocytes, DCs, and activated T cells, not on the naive T cells. We found that LAIR1 blockade enhanced survival in preclinical GBM models. LAIR1 blockade reduced the presentation and function of TAMCs in tumors. What's more, LAIR1 blockade provided a synergetic antitumor effect with CD70 CAR T cells. CONCLUSION This study suggests that we identified a novel immune checkpoint molecule, LAIR1, which can limit tumor progression.

Multifunctional Mesoporous Hollow Cobalt Sulfide Nanoreactors for Synergistic Chemodynamic/Photodynamic/Photothermal Therapy with Enhanced Efficacy.

The unique tumor microenvironment (TME) characteristic of severe hypoxia, overexpressed intracellular glutathione (GSH), and elevated hydrogen peroxide (H2O2) concentration limit the anticancer effect by monotherapy. In this report, glucose oxidase (GOx)-encapsulated mesoporous hollow Co9S8 nanoreactors are constructed with the coverage of polyphenol diblock polymers containing poly(oligo(ethylene glycol) methacrylate) and dopamine moieties containing methacrylate polymeric block, which are termed as GOx@PCoS. After intravenous injection, tumor accumulation, and cellular uptake, GOx@PCoS deplete GSH by Co3+ ions. GOx inside the nanoreactors produce H2O2 via oxidation of glucose to enhance •OH-based chemodynamic therapy (CDT) through the Fenton-like reaction under the catalysis of Co2+. Moreover, Co3+ ions possess catalase activity to catalyze production of O2 from H2O2 to relieve tumor hypoxia. Upon 808 nm laser irradiation, GOx@PCoS exhibit photothermal and photodynamic effects with a high photothermal conversion efficiency (45.06%) and generation capacity of the toxic superoxide anion (•O2-) for photothermal therapy (PTT) and photodynamic therapy (PDT). The synergetic antitumor effects can be realized by GSH depletion, starvation, and combined CDT, PTT, and PDT with enhanced efficacy. Notably, GOx@PCoS can also be used as a magnetic resonance imaging (MRI) contrast agent to monitor the antitumor performance. Thus, GOx@PCoS show great potentials to effectively modulate TME and perform synergistic multimodal therapy.

Integrated assessment of the clinical and biological value of ferroptosis-related genes in multiple myeloma

BackgroundFerroptosis is an iron-dependent mode of cell death that could be induced by erastin and exert antitumor effects. However, the clinical and biological roles of ferroptosis-related gene (FRG) signature and the therapeutic value of erastin in multiple myeloma (MM) remained unknown.MethodsClinical and gene expression data of MM subjects were extracted from the Gene Expression Omnibus (GEO) public database. Univariable cox analysis was applied to determine FRGs related to survival and the least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a prognostic model. Prediction accuracy of the model was estimated by receiver operating characteristic (ROC) curves. Functional pathway enrichments and infiltrating immune status were also analyzed. We conducted in vitro experiments to investigate the combination therapy of erastin and doxorubicin.Results17 FRGs were strongly associated with patient survival and 11 genes were identified to construct the prognostic model. ROC curves indicated great predictive sensitivity and specificity of the model in all cohorts. Patients were divided into low- and high-risk groups by median risk score in each cohort and the survival of the low-risk group was significantly superior than that of the high-risk group. We also observed a close relevance between functional pathways and immune infiltration with risk scores. Moreover, we combined erastin and doxorubicin in our in vitro experiments and found synergetic antitumor effects of the two agents, and the underlying mechanism is the overgeneration of intracellular Reactive Oxygen Species (ROS).ConclusionsWe demonstrated the important value of ferroptosis in patient prognosis and as a potential antitumor target for MM.

Nanoscale CaO2 materials for synergistic transarterial chemoembolization in a VX2 orthotopic rabbit liver cancer model

