Inhibit Tumor Cell Growth Research Articles

Dual-Targeting AIE Polymer Micelles Mediate Immunogenic Sonodynamic Therapy for Tumor Cell Growth Inhibition and Macrophage Reprogramming.

Sonodynamic therapy (SDT) is a promising cancer treatment known for its deep tumor penetration and high efficacy. However, developing highly efficient sonosensitizers remains a significant challenge. Reports on SDT using aggregation-induced emission luminogens (AIEgens) are rare, highlighting the urgent need for novel AIE-active sonosensitizers. For the first time, we have developed tumor- and macrophage-targeting nano micelles, AIE/Biotin/Mannose-M (ABM-M), utilizing aggregation-induced emission polymers. The ABM-M mediate immunogenic cell death through SDT. By reprogramming tumor-associated macrophages (TAMs), they promote the conversion of M2 macrophages into M1 macrophages, reversing the tumor's immunosuppressive environment. We optimized the ratio of functional molecules to achieve maximum fluorescence intensity and reactive oxygen species (ROS) generation. The multi-targeting nature of ABM-M enables them to bind to relevant antibodies or other molecules, enhancing the capture and presentation of tumor antigens. This, in turn, activates the immune responses of dendritic cells and T cells while inhibiting angiogenesis, creating a more favorable microenvironment for antitumor therapy. Furthermore, ABM-M can be combined with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, to achieve promising outcomes in cancer immunotherapy. The ABM-M nanomaterials offer multi-layered and multi-targeting immune regulation. This study provides a blueprint for developing next-generation cancer diagnostic and therapeutic strategies. STATEMENT OF SIGNIFICANCE: Our research pioneers the use of nanomicelles to simultaneously target both tumor cells and tumor-associated macrophages (TAMs), integrated with sonodynamic therapy. Through precise ratio adjustments, we engineered nanomicelles capable of multi-target regulation. These micelles uniquely induce immunogenic cell death (ICD) and repolarize macrophages from an immunosuppressive M2 phenotype to an immunostimulatory M1 phenotype, reversing the tumor's immunosuppressive microenvironment. This dual mechanism can be enhanced by combining with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, offering a promising strategy to treat refractory cancers. Extensive in vitro and in vivo validation confirms their therapeutic potential, providing a solid foundation for clinical application. This innovative approach shows significant promise for revolutionizing cancer treatment and improving patient outcomes.

In vitro and In vivo Growth Inhibition and Apoptosis of Cancer Cells by Ethyl 4-[(4-methylbenzyl)oxy] Benzoate Complex.

Cancer chemotherapy is one of the best ways to treat the patients with cancer as they can remove cancer cells, which can't be remove by radiation or surgery. Our study is focused on identifying potent chemotherapeutic drugs with minor or no adverse side effects. Therefore, in this study, we aimed to synthesize ethyl 4-[(4-methylbenzyl)oxy] benzoate complex, a macrocyclic aromatic compound followed by testing its antineoplastic activity against Ehrlich ascites carcinoma (EAC) human breast cancer (MCF7) cells. In vitro and in vivo assays were used for monitoring, cytotoxicity, tumor weight, survival time, tumor cell growth inhibition, and hematological parameters to investigate the anticancer effectiveness of the tested compound. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to examine the expression of growth and apoptotic related genes. Haematological and biochemical parameters were assessed to examine the host toxicity in mice. The compound exhibited notable anticancer activity against both EAC and MCF7cells. It showed 40.70 and 58.98 % cell growth inhibition at the doses of 0.5 and 1.00 mg/kg, respectively in comparison to that of control EAC-bearing mice (p < 0.0001). The result is comparable with clinically used chemotherapeutic drugs cisplatin (59.2% growth inhibition at the dose of 1.0 mg/kg body weight). A four folds reduction of tumor weight (volume) of treated group at higher dose (1.0 mg/kg/day) was noted in comparison to that of untreated EAC-bearing mice. Also, the mean survival time of treated mice (1.00 mg/kg) increased by more than 83.07% when compared to that of control EAC-bearing mice (p<0.001). In addition, EAC-bearing control mice showed drastic deterioration of RBC, WBC, and % of hemoglobin, however, in the treated mice these parameters were restored towards normal levels. A dose dependent reduction of growth and proliferation of MCF7 cells was noted in compound treated cells. Most importantly, apoptosis of MCF7 was induced followed by activation of pro-apoptotic genes (p53, Bax, Parp, Caspase-3, -8, -9) and inactivation of antiapoptotic, e.g. Bcl2 gene. Toxicological studies reveal that there were changes in hematological (RBC, WBC, % of Hb) and biochemical (serum glucose, cholesterol, creatinine, SGOT, SGPT) parameters during the treatment period, however, the parameters returned towards normal levels after the treatment period, indicating no or minor toxic effect of the compound on the host. The compound has promising anticancer activity with no or minimum host toxic effects. Thus, it has the potential to be formulated as an effective chemo-agent, however, further preclinical and clinical research is imperative using animal and human models.

