Tumor Growth Inhibition Effect Research Articles

A manganese-doped layered double hydroxide loaded with lactate oxidase and DNA repair inhibitors for synergistically enhanced tumor immunotherapy

Tumor immunotherapy has gained more and more attention in tumor treatment. However, the accumulation of lactic acid in tumor tissue inhibits the response of immune cells to form an immunosuppressive microenvironment (ISME). To reverse the ISME, an acid-responsive nanoplatform (termed as MLLN@HA) is reported for synergistically enhanced tumor immunotherapy. MLLN@HA is constructed by the co-loading of lactate oxidase (LOX) and DNA repair inhibitor (NU7441) in a manganese-doped layered double hydroxide (Mn-LDH), and then modified with hyaluronic acid (HA) for tumor-targeted delivery. After endocytosis by tumor cells, MLLN@HA decomposes and releases LOX, NU7441 and Mn2+ ions in the acidic tumor microenvironment. The released LOX catalyzes the conversion of lactic acid into hydrogen peroxide (H2O2), which not only alleviates the ISME, but also provides reactants for the Mn2+-mediated Fenton-like reaction to enhance chemodynamic therapy (CDT). Released NU7441 prevents CDT-induced DNA damage from being repaired, thereby increasing double-stranded DNA (dsDNA) fragments within tumor cells. Importantly, the released Mn2+ ions enhance the sensitivity of cyclic GMP-AMP synthase (cGAS) to dsDNA fragments, and activate the stimulator of interferon genes (STING) to induce an anti-tumor immune response. Such an orchestrated immune-boosting strategy ultimately achieves effective tumor growth inhibition and prevents tumor lung metastasis. Statement of significanceTo improve the efficacy of tumor immunotherapy, an innovative acid-responsive MLLN@HA nanoplatform was developed for synergistically enhanced tumor immunotherapy. The MLLN@HA actively targets to tumor cells through the interaction of HA with CD44, and then degrades to release LOX, NU7441 and Mn2+ ions in the acidic tumor microenvironment. The released LOX generates H2O2 for the Mn2+-mediated Fenton reaction and reverses the ISME by consuming lactate. NU7441 prevents DNA damage repair, leading to an increased concentration of free DNA fragments, while Mn2+ ions activate the cGAS-STING pathway, enhancing the systemic anti-tumor immune response. The orchestrated immune-boosting nanoplatform effectively inhibits tumor growth and lung metastasis, presenting a promising strategy for cancer treatment.

1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol treatment inhibits abnormal tumor growth by regulating neutrophil infiltration in a non-small cell lung carcinoma mouse model

Excessive neutrophil infiltration into the tumor microenvironment (TME) is an important factor that contributes to tumor overgrowth and limited immunotherapy efficacy. Neutrophils activate various receptors involved in tumor progression, while suppressing the infiltration and activity of cytotoxic T cells and creating optimal conditions for tumor growth. Therefore, the appropriate control of neutrophil infiltration is an effective strategy for tumor treatment.In the present study, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) inhibited tumor overgrowth by suppressing excessive neutrophil infiltration, resulting in >74.97 % reduction in tumor size in a Lewis lung carcinoma (LLC-1) mouse model. All subjects in the positive control group died during the 90-day survival period, whereas only four subjects in the PLAG treatment group survived. PLAG had a significantly higher tumor growth inhibitory effect and survival rate than other neutrophil infiltration-targeting inhibitors (e.g., Navarixin, lymphocyte antigen 6 complex locus G6D antibody [aLy6G]). The ability of PLAG to regulate neutrophil infiltration and inhibit tumor growth depends on thioredoxin-interacting protein (TXNIP). In tumors lacking TXNIP expression, PLAG failed to control neutrophil infiltration and infiltration-related factor release, and the inhibitory effect of PLAG on tumor growth was reduced. PLAG-mediated inhibition of neutrophil infiltration enhances the efficacy of immune checkpoint inhibitors (ICIs), increasing the antitumor efficacy and survival rate by 30 %.In conclusion, PLAG could be a novel alternative to anti-tumor drugs that effectively targets excessive neutrophil infiltration into cancer tissues.