Transcatheter arterial chemoembolization (TACE) is extensively used in the treatment of hepatocellular carcinoma (HCC), but its efficacy is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). Herein, we synthesized polyvinyl pyrrolidone (PVP)-coated CaO2 nanoparticles (CaO2 NPs) and applied them as a synergistic agent to improve the antitumor efficacy of TACE. After injection into the tumor, CaO2 NPs reacted with water to generate abundant oxygen, hydroxyl ions (OH−), and calcium ions (Ca2+), thereby relieving tumor hypoxia, neutralizing acid, and overloading Ca2+ to mediate antitumor effects. Moreover, the effect of chemotherapeutic drugs within the TACE was improved due to the modulated TME. CaO2 NPs efficiently regulated the TME and improved the antitumor effect of doxorubicin under hypoxia conditions in vitro. Compared to other groups, the TACE+CaO2 NPs group achieved the lowest tumor growth rate, highest tumor necrosis rate, lowest expression of histological markers associated with hypoxia and angiogenesis (HIF-α, VEGF, and CD31), and highest CD8+ T cell recruitment in vivo. Thus, these findings demonstrated that CaO2 NPs provide synergy for TACE therapy in the VX2 orthotopic rabbit liver cancer model, suggesting that they have a potential broad clinical application. Statement of significanceThe efficacy of transcatheter arterial chemoembolization (TACE) for treatment of hepatocellular carcinoma is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). To address this issue, we synthesized CaO2 nanoparticles (CaO2 NPS) which would react with water to generate abundant oxygen, hydroxyl ions (OH−), and calcium ions (Ca2+), thereby relieving tumor hypoxia, neutralizing the acidic TME, and inducing Ca2+ overloading. The efficacy of CaO2 NPs in combination with TACE was investigated in an orthotopic rabbit liver cancer model, and the results showed the great synergetic antitumor effect of TACE and CaO2 NPs.

Inhibition of PCSK9 enhances the antitumor effect of PD-1 inhibitor in colorectal cancer by promoting the infiltration of CD8+ T cells and the exclusion of Treg cells.

Immunotherapy especially immune checkpoint inhibitors (ICIs) has brought favorable clinical results for numerous cancer patients. However, the efficacy of ICIs in colorectal cancer (CRC) is still unsatisfactory due to the poor median progression-free survival and overall survival. Here, based on the CRC models, we tried to elucidate novel relapse mechanisms during anti-PD-1 therapy. We found that PD-1 blockade elicited a mild antitumor effect in these tumor models with both increased CD8+ T cells and Treg cells. Gene mapping analysis indicated that proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, transforming growth factor-β (TGF-β), and CD36 were unexpectedly upregulated during PD-1 blockade. To investigate the critical role of these proteins especially PCSK9 in tumor growth, anti-PCSK9 antibody in combination with anti-PD-1 antibody was employed to block PCSK9 and PD-1 simultaneously in CRC. Data showed that neutralizing PCSK9 during anti-PD-1 therapy elicited a synergetic antitumor effect with increased CD8+ T-cell infiltration and inflammatory cytokine releases. Moreover, the proportion of Treg cells was significantly reduced by co-inhibiting PCSK9 and PD-1. Overall, inhibiting PCSK9 can further enhance the antitumor effect of anti-PD-1 therapy in CRC, indicating that targeting PCSK9 could be a promising approach to potentiate ICI efficacy.

Abstract 3736: SETD2 aberrancy enhanced the synergetic anti-tumor effects of DNA hypomethylating agents and PARP inhibitors in aggressive clear cell renal cell carcinoma

Abstract Purpose: SETD2 aberrancy, as the main reason of depleted levels of H3K36me3, plays an important role in diverse forms of cancer and is most notably in clear cell renal cell carcinoma (ccRCC). Altered chromatin modelers related to impaired H3K36me3 occupancy are linked to renal cancer aggressiveness and metastasis, where the latter dramatically drops the relative 5-year survival rate of ccRCC from 91% to 11%. Developing novel treatment targeting H3K36me3-compromised cancer cell is urgently needed for diagnostic and treatment purposes. Methods: Phenotypic and animal experiments were conducted to test the sensitivity of kidney cancer cells with impaired H3K36me3 to hypomethylating agent (HMA), PARP inhibitor (PARPi), and HMA + PARPi combination treatments. Comet assay, flow cytometry, western blot and bioinformatic analysis were performed to explore the mechanism beneath. Results: Combination treatment of 5-Aza-CdR (DAC) and Talazoparib (PARPi) generate more cytotoxicity in SETD2-altered ccRCC cell lines than in SETD2-intact cell lines, including inhibited cell growth, incomplete colony formation, more apoptosis, increased DNA damage and impaired DNA damage repair. The up-regulation of STING and transposable element (TE), as well as the loss of chromatin stability, were more remarkable in SETD2-altered ccRCC cell lines when treated with DAC + PARPi. Conclusion: Combination treatment of DAC and Talazoparib showed greater synergistic anti-tumor effect in SETD2 aberrant than in SETD2 wild-type ccRCC cells, making it a potential treatment strategy for H3K36me3-compromised cancers. Further pre-clinical studies should be conducted to make a precise medicine-based approach. Citation Format: Xinyi Zhou, Guanghou Fu, Hong-Tao Li, Hemant Gujar, Daniel J. Weisenberger, David I. Quinn, Bo Han, Gangning Liang. SETD2 aberrancy enhanced the synergetic anti-tumor effects of DNA hypomethylating agents and PARP inhibitors in aggressive clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3736.