Cinnamaldehyde-Based ROS-Responsive Polymeric Gene Vectors for Efficient Gene Delivery and Tumor Cell Growth Inhibition.

Reactive oxygen species (ROS)-sensitive polymers are extensively used in cancer therapies. However, the ROS levels in the tumor microenvironment are often insufficient to trigger an adequate therapeutic response. Herein, we report a cinnamaldehyde (CA)-based ROS-responsive cationic polymer (PCA) and demonstrate its high efficiency in gene delivery and tumor cell growth inhibition. CA could be released from the polymer via a ROS-sensitive thioacetal bond by endogenous ROS. The released CA successively induced more ROS accumulation through GSH depletion, and the positive feedback helped PCA to achieve self-accelerating degradation. Results proved that PCA/p53 complexes were efficient in depleting GSH, upregulating ROS levels, and gene transfection. Besides, PCA was also shown to be effective in delivering the therapeutic gene p53. More importantly, PCA/p53 complexes could significantly induce tumor cell growth suppression by a synergistic effect of PCA and p53, providing valuable insights into the design of self-amplifying ROS-responsive polymeric gene vectors.

Emerging roles of mitochondrial sirtuin SIRT5 in succinylation modification and cancer development

Succinylation represents an emerging class of post-translational modifications (PTMs), characterized by the enzymatic or non-enzymatic transfer of a negatively charged four-carbon succinyl group to the ϵ-amino group of lysine residues, mediated by succinyl-coenzyme A. Recent studies have highlighted the involvement of succinylation in various diseases, particularly cancer progression. Sirtuin 5 (SIRT5), a member of the sirtuin family, has been extensively studied for its robust desuccinylase activity, alongside its deacetylase function. To date, only a limited number of SIRT5 substrates have been identified. These substrates mediate diverse physiological processes such as glucose oxidation, fatty acid oxidation, ammonia detoxification, reactive oxygen species scavenging, anti-apoptosis, and inflammatory responses. The regulation of these activities can occur through either the same enzymatic activity acting on different substrates or distinct enzymatic activities targeting the same substrate. Aberrant expression of SIRT5 has been closely linked to tumorigenesis and disease progression; however, its role remains controversial. SIRT5 exhibits dual functionalities: it can promote tumor proliferation, metastasis, drug resistance, and metabolic reprogramming, thereby acting as an oncogene; conversely, it can also inhibit tumor cell growth and induce apoptosis, functioning as a tumor suppressor gene. This review aims to provide a comprehensive overview of the current research status of SIRT5. We discuss its structural characteristics and regulatory mechanisms, compare its functions with other sirtuin family members, and elucidate the mechanisms regulating SIRT5 activity. Specifically, we focus on the role of succinylation modification mediated by SIRT5 in tumor progression, highlighting how desuccinylation by SIRT5 modulates tumor development and delineating the underlying mechanisms involved.

Verticillin A-Loaded Surgical Buttresses Prevent Local Pancreatic Cancer Recurrence in a Murine Model.

