Prevent Tumor Development Research Articles

The role of curcumin in modulating circular RNAs and long non-coding RNAs in cancer.

Cancer is one of the primary causes of human disease and death, with high morbidity and mortality rates. Chemotherapy, one of the most common therapeutic techniques, functions through a variety of mechanisms, including the production of apoptosis and the prevention of tumor development. Herbal medicine has been the subject of numerous investigations due to its potential as a valuable source of innovative anti-cancer products that target multiple protein targets and cancer cell genomes. Curcumin, a polyphenol that is the major bioactive ingredient of turmeric, exhibits pharmacological and biological efficacy with antioxidant, anti-inflammatory, anticancer, cardioprotective, neuroprotective, and hypoglycemic activity in humans and animals. Recent research suggests that curcumin changes noncoding RNA (ncRNA), such as long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), in various types of cancers. Both circRNAs and lncRNAs are ncRNAs that can epigenetically modulate the expression of multiple genes via post-transcriptional regulation. In this study, we outline curcumin's activities in modulating signaling pathways and ncRNAs in various malignancies. We also described curcumin's regulatory function, which involves blocking carcinogenic lncRNAs and circRNAs while increasing tumor-suppressive ones. Furthermore, we intend to demonstrate how ncRNAs and signaling pathways interact with each other across regulatory boundaries to gain a better understanding of how curcumin fights cancer and create a framework for its potential future therapeutic uses.

Targeting immunosenescence for improved tumor immunotherapy

AbstractTumor immunotherapy has significantly transformed the field of oncology over the past decade. An optimal tumor immunotherapy would ideally elicit robust innate and adaptive immune responses within tumor immune microenvironment (TIME). Unfortunately, immune system experiences functional decline with chronological age, a process termed “immunosenescence,” which contributes to impaired immune responses against pathogens, suboptimal vaccination outcomes, and heightened vulnerability to various diseases, including cancer. In this context, we will elucidate hallmarks and molecular mechanisms underlying immunosenescence, detailing alterations in immunosenescence at molecular, cellular, organ, and disease levels. The role of immunosenescence in tumorigenesis and senescence‐related extracellular matrix (ECM) has also been addressed. Recognizing that immunosenescence is a dynamic process influenced by various factors, we will evaluate treatment strategies targeting hallmarks and molecular mechanisms, as well as methods for immune cell, organ restoration, and present emerging approaches in immunosenescence for tumor immunotherapy. The overarching goal of immunosenescence research is to prevent tumor development, recurrence, and metastasis, ultimately improving patient prognosis. Our review aims to reveal latest advancements and prospective directions in the field of immunosenescence research, offering a theoretical basis for development of practical anti‐immunosenescence and anti‐tumor strategies.

Regulation of m6A (N6-Methyladenosine) methylation modifiers in solid cancers.

Solid cancers constitute a tremendous burden on global healthcare, requiring a deeper understanding of the molecular mechanisms underlying cancer development and progression. Epigenetic changes, notably N6-methyladenosine (m6A) RNA methylation, have emerged as important contributors to the biology of solid tumors in recent years. This epigenetic mark dynamically affects gene expression at the post-transcriptional level and modulates a variety of cellular processes, making it a focus of research in the context of solid tumors. m6A modification patterns are dysregulated in a variety of solid cancers, including ovarian, breast, lung, colorectal, pancreatic, and others. This dysregulated m6A landscape has been shown to induce significant changes in the expression of oncogenes, tumor suppressors, and genes involved in cancer stem cells, metastasis, and treatment resistance. In solid tumors, the interaction of m6A "writers" (e.g., METTL3, METTL14, and others), "erasers" (e.g., ALKBH5, FTO), and "readers" (e.g., members of YTHDF proteins and others) delicately changes the m6A methylome. Targeting m6A regulators as a potential therapeutic method to control gene expression and prevent tumor development seems a novel strategy. To enhance treatment results, advances in this area of research have led to the development of targeted treatments aiming at restoring or altering m6A alteration patterns in solid tumors.

Nutritional aspects in neuroendocrine neoplasms. bridging the gap between dietary interventions and cancer care strategies: a scoping review.

Neuroendocrine neoplasms (NENs) represent heterogeneous tumors arising from neuroendocrine cells in different organs. Despite growing interest in the nutritional aspects of NEN management, research in this area is limited. Aim of this review is to summarize the current state of knowledge, highlight research gaps, and underscore the significance of nutrition in the comprehensive care of NEN patients. We conducted an extensive bibliographic search focusing on studies (including retrospective and prospective studies, systematic reviews, case series, and guidelines) exploring the relationship between nutritional assessments, dietary interventions, micronutrient deficiencies, and their impact on NEN outcomes. Significant gaps exist in current research, particularly in understanding the specific nutritional needs of NEN patients and how tailored nutritional interventions can improve clinical outcomes. Evidence suggests that a high-fat Western diet may promote the growth of NEN, while a Mediterranean diet may help lower insulin levels and strengthen the immune system, potentially preventing tumor development. The ketogenic diet and intermittent fasting may also have positive impacts. Addressing common micronutrient deficiencies, such as vitamin D and niacin, is crucial to mitigate disease progression. There's a crucial need for future studies to include a comprehensive nutritional assessment incorporating patient-reported outcomes, to fully capture the impact of nutritional strategies. Nutritional management, an important but under-researched facet of NEN treatment, significantly improves patients' quality of life and survival. Integrating nutrition into personalized cancer care is essential, highlighting the role of nutritional strategies in optimizing patient outcomes.

Exploring Piperine: Unleashing the multifaceted potential of a phytochemical in cancer therapy.