Resveratrol liposomes reverse sorafenib resistance in renal cell carcinoma models by modulating PI3K-AKT-mTOR and VHL-HIF signaling pathways

RCC is a malignant tumor arising from the urothelium of renal parenchyma that remains challenging to be treated. In this study, we assessed the anti-tumor effects of Resveratrol liposomes (RES-lips) combined with sorafenib on renal cell carcinoma (RCC) and explored the potential mechanisms underlying the improvement of sorafenib resistance models. Tumor growth and survival following treatment with sorafenib alone or in combination with RES-lips was evaluated in a RCC xenograft mouse model. Flow cytometry results demonstrated that the combination of RES-lips and sorafenib significantly enhanced the G1/S phase arrest of sorafenib-resistant cells. When compared with the PBS or monotherapy groups, treatment with RES-lips combined with sorafenib exhibited significant inhibition of tumor growth in the RCC xenograft mouse model with tumor growth inhibition (TGI) rates and complete remission (CR) rates of 90.1 % and 50 %, respectively. Concersely, the maximum TGI rate was 53.6 % in the RES-lips monoherapy group and 29.2 % and in the sorafenib monotherapy group, and no animals achieved CR. Additionally, the current combination therapy promoted the proliferation of unactivated splenic lymphocytes and the proliferation of soybean protein A- and lipopolysaccharide-stimulated lymphocytes compared with PBS or monotherapy treatments. Further western blotting analysis suggested that RES-lips may enhance the resistance of RCC to sorafenib by inhibiting PI3K-AKT-mTOR and VHL-HIF signaling pathways, ultimately augmenting the tumor growth inhibition effect of the combination therapy. RES-lips may improve the sorafenib resistance in RCC, and the underlying mechanism may be related to the regulation of PI3K-AKT-mTOR and VHL-HIF signaling pathways.

Ultrasound -Induced Thermal Effect Enhances the Efficacy of Chemotherapy and Immunotherapy in Tumor Treatment.

The inadequate perfusion, frequently resulting from abnormal vascular configuration, gives rise to tumor hypoxia. The presence of this condition hinders the effective delivery of therapeutic drugs and the infiltration of immune cells into the tumor, thereby compromising the efficacy of treatments against tumors. The objective of this study is to exploit the thermal effect of ultrasound (US) in order to induce localized temperature elevation within the tumor, thereby facilitating vasodilation, augmenting drug delivery, and enhancing immune cell infiltration. The selection of US parameters was based on intratumor temperature elevation and their impact on cell viability. Vasodilation and hypoxia improvement were investigated using enzyme-linked immunosorbent assay (ELISA) and immunofluorescence examination. The distribution and accumulation of commercial pegylated liposomal doxorubicin (PLD) and PD-L1 antibody (anti-PD-L1) in the tumor were analyzed through frozen section analysis, ELISA, and in vivo fluorescence imaging. The evaluation of tumor immune microenvironment was conducted using flow cytometry (FCM). The efficacy of US-enhanced chemotherapy in combination with immunotherapy was investigated by monitoring tumor growth and survival rate after various treatments. The US irradiation condition of 0.8 W/cm2 for 10 min effectively elevated the tumor temperature to approximately 40 °C without causing any cellular or tissue damage, and sufficiently induced vasodilation, thereby enhancing the distribution and delivery of PLD and anti-PD-L1 in US-treated tumors. Moreover, it effectively mitigated tumor hypoxia while significantly increasing M1-phenotype tumor-associated macrophages (TAMs) and CD8+ T cells, as well as decreasing M2-phenotype TAMs. By incorporating US irradiation, the therapeutic efficacy of PLD and anti-PD-L1 was substantially boosted, leading to effective suppression of tumor growth and prolonged survival in mice. The application of US (0.8 W/cm2 for 10 min) can effectively induce vasodilation and enhance the delivery of PLD and anti-PD-L1 into tumors, thereby reshaping the immunosuppressive tumor microenvironment and optimizing therapeutic outcomes.