The fungal metabolite verticillin A is a potent and selective histone methyltransferase inhibitor. It regulates apoptosis, the cell cycle, and stress response, and displays potent activity in the suppression of tumor cell growth in several different in vivo models. Verticillin A sensitizes pancreatic cancer cells to anti-PD-1 immunotherapy by regulating PD-L1 expression. However, as with many natural products, delivery and systemic toxicity are challenges that must be overcome to advance their use as a chemotherapeutic. To both reduce systemic toxicity and improve delivery, we report a verticillin A-loaded surgical buttress, which is well-tolerated at a dose as high as 40 mg/kg. In contrast, free verticillin A administered systemically results in toxicity at a dose of 3 mg/kg. The verticillin A-loaded buttress suppresses tumor recurrence in vivo in a safe and dose-dependent manner against a highly aggressive and metastatic model of pancreatic cancer.

A Hydrogel for Nitric Oxide Sensitization Chemotherapy Mediated by Tumor Microenvironment Changes in 3D Spheroids and Breast Tumor Models.

Nitric oxide (NO) is a low-toxicity and high-efficiency anticancer treatment that can augment the cytotoxicity of doxorubicin (DOX) towards breast cancer cells, thereby exhibiting a favorable effect on chemotherapy sensitization. The study aimed to establish a hydrogel that sensitizes chemotherapy by inducing local inflammatory stimulation to change the tumor microenvironment and promote NO production. The purpose of the study was to examine the anti-tumor effect in vivo and in vitro. The functional properties of the composite hydrogels were tested by UV spectrophotometry and NO detection kit. CCK8, DCFH-DA fluorescent probe, Calcein-AM/PI detection kit, and confocal detection methods were used for the cytocompatibility and cytotoxicity of the composite hydrogels. The subcutaneous tumor volume, weight, and tumor inhibition rate of 4T1 breast cancer cells were evaluated for pharmacodynamic study in vivo. Each component of hydrogel has good biocompatibility. The combination of gas therapy and chemotherapy can significantly enhance the effect of inhibiting tumor cell growth. The tumor growth of tumor- bearing mice in the hydrogel administration group was slow, and the tumor inhibition rate was 85.10%. The body weight grew steadily, and no significant pathological changes were observed in the H&E staining of major organs. A composite hydrogel with alginate as the carrier was successfully established, which was based on improving the tumor microenvironment to trigger gas therapy combined with chemotherapy for tumor treatment.

Developing novel Lin28 inhibitors by computer aided drug design

Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In this contribution, we applied computer-aided drug design (CADD) in combination with quantitative biochemical and biological assays. These efforts led to the discovery of Ln268 as a drug candidate that can block Lin28 from binding to its RNA substrates and inhibit Lin28 activities. Ln268 suppressed Lin28-mediated cancer cell proliferation and spheroid growth. Results from nuclear magnetic resonance spectroscopy confirmed that Ln268 perturbs the conformation of the zinc knuckle domain of Lin28, validating the rational drug design by CADD. The inhibitory effects of Ln268 are dependent on Lin28 protein expression in cancer cells, highlighting limited off-target effects of Ln268. Moreover, Ln268 synergizes with several chemotherapy drugs to suppress tumor cell growth. In summary, Ln268 is a promising candidate for further development to target Lin28 as a cancer therapy.

A DNA origami-based enzymatic cascade nanoreactor for chemodynamic cancer therapy and activation of antitumor immunity.

Chemodynamic therapy (CDT) is a promising and potent therapeutic strategy for the treatment of cancer. We developed a DNA origami-based enzymatic cascade nanoreactor (DOECN) containing spatially well-organized Au nanoparticles and ferric oxide (Fe2O3) nanoclusters for targeted delivery and inhibition of tumor cell growth. The DOECN can synergistically promote the generation of hydrogen peroxide (H2O2), consumption of glutathione, and creation of an acidic environment, thereby amplifying the Fenton-type reaction and producing abundant reactive oxygen species, such as hydroxyl radicals (•OH), for augmenting the CDT outcome. The DOECN is decorated with targeting groups to achieve efficient cellular uptake and efficiently induce tumor cell apoptosis, ferroptosis, and immunogenetic cell death, thus realizing potent anticancer therapeutic effects. Intravenous injection of the DOECN effectively promoted the maturation of dendritic cells, triggered adaptive T cell responses, and suppressed tumor growth in a murine cancer model. The DOECN provides a programmable platform for the integration of multiple therapeutic components, showing great potential for combined cancer therapy.