Hyaluronic acid-based multifunctional nanoplatform for glucose deprivation-enhanced chemodynamic/photothermal synergistic cancer therapy

We present a hyaluronic acid (HA)-based nanoplatform (CMGH) integrating starvation therapy (ST), chemodynamic therapy (CDT), and photothermal therapy (PTT) for targeted cancer treatment. CMGH fabrication involved the encapsulation of glucose oxidase (GOx) within a copper-based metal-organic framework (CM) followed by surface modification with HA. CMGH exerts its antitumor effects by catalyzing glucose depletion at tumor sites, leading to tumor cell starvation and the concomitant generation of glucuronic acid and H2O2. The decreased pH and elevated H2O2 promote the Fenton-like reaction of Cu ions, leading to hydroxyl radical production. HA modification enables targeted accumulation of CMGH at tumor sites via the CD44 receptor. Under near-infrared light irradiation, CM exhibits photothermal conversion capability, enhancing the antitumor effects of CMGH. In vitro and in vivo studies demonstrate the effective inhibition of tumor growth by CMGH. This study highlights the potential of CMGH as a targeted cancer therapeutic platform.

Development of a PAK4-targeting PROTAC for renal carcinoma therapy: concurrent inhibition of cancer cell proliferation and enhancement of immune cell response

Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation invitro and invivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

Binary Proton Therapy of Ehrlich Carcinoma Using Targeted Gold Nanoparticles.

Proton therapy can treat tumors located in radiation-sensitive tissues. This article demonstrates the possibility of enhancing the proton therapy with targeted gold nanoparticles that selectively recognize tumor cells. Au-PEG nanoparticles at concentrations above 25 mg/L and 4 Gy proton dose caused complete death of EMT6/P cells in vitro. Binary proton therapy using targeted Au-PEG-FA nanoparticles caused an 80% tumor growth inhibition effect in vivo. The use of targeted gold nanoparticles is promising for enhancing the proton irradiation effect on tumor cells and requires further research to increase the therapeutic index of the approach.

Tumor Growth, Glycolytic and Cell Cycle Inhibitory Effects of Ketogenic Diet in Ehrlich Solid Tumor-Bearing Female Mice

Tumor Growth, Glycolytic and Cell Cycle Inhibitory Effects of Ketogenic Diet in Ehrlich Solid Tumor-Bearing Female Mice

Polycationic Photosensitizers as Effective Anticancer Agents That Destroy Cancer Stem Cells, Cancer Vascularization and Induce Protective Desmoplastic Reaction around Lung Cancers

PDT using PSs based on polycationic derivatives of synthetic bacteriochlorin against Lewis lung carcinoma provides effective inhibition of tumor growth with an increase in the lifespan and survival of mice in the group. PDT with polycationic photosensitizers destroys CSCs and tumor neovascularization, and activates the desmoplastic reaction. These results open up new opportunities for increasing the effectiveness of treatment and reducing the incidence of relapses and metastases after PDT.

T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.

Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy.

Tumor metastases and reoccurrence are considered the leading causes of cancer-associated deaths. As an emerging therapeutic method, increasing research efforts have been devoted to immunogenic cell death (ICD)-inducing compounds to solve the challenge. The clinically approved chemotherapeutic Pt complexes are not or are only poorly able to trigger ICD. Herein, the axial functionalization of the Pt(II) complex cisplatin with perfluorocarbon chains into ICD-inducing Pt(IV) prodrugs is reported. Strikingly, while the Pt(II) complex as well as the perfluorocarbon ligands did not induce ICD, the Pt(IV) prodrug demonstrated unexpectantly the induction of ICD through accumulation in the endoplasmic reticulum and generation of reactive oxygen species in this organelle. To enhance the pharmacological properties, the compound was encapsulated with human serum albumin into nanoparticles. While selectively accumulating in the tumorous tissue, the nanoparticles demonstrated a strong tumor growth inhibitory effect against osteosarcoma inside a mouse model. In vivo tumor vaccine analysis also demonstrated the ability of Pt(IV) to be an ideal ICD inducer. Overall, this study reports on axially perfluorocarbon chain-modified Pt(IV) complexes for ICD induction and chemoimmunotherapy in osteosarcoma.

Evaluation of the antitumor effect of neoantigen peptide vaccines derived from the translatome of lung cancer

Emerging evidence suggests that tumor-specific neoantigens are ideal targets for cancer immunotherapy. However, how to predict tumor neoantigens based on translatome data remains obscure. Through the extraction of ribosome-nascent chain complexes (RNCs) from LLC cells, followed by RNC-mRNA extraction, RNC-mRNA sequencing, and comprehensive bioinformatic analysis, we successfully identified proteins undergoing translatome and exhibiting mutations in the cells. Subsequently, novel antigens identification was analyzed by the interaction between their high affinity and the Major Histocompatibility Complex (MHC). Neoantigens immunogenicity was analyzed by enzyme-linked immunospot assay (ELISpot). Finally, in vivo experiments in mice were conducted to evaluate the antitumor effects of translatome-derived neoantigen peptides on lung cancer. The results showed that ten neoantigen peptides were identified and synthesized by translatome data from LLC cells; 8 out of the 10 neoantigens had strong immunogenicity. The neoantigen peptide vaccine group exhibited significant tumor growth inhibition effect. In conclusion, neoantigen peptide vaccine derived from the translatome of lung cancer exhibited significant tumor growth inhibition effect.

Novel selective agents for the degradation of AR/AR-V7 to treat advanced prostate cancer

The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). Even though they are effective at first, resistance to both drugs occurs frequently. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification and the expression of AR splice variants (e.g. AR-V7). This highlights the urgent need for alternative therapeutic strategies. Here, a total of 24 compounds were synthesized and biologically evaluated to disclose compound 20i, exhibiting potent AR antagonistic activities (IC50 = 172.85 ± 21.33 nM), promising AR/AR-V7 protein degradation potency, and dual targeting site of probably AR (ligand-binding domain, LBD and N-terminal domain, NTD). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 μM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

Abstract LB322: ARC2-001, a CAF-targeting drug exhibits strong anticancer effect in in vivo setting

Abstract For more effective tumor growth suppression, a combinatorial treatment of CAF-targeting agent and other well-validated therapies such as chemotherapy, radiotherapy, and immune checkpoint therapy should be considered. Thus, we hypothesized that co-administration of the CAF-targeting drug, ARC2-001 (the in vitro-approved CAF-targeting candidate) and clinically practiced anticancer drugs could be useful strategy for treating under clinical settings. However, it is essentially important to evaluate this using well-established pre-clinical models. We thoroughly verified the anticancer effect of ARC-001 using two in vivo model systems. ( 2nd- in vivo systems for CAF targeted drugs Research). 1. (Subcutaneous model) Immune-deficient mice (NOD/SCID): in which human colon cancer cell line HCT116 was co-injected with human CAF (CAFs were obtained from stage IV CRC patients) followed by administration of ARC2-001 alone or in combination with 5-fluorouracil (5FU). 2. (Subcutaneous and Orthotopic model) Wild-type mice (C57BL/6): in which mouse colon cancer cells was co-injected with mouse colon CAFs (both cancer cells and CAFs were obtained from chemically-induced colorectal cancer model with rich desmoplastic stroma) followed by administration of ARC2-001 alone or in combination with aPD-1. We observed a magnificent inhibition of tumor growth and metastasis in the combined treatment group over singular treatment groups in both models. This denotes that ARC2-001 largely augments the anti-cancer effect of widely employed anticancer drugs, such as 5FU, and thus can be exploited as an adjuvant for enhanced colorectal cancer chemotherapy.Collectively, our results evidenced the necessity of considering CAF-targeting agents for a more regulated therapeutic strategy to treat desmoplastic cancers. Citation Format: So-Young Yeo, Mohamed Farh, InSuk Sohn, Seok-Hyung Kim, Keun-Woo Lee. ARC2-001, a CAF-targeting drug exhibits strong anticancer effect in in vivo setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB322.