Artificial intelligence-driven identification and mechanistic exploration of synergistic anti-breast cancer compound combinations from Prunella vulgaris L.-Taraxacum mongolicum Hand.-Mazz. herb pair.

The Prunella vulgaris L. (PVL) and Taraxacum mongolicum Hand.-Mazz. (TH) herb pair, which is commonly used in traditional Chinese medicine (TCM), has been applied for the treatment of breast cancer. Although its efficacy is validated, the synergistic anti-breast cancer compound combinations within this herb pair and their underlying mechanisms of action remain unclear. This study aimed to identify and validate synergistic anti-breast cancer compound combinations within the PVL-TH pair using large-scale biomedical data, artificial intelligence and experimental methods. The first step was to investigate the anti-breast cancer effects of various PVL and TH extracts using in vitro cellular assays to identify the most effective superior extracts. These superior extracts were subjected to liquid chromatography-mass spectrometry (LC-MS) analysis to identify their constituent compounds. A deep learning-based prediction model, DeepMDS, was applied to predict synergistic anti-breast cancer multi-compound combinations. These predicted combinations were experimentally validated for their anti-breast cancer effects at actual content ratios found in the extracts. Preliminary bioinformatics analyses were conducted to explore the mechanisms of action of these superior combinations. We also compared the anti-breast cancer effects of superior extracts from different geographical origins and analyzed the contents of compounds to assess their representation of the anti-tumor effect of the corresponding TCM. The results revealed that LC-MS analysis identified 27 and 21 compounds in the superior extracts (50% ethanol extracts) of PVL and TH, respectively. Based on these compounds, DeepMDS model predicted synergistic anti-breast cancer compound combinations such as F973 (caffeic acid, rosmarinic acid, p-coumaric acid, and esculetin), T271 (chlorogenic acid, cichoric acid, and caffeic acid), and T1685 (chlorogenic acid, rosmarinic acid, and scopoletin) from single PVL, single TH and PVL-TH herb pair, respectively. These combinations, at their actual concentrations in extracts, demonstrated superior anti-breast cancer activity compared to the corresponding extracts. The bioinformatics analysis revealed that these compounds could regulate tumor-related pathways synergistically, inhibiting tumor cell growth, inducing cell apoptosis, and blocking cell cycle progression. Furthermore, the concentration ratio and total content of compounds in F973 and T271 were closely associated with their anti-breast cancer effects in extracts from various geographical origins. The compound combination T1685 could represent the synergistic anti-breast cancer effects of the PVL-TH pair. This study provides insights into exploring the representative synergistic anti-breast cancer compound combinations within the complex TCM.

Bacopaside I, acting as an aquaporin 1 inhibitor, ameliorates rheumatoid arthritis via suppressing aquaporin 1-mediated autophagy.

Aquaporin 1 (AQP1) is a promising target for regulating fibroblast-like synoviocyte (FLS) behaviors in rheumatoid arthritis (RA). Bacopaside I (BSI), the main active compound of the herbal medicine Bacopa monnieri with anti-RA effects, inhibits tumor cell growth by blocking AQP1, but its potential use in RA is unclear. To address BSI's anti-RA effects and elucidate its underlying mechanisms. We investigated BSI's therapeutic effects on TNF-α-induced RA FLS and identified AQP1 as its direct target through molecular docking, cellular thermal shift assay (CETSA), and AQP1 knockdown experiments. We studied BSI's impacts on rat adjuvant-induced arthritis (AIA) and synovial proliferation, apoptosis, and autophagy in AIA rat synovium. We explored the role of autophagy inhibition in BSI's effects in vitro and in vivo by co-treating with the autophagy activator rapamycin (Rapa) and/or the inhibitor 3-methyladenine (3-MA). BSI suppressed proliferation, promoted apoptosis, and reduced autophagy in TNF-α-stimulated RA FLS. Notably, BSI's in vitro effects were reduced by Rapa and enhanced by 3-MA. The molecular docking and CETSA confirmed BSI's binding to AQP1, while AQP1 knockdown invalidated BSI's in vitro effects, further indicating AQP1 as the target of BSI. In vivo, BSI attenuated the severity of rat AIA, alongside reduced synovial proliferation, increased apoptosis, and decreased autophagy within AIA rat synovium. Moreover, Rapa co-treatment negated BSI's effects on synovial proliferation and apoptosis and abolished its anti-AIA activity. BSI, as an AQP1 inhibitor, hindered AQP1-mediated autophagy, causing increased apoptosis, reduced proliferation in RA FLS, and relieved rat AIA symptoms.

M6A methyltransferase METTL3 promotes non-small-cell lung carcinoma progression by inhibiting the RIG-I-MAVS innate immune pathway

Our experimental study showed that METTL3 was highly expressed in NSCLC cells and promoted the growth of tumor cells. METTL3 takes N6-methyladenosine (m6A) as the main means of mRNA modification to control the expression and function of RIG-I-MAVS signalling pathway. RIG-I-MAVS constitute the first line frontier in the innate immune defense of human cells. Activation of RIG-I-MAVS signaling can inhibit tumor cell growth and activate the immune microenvironment. Our experimental data reveal that lung cancer cells utilize METTL3-mediated methylation modifications to inhibit the activation of RIG-I-MAVS signaling pathway and immune responses. Our work provides new ideas for biotherapy and immunotherapy.

Fasting enhances the efficacy of Sorafenib in breast cancer via mitophagy mediated ROS-driven p53 pathway.

The multi-kinase inhibitor sorafenib has shown potential to inhibit tumor cell growth and intra-tumoral angiogenesis by targeting several kinases, including VEGFR2 and RAF. Abnormal activation of the Ras/Raf/MAPK/ERK kinase cascade and the VEGF pathway is a common feature in breast cancer. However, the efficacy of sorafenib in breast cancer treatment remains limited. Recently, fasting has emerged as a promising non-pharmacological approach to modulate cancer metabolism and enhance the effectiveness of cancer therapies. In this study, we found that fasting significantly enhances the anti-cancer effects of sorafenib monotherapy and its combination with immunotherapy in breast cancer models without causing obvious side effects. This combined treatment effectively inhibits tumor cell proliferation and intra-tumoral angiogenesis. The fasting-induced reduction in peripheral blood glucose levels strongly correlated with enhanced sensitivity to sorafenib. Mechanistically, the combined treatment induced mitophagy, characterized by mitochondrial dysfunction and activation of the PINK1-Parkin pathway. Consequently, increased mitochondrial ROS levels promoted p53 expression, amplifying cell cycle arrest and apoptosis in breast cancer cells. Furthermore, fasting reduced lactate levels within the tumor, and the consequent glucose limitation synergized with sorafenib to activate AMPK, which in turn elevated PD-L1 expression in tumor cells, potentially enhancing their sensitivity to immunotherapy. In summary, our findings demonstrate that fasting and sorafenib, as a rational combination therapy, induce mitophagy, thereby enhancing sorafenib's efficacy in treating breast cancer through the ROS-driven p53 pathway. This study underscores the potential of fasting in breast cancer therapy and provides a foundation for optimizing the clinical application of sorafenib.

S6K1 is a Targetable Vulnerability in Tumors Exhibiting Plasticity and Therapy Resistance.