Abstract LB128: A novel tri-specific T cell engager targeting BCMA and GPRC5D for treatment of multiple myeloma

Abstract Introduction Multiple myeloma (MM) accounts for 10% of all hematologic cancers. Recent advances in MM therapy have greatly increased the overall response and survival rate. However, almost all patients eventually relapse. The prognosis still remains poor. BCMA and GPRC5D are overexpressed in myeloma cells. Although CAR-T and T cell engager (TCE) targeting BCMA or GPRC5D have been efficacious in MM patients, resistance does occur. Since the expression of BCMA and GPRC5D in MM are heterogeneous, to further improve the overall response and survival, we have recently generated a novel tri-specific T-cell engager, GBD218, targeting both BCMA and GPRC5D. GBD218 has demonstrated potent in vitro and in vivo activity against myeloma cells. Methods Anti-BCMA and GPRC5D nanobodies were screened from alpaca immune libraries, and anti-CD3 antibody was engineered from mouse hybridoma clone. The tri-specific antibodies were constructed in a “1+1+1” format through “knob into hole” technology fused with silenced IgG1 Fc. The format of the tri-specific antibodies was optimized by multiple rounds of in vitro activity and druggability evaluation. The in vivo tumor growth inhibition effects were evaluated in PBMC-humanized xenograft mouse models. Results GBD218 has been designed to potently bind hBCMA (KD=0.4nM) and hGPRC5D (cell binding EC50 ~ 2nM). To reduce CRS and other potential AEs associated with TCEs, a low affinity of anti-CD3 Fab was used. In cell-based functional assays, GBD218 showed efficient cytotoxicity against single and double positive MM cell lines with various expression levels of BCMA and GPRC5D. T cell activation and cytokine release induced by GBD218, in the presence or absence of MM cancer cells, is nicely balanced for great killing efficacy and the low risk of CRS. Importantly, the results showed that GBD218 exhibited superior in vitro killing activity compared to benchmarks, including teclistamab, talquetamab, the combination of teclistamab and talquetamab, suggesting a synergistic effect of GBD218 by targeting BCMA and GPRC5D. In xenograft models, GBD218 showed excellent anti-tumor activity, indicating great potential for GBD218 as a promising therapeutics for MM. Conclusion GBD218 is a novel tri-specific antibody that showed potent in vitro and in vivo anti-tumor activity. GBD218 efficiently kills both BCMA and/or GPRC5D expressing MM cells, which may hold promise to increase response rate and improve survival in MM patients in clinic. Citation Format: Yongcong Tan, Xuezhen Li, Fan Yu, Juehua Xu, Zhen Qian, Yiqi Cao, Xueyan Yang, Qinglin Du, Fei Peng, Shuhua Han, Qian Ding. A novel tri-specific T cell engager targeting BCMA and GPRC5D for treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB128.

Abstract LB022: Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model

Abstract Adenoid cystic carcinoma (ACC) is a rare type of salivary gland cancer. Despite the many advances made in helping understand the disease behavior and characteristics, the prevailing challenge in managing patients with ACC is the lack of clinically approved systemic therapy drugs to successfully treat those with advanced recurrent or metastatic disease. There are multiple promising candidate agents being evaluated preclinically and in early phase clinical trials, yet an effective drug with consistent overall response remains to be identified. AXL is a member of the TAM family of tyrosine kinase receptors, and its overexpression and activation is generally associated with poor prognosis and chemoresistance in many cancer types. Previous reports show AXL is significantly upregulated in a subset of ACC tumors. Here, we evaluate the tumor growth inhibition effects of a newly developed antibody-drug-conjugate targeting AXL (ADCT-601) in a xenograft ACC cell line model. MDA-ACC-01 cells express high levels of cell surface AXL as confirmed by biochemical analysis. The tumor growth inhibition of MDA-ACC-01 cell xenograft was tested in a single-dose drug administration study. Immunodeficient mice bearing ACC tumors were either injected with vehicle (n=7) or with ADCT-601 at 0.5 (n=9) or 1.0 mg/kg (n=7). ADCT-601 treatment with either 0.5 mg/kg or 1.0 mg/kg resulted in complete response (CR) for all tumor implants. To reaffirm the drug’s efficacy, we challenged the vehicle-treated tumor, prior to exceeding the tumor volume endpoint, with a single-dose of ADCT-601 at 1.0 mg/kg. Strikingly, by day 6 post-treatment, tumor volume began to shrink and eventually resulted in CR except in all but one case. These results demonstrate ADCT-601 is an effective drug with significant anti-tumor activity in our preclinical models and is worthy of additional investigation to determine its translational potential. Citation Format: Joseph O. Humtsoe, Anita Pothukuchi, Hyunseok Kang, Patrick Ha. Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB022.