Background: Most tumors initially respond to treatment, yet refractory clones subsequently develop owing to resistance mechanisms associated with cancer cell plasticity and heterogeneity. Methods: We used a chemical biology approach to identify protein targets in cancer cells exhibiting diverse driver mutations and representing models of tumor lineage plasticity and therapy resistance. An unbiased screen of a drug library was performed against cancer cells followed by synthesis of chemical analogs of the most effective drug. The cancer subtype target range of the leading drug was determined by PRISM analysis of over 900 cancer cell lines at the Broad Institute, MA. RNA-sequencing and enrichment analysis of differentially expressed genes, as well as computational molecular modeling and pull-down with biotinylated small molecules were used to identify and validate RPS6KB1 (p70S6K or S6K1) as an essential target. Genetic restoration was used to test the functional role of S6K1 in cell culture and xenograft models. Results: We identified a novel derivative of the antihistamine drug ebastine, designated Super-ebastine (Super-EBS), that inhibited the viability of cancer cells representing diverse KRAS and EGFR driver mutations and models of plasticity and treatment resistance. Interestingly, PRISM analysis indicated that over 95% of the diverse cancer cell lines tested were sensitive to Super-EBS and the predicted target was the serine/threonine kinase S6K1. S6K1 is upregulated in various cancers relative to counterpart normal/benign tissues and phosphorylated-S6K1 predicts poor prognosis for cancer patients. We noted that inhibition of S6K1 phosphorylation was necessary for tumor cell growth inhibition, and restoration of phospho-S6K1 rendered tumor cells resistant to Super-EBS. Inhibition of S6K1 phosphorylation by Super-EBS induced caspase-2 dependent apoptosis via inhibition of the Cdc42/Rac-1/p-PAK1 pathway that led to actin depolymerization and caspase-2 activation. The essential role of S6K1 in the action of Super-EBS was recapitulated in xenografts, and knockout of S6K1 abrogated tumor growth in mice. Conclusion: S6K1 is a therapeutic vulnerability in tumors exhibiting intrinsic and/or acquired resistance to treatment.

Melanoma cell line-derived exosomal miR-424-5p: a key promoter of angiogenesis through LATS2 interaction.

Melanoma is a highly aggressive and metastatic form of cancer, and the role of exosomal microRNAs (miRNAs) in its progression remains largely unexplored. This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms. Exosomes were isolated from melanoma cell lines A375 and A2058, and their effects on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were examined. The interaction between miR-424-5p and its target gene, large tumor suppressor kinase 2 (LATS2), was analyzed using luciferase reporter assays and functional experiments. In vivo, tumor growth and angiogenesis were studied in a xenograft model using nude mice. Melanoma cell-derived exosomes could be internalized by HUVECs, which promoted proliferation, migration, and angiogenesis. miR-424-5p was highly expressed in melanoma cells and their exosomes, and its inhibition in exosomes suppressed HUVEC proliferation, migration, and angiogenesis. LATS2 was identified as a direct target of miR-424-5p, and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions. In vivo, exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models. Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2, contributing to melanoma progression. Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.

Tropisetron-Induced Apoptosis: A Study on SKOV3 Cell Viability and Gene Expression

Background: Ovarian tumors account for 1% of all childhood neoplasms and are the most common genital neoplasm in children. Considering the role of serotonin in the promotion of tumor growth and metastasis in some cancers, tropisetron as a 5-hydroxytryptamine (5-HT3) receptor antagonist can exert anti-neoplastic effects. The current study seeks to determine the association between the use of tropisetron and ovarian cancer­cell lines (SKOV3) by evaluating apoptotic regulators. Materials and Methods: In this experimental study, after the addition of tropisetron to SKOV3 cancer cells at the concentrations of 1, 10, and 100 μM, the MTT assay was employed to assess the cell viability percentage within 24, 48, and 72 hours. The level of expression of Bcl2 and Bax genes after 24 hours were determined by Real Time-PCR, and Caspase 3 enzyme activity was measured by the ELISA method. Differences between groups were statistically analyzed by one-way analysis of variance (ANOVA). A p-value less than 0.05 is considered to be statistically significant. Results: Based on the MTT test, tropisetron significantly decreased the viability of SKOV3 cancer cells. It decreased the levels of Bcl2 expression according to real-time PCR results (P =0.0015) but increased the expression levels of Bax (P = 0.011) in SKOV3 cells. Both caspase-3 enzyme activity and the ratio of Bax to Bcl2 expression (Bax/Bcl2) were increased (P = 0.008 and P = 0.011, respectively). Conclusion: Tropisetron could inhibit tumor cell growth via apoptosis induction and exert proapoptotic effects in an ovarian cancer ¬cell line. Therefore, it seems that it can be considered as a possible chemotherapy drug for ovarian cancer. However, more studies should be conducted in this regard.

Safety and Efficacy of Tinostamustine in a Subpopulation of Patients With Relapsed/Refractory Hodgkin Lymphoma From a Phase I Trial.

A significant unmet need remains for patients with Hodgkin lymphoma (HL) who fail to respond to first-line treatment or experience an early relapse. Tinostamustine, a novel alkylating deacetylase inhibitor, inhibits tumor cell growth and slows disease progression in models of hematological malignancies and solid tumors. This was a Phase I, multicenter, open-label, two-stage trial investigating the safety and efficacy of tinostamustine in patients ≥ 18years with relapsed/refractory (R/R) hematological malignancies, including HL. Stage 1 involved dose-escalation to determine the maximum tolerated dose (MTD) of tinostamustine, optimal infusion time and recommended Phase II dose (RP2D). Stage 2 confirmed the safety and efficacy of the RP2D in expansion cohorts of selected R/R hematological malignancies. Ten patients with heavily pre-treated HL entered dose-escalation, with nine patients experiencing treatment-emergent adverse events (TEAEs) considered to be related to study treatment-primarily hematological toxicities. MTD was 100mg/m2 tinostamustine over 60min and signals of efficacy were observed for patients with HL. In Stage 2, all 20 patients with HL experienced ≥ 1 TEAE, which were principally hematological or gastrointestinal. There were no tinostamustine-related deaths in either stage of the study. Overall response rate in Stage 2 was 37% (2 complete responses, 5 partial responses; 95% confidence interval [CI]: 16%, 62%) and median progression-free survival 3.8months (95% CI: 2.2-9.4months). Tinostamustine is a promising new therapeutic approach for the treatment of patients with R/R classical HL with limited options. This study demonstrates a predictable and manageable safety profile with signals of efficacy. Trial Registration: ClinicalTrials.gov identifier: NCT02576496.

Balancing CIK Cell Cancer Immunotherapy and PPAR Ligands: One Potential Therapeutic Application for CNS Malignancies.

Cytokine-induced killer (CIK) cell therapy has proven successful in clinical trials regarding glioblastoma. Equally important are the hints suggesting peroxisome proliferator-activated receptors (PPARs) ligands being co-expressed in the central nervous system (CNS). This provides a rationale about investigating the possible synergistic effect of CIK cells and PPARs. We investigated neuroblastoma and glioblastoma cell lines with mature CIK cells and the PPARγ antagonist GW-9662 to assess the effects on cell viability, candidate gene expression (Wnt/β-catenin signalling, DNMT1) and global methylation levels (5-methylcytosine, LINE-1). Using a clinical applicable PPAR-γ inhibitor, we showed that (1) PPARγ-antagonist GW-9662 suppressed tumor cell growth in both neuroblastoma and glioblastoma cells, (2) PPARγ inhibition had restricted effect on the expression of Wnt/β-catenin associated genes, (3) inhibition of PPARγ led to downregulation of DNMT1 expression, supporting their hypothesized interaction in cancer, (4) a partial modulation of global LINE-1 methylation levels was observed, indicating their role in epigenetic processes, and (5) Combining PPARγ inhibition with CIK cell immunotherapy enhanced cell lysis significantly. We provide evidence that PPAR ligands in combination with CIK cell immunotherapy could be a valuable option for malignant CNS tumors.

M6A Reader PRRC2A Promotes Colorectal Cancer Progression via CK1ε-Mediated Activation of WNT and YAP Signaling Pathways.

Colorectal cancer (CRC) is the third most common cancer type and the second highest mortality rate among cancers. However, the mechanisms underlying CRC progression remain to be fully understood. In this work, a recently identified m6A-modified RNA reader protein Proline-rich Coiled-coil 2a (PRRC2A)is markedly upregulated in CRC, and intestinal epithelium-specific deletion of Prrc2a significantly suppressed tumor cell growth, stemness, and migratory capacity, while its overexpression promoted these behaviors. Through multiomics analysis, PRRC2A directly targeted CSNK1E (encoding CK1ε), maintaining its RNA stability in an m6A-dependent manner, and that elevated CK1ε can concomitantly result in activation of the WNT and YAP signaling pathways. Interestingly, PRRC2A is directly regulated by the transcription factor ATF1 in its promoter. In summary, the work reveals a novel mechanism by which m6A reader PRRC2A promotes colorectal cancer progression via CK1ε and aberrant upregulation of WNT and YAP signaling. Therefore, PRRC2A and CK1ε can be potential therapeutic targets for treating CRC.