Combination of Molecule-Targeted Therapy and Photodynamic Therapy Using Nanoformulated Verteporfin for Effective Uveal Melanoma Treatment.

Uveal melanoma (UM) is the most common primary ocular malignancy in adults and has high mortality. Recurrence, metastasis, and therapeutic resistance are frequently observed in UM, but no beneficial systemic therapy is available, presenting an urgent need for developing effective therapeutic drugs. Verteporfin (VP) is a photosensitizer and a Yes-Associated Protein (YAP) inhibitor that has been used in clinical practice. However, VP's lack of tumor targetability, poor biocompatibility, and relatively low treatment efficacy hamper its application in UM management. Herein, we developed a biocompatible CD44-targeting hyaluronic acid nanoparticle (HANP) carrying VP (HANP/VP) to improve UM treatment efficacy. We found that HANP/VP showed a stronger inhibitory effect on cell proliferation than that of free VP in UM cells. Systemic delivery of HANP/VP led to targeted accumulation in the UM-tumor-bearing mouse model. Notably, HANP/VP mediated photodynamic therapy (PDT) significantly inhibited UM tumor growth after laser irradiation compared with no treatment or free VP treatment. Consistently, in HANP/VP treated tumors after laser irradiation, the tumor proliferation and YAP expression level were decreased, while the apoptotic tumor cell and CD8+ immune cell levels were elevated, contributing to effective tumor growth inhibition. Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.

CXCR4-Targeted Macrophage-Derived Biomimetic Hybrid Vesicle Nanoplatform for Enhanced Cancer Therapy through Codelivery of Manganese and Doxorubicin.

Immune-cell-derived membranes have garnered significant attention as innovative delivery modalities in cancer immunotherapy for their intrinsic immune-modulating functionalities and superior biocompatibilities. Integrating additional parental cell membranes or synthetic lipid vesicles into cellular vesicles can further potentiate their capacities to perform combinatorial pharmacological activities in activating antitumor immunity, thus providing insights into the potential of hybrid cellular vesicles as versatile delivery vehicles for cancer immunotherapy. Here, we have developed a macrophage-membrane-derived hybrid vesicle that has the dual functions of transporting immunotherapeutic drugs and shaping the polarization of tumor-associated macrophages for cancer immunotherapy. The platform combines M1 macrophage-membrane-derived vesicles with CXCR4-binding-peptide-conjugated liposomes loaded with manganese and doxorubicin. The hybrid nanovesicles exhibited remarkable macrophage-targeting capacity through the CXCR4-binding peptide, resulting in enhanced macrophage polarization to the antitumoral M1 phenotype characterized by proinflammatory cytokine release. The manganese/doxorubicin-loaded hybrid vesicles in the CXCR4-expressing tumor cells evoked potent cancer cytotoxicity, immunogenic cell death of tumor cells, and STING activation. Moreover, cotreatment with manganese and doxorubicin promoted dendritic cell maturation, enabling effective tumor growth inhibition. In murine models of CT26 colon carcinoma and 4T1 breast cancer, intravenous administration of the manganese/doxorubicin-loaded hybrid vesicles elicited robust tumor-suppressing activity at a low dosage without adverse systemic effects. Local administration of hybrid nanovesicles also induced an abscessive effect in a bilateral 4T1 tumor model. This study demonstrates a promising biomimetic manganese/doxorubicin-based hybrid nanovesicle platform for effective cancer immunotherapy tailored to the tumor microenvironment, which may offer an innovative approach to combinatorial immunotherapy.

Abstract 3286: Synergistic impact of long non-coding RNA TUG1 depletion in overcoming temozolomide chemoresistance in glioblastoma

Abstract Glioblastoma (GBM) stands out as the most prevalent and aggressive primary brain tumor in adults, marked by a high mortality rate. Standard therapy involves temozolomide (TMZ) chemotherapy, an alkylating agent. However, most cases develop resistance to TMZ, necessitating the development of new treatment options to overcome TMZ-resistant GBM. Long non-coding RNAs (lncRNAs) constitute a class of RNA molecules that, despite not encoding proteins, play pivotal roles in regulating diverse cellular processes. Overexpression of specific lncRNAs in cancer is linked to crucial aspects of cancer progression, such as cell proliferation, apoptosis, and metastasis. Taurine upregulated gene 1 (TUG1) is a highly expressed lncRNA in GBM, playing a crucial role in preventing excessive DNA replication stress and associated DNA damage (Nat Commun 2023).This study aimed to investigate the combined effects of TUG1 depletion and TMZ in TMZ-resistant GBM. First, we established a TMZ-resistant U251MG cell line, U251MG-R, characterized by a low DNA methylation level of the O6-methylguanine-DNA methyltransferase (MGMT) promoter. We observed that TMZ increased DNA replication stress in the U251MG-R. Depleting TUG1 by using antisense oligonucleotide (TUG1-ASO) sensitized U251MG-R cells to TMZ. Treatment with TMZ or TUG1-ASO alone inhibited cell proliferation, with the most significant inhibition observed when both were combined. Next, we employed a xenograft mouse model to evaluate the efficacy of intravenous TUG1-ASO treatment coupled with a tumor-specific drug delivery system (antiTUG1-DDS). The combination of antiTUG1-DDS with TMZ displayed the most effective suppression of tumor growth compared to either TMZ or antiTUG1-DDS alone. Targeted therapy aimed at TUG1 may be a promising approach for overcoming TMZ resistance in GBM. Citation Format: Hidekazu Kito, Yuji Kibe, Miho Suzuki, Keiko Shinjo, Yutaka Kondo. Synergistic impact of long non-coding RNA TUG1 depletion in overcoming temozolomide chemoresistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3286.

Abstract 6741: Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer

Abstract Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide, causing substantial mortality. The urgent need for effective treatments has driven research into immune checkpoint blockade (ICB) therapies, which have demonstrated significant clinical benefits across various cancer types. Despite the success of ICB therapies, a significant proportion of CRC patients exhibit resistance to treatment, prompting the identification of mechanisms that hinder therapy resistance or enhance treatment response. CRC cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro-tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. In this study, we found that colorectal tumors with high glutaminase (GLS) expression exhibit reduced T-cell infiltration and cytotoxicity, leading to poor clinical outcomes. To validate these findings, we applied the ovalbumin (OVA)/OT-I T cell-based cytotoxicity assay and the CRC patient-derived organoids (PDOs)/autologous T cell killing assay. Our results indicated that inhibition of GLS significantly enhanced T-cell cytotoxicity in vitro and ex vivo. Mechanistically, we elucidated that inhibition of GLS activated reactive oxygen species-related signaling pathways in tumor cells, thereby potentially increasing tumor immunogenicity by promoting antigen presentation. The combinational therapy of GLS inhibitor and ICB exhibited a superior tumor growth inhibitory effect in comparison with either of the monotherapies. These findings shed new light on clinical therapeutic strategies for CRC patients, offering a promising approach to enhance the efficacy of ICB therapy. Citation Format: Tao Yu, Kevin Van der Jeught, Haiqi Zhu, Zhuolong Zhou, Samantha Sharma, Sheng Liu, Ka Man So, Haniyeh Eyvani, Xiyu Wang, George E. Sandusky, Yunlong Liu, Mateusz Opyrchal, Sha Cao, Jun Wan, Chi Zhang, Xinna Zhang. Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6741.