Stearoyl-CoA desaturase in CD4+ T cells suppresses tumor growth through activation of the CXCR3/CXCL11 axis in CD8+ T cells

BackgroundWithin the tumor microenvironment, altered lipid metabolism promotes cancer cell malignancy by activating oncogenic cascades; however, impact of lipid metabolism in CD4+ tumor-infiltrating lymphocytes (TILs) remains poorly understood. Here, we elucidated that role of stearoyl-CoA desaturase (SCD) increased by treatment with cancer-associated fibroblast (CAF) supernatant in CD4+ T cells on their subset differentiation and activity of CD8+ T cells.ResultsIn our study, we observed that CD4+ TILs had higher lipid droplet content than CD4+ splenic T cells. In tumor tissue, CAF-derived supernatant provided fatty acids to CD4+ TILs, which increased the expression of SCD and oleic acid (OA) content. Increased SCD expression by OA treatment enhanced the levels of Th1 cell markers TBX21, interleukin-2, and interferon-γ. However, SCD inhibition upregulated the expression of regulatory T (Treg) cell markers, FOXP3 and transforming growth factor-β. Comparative fatty acid analysis of genetically engineered Jurkat cells revealed that OA level was significantly higher in SCD-overexpressing cells. Overexpression of SCD increased expression of Th1 cell markers, while treatment with OA enhanced the transcriptional level of TBX21 in Jurkat cells. In contrast, palmitic acid which is higher in SCD-KO cells than other subclones enhanced the expression of Treg cell markers through upregulation of mitochondrial superoxide. Furthermore, SCD increased the secretion of the C–X–C motif chemokine ligand 11 (CXCL11) from CD4+ T cells. The binding of CXCL11 to CXCR3 on CD8+ T cells augmented their cytotoxic activity. In a mouse tumor model, the suppressive effect of CD8+ T cells on tumor growth was dependent on CXCR3 expression.ConclusionThese findings illustrate that SCD not only orchestrates the differentiation of T helper cells, but also promotes the antitumor activity of CD8+ T cells, suggesting its function in adverse tumor microenvironments.Graphical abstract

Abstract B026: Glioblastoma multiforme disseminates outside the central nervous system

Abstract Introduction: The liquid biopsy (LB) concept has gained significant attention in the last decade and has the potential to revolutionize cancer care. However, more validation in clinical trials is required on the value of LB in medical settings. Here, we focus on glioblastoma multiforme (GBM), a highly invasive and fatal subtype of the central nervous system malignant tumors. Circulating tumor cells (CTCs) are primary tumor cells released into the peripheral blood and migrating to distant organs. CTC presence is related to tumor spread and recurrence. In GBM, factors like short patient survival, the blood-brain barrier (BBB), and lack of lymphatic drainage in brain tissue make systemic dissemination rare but possible. Thus, noninvasive CTC detection can hold potential for diagnostic, predictive, and prognostic applications. Material and Methods: For cell stability preservation before sample processing, the peripheral blood samples from curatively resected GBM patients were collected preoperatively in Cell-Free DNA BCT® tubes (Streck, Inc.). CTCs were identified using CytoTrack CT11TM (2/C), a semi-automated immunofluorescence microscopy using glial fibrillary acidic protein, vimentin, and CD45 immunostaining, and DAPI counterstaining. The preliminary Kaplan-Maier survival analysis based on CTC positivity was performed in 39 patients with a follow-up longer than two years. Results: We analyzed the CTC presence in 100 GBM patient peripheral blood samples. The CTCs or cancer cell clusters were found in 35% of GBM patients. The Kaplan-Maier survival analysis did not show a correlation between CTC presence and survival. This phenomenon may be associated with the generally short survival of these patients, which is expected to increase with advances in oncology and palliative care and/or a possible suppression of tumor cell growth outside the CNS. Conclusions: We have observed the CTCs in the peripheral blood of GBM patients. The patient enrollment and clinical data recording are still ongoing. Citation Format: Pavel Stejskal, Josef Srovnal, Alona Rehulkova, Ondrej Kalita, Marek Slachta, Marian Hajduch. Glioblastoma multiforme disseminates outside the central nervous system [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B026.