Radiotherapy is a cornerstone in the treatment of solid tumors, with extensive Phase III trials confirming its effectiveness. As advancements in treatment technologies and our understanding of tumor resistance mechanisms continue, the role of radiation oncology is set to become even more pivotal. Addressing the global challenge of lethal cancers demands innovative strategies, particularly in minimizing the side effects associated with traditional chemotherapy and ionizing radiation (IR). Recently, there has been growing interest in natural compounds for radioprotection, aiming to prevent tumor development and metastasis. Piperine, a compound found in black and long pepper, has emerged as a promising chemopreventive agent that works effectively without harming normal cells. Mechanistically, piperine modulates key signaling pathways, inhibits cancer cell migration and invasion, and enhances sensitivity to IR. Combining piperine with radiotherapy offers a compelling approach, boosting treatment efficacy while protecting healthy tissues from radiation damage. Piperine's versatile role goes beyond radiosensitization to include radioprotection by inhibiting NF-κB activation, reducing autophagy, and promoting apoptosis in cancer cells. This dual action makes it a promising candidate for personalized cancer care. As research advances, the therapeutic potential of piperine may drive new frontiers in cancer treatment strategies.

Lipopolyplex-formulated mRNA cancer vaccine elicits strong neoantigen-specific T cell responses and antitumor activity.

mRNA neoantigen cancer vaccine inducing neoantigen-specific T cell responses holds great promise for cancer immunotherapy; however, its clinical translation remains challenging because of suboptimal neoantigen prediction accuracy and low delivery efficiency, which compromise the in vivo therapeutic efficacy. We present a lipopolyplex (LPP)-formulated mRNA cancer vaccine encoding tandem neoantigens as a cancer therapeutic regimen. The LPP-formulated mRNA vaccines elicited robust neoantigen-specific CD8+ T cell responses in three syngeneic murine tumor models (CT26, MC38, and B16F10) to suppress tumor growth. Prophylactic cancer vaccine treatment completely prevented tumor development, and long-lasting memory T cells protected mice from tumor cell rechallenge. Combining the vaccine with immune checkpoint inhibitor further boosted the antitumor activity. Of note, LPP-based personalized cancer vaccine was administered in two cancer patients and induced meaningful neoantigen-specific T cell and clinical responses. In conclusion, we demonstrated that the LPP-based mRNA vaccine can elicit strong antitumor immune responses, and the results support further clinical evaluation of the therapeutic mRNA cancer vaccine.

MiRNAs that regulate apoptosis in breast cancer and cervical cancer.

In today's world, one of the main problems is cancer, which still has a long way to go to cure it, and it brings a lot of financial and emotional costs to the people of society and governments. Breast cancer (BC) and cervical cancer (CC), two of the most common cancers, are caused by several genetic and environmental factors in women. These two cancers' involvement rate is higher than other cancers in women. microRNAs (miRNAs) are non-coding RNA molecules with a length of 18 to 24 nucleotides, which play an important role in post-translational changes. miRNAs themselves are divided into two categories, oncomiRs and tumor suppressors. OncomiRs have a part in tumor expansion and tumor suppressors prevent tumor development and progress. miRNAs can control cellular processes by regulating various pathways including autophagy, apoptosis, and signaling. Apoptosis is a type of programmed cell death that includes intrinsic and extrinsic pathways and is different from other cell death pathways such as necrosis and ferroptosis. Apoptosis controls the growth, differentiation, and death of cells by regulating the death of damaged and old cells, and since miRNAs are one of the factors that regulate apoptosis, and divided into two categories: pro-apoptotic and anti-apoptotic. We decided in this study to investigate the relationship between miRNAs and apoptosis in the most common women's cancers, BC and CC.

Role of Nutrients Regulating Myeloid Derived Suppressor Cells in Cancer: A Scoping Review.

Myeloid-derived suppressor cells (MDSCs) are immature cells with an immunosuppressive function. MDSCs have been related to inflammation in many settings, including infections, transplantation, obesity, aging, or cancer. In oncological settings, MDSCs participate in tumor immunoescape, growth, and metastasis. Certain nutrients can modify chronic inflammation by their interaction with MDSCs. Therefore, the possible influence of certain nutrients on immune surveillance by their actions on MDSCs and how this may affect the prognosis of cancer patients were evaluated in this scoping review. We identified seven papers, six of which were murine model studies and only one was a human clinical trial. Globally, a significant reduction in cancer growth and progression was observed after achieving a reduction in both MDSCs and their immunosuppressive ability with nutrients such as selected vegetables, icaritin, retinoic acid, curdlan, active vitamin D, soy isoflavones, and green tea. In conclusion, the consumption of certain nutrients may have effects on MDSCs, with beneficial results not only in the prevention of tumor development and growth but also in improving patients' response.

Pre-clinical safety and efficacy evaluation of sodium chloride nanoparticles for treating non-muscle invasive bladder cancer.

e14591 Background: Non-muscle invasive bladder cancer (NMIBC) presents a significant therapeutic challenge. Current treatment modalities such as BCG and intravesical chemotherapy given after transurethral resection of bladder tumors (TURBT), while effective, are associated with high cost burdens and are difficult for patients to tolerate due to side effects. This ultimately limits treatment regimen duration and decreases the effectiveness of the therapy which frequently leads to local recurrence. Sodium Chloride Nanoparticles (NaCl-NPs) have previously shown promise in preclinical models of intra-tumoral injection of various tumor types but has not been tested in more clinically relevant models of bladder cancer. In this study, we evaluate the safety and efficacy of NaCl-NPs as a local intravesical therapy for preventing tumor development in a preclinical murine model of bladder cancer. Methods: We conducted a dose escalation experiment via intravesical instillation of increasing doses of NaCl-NPs (300 ug/ml-2700 ug/ml, n=3 mice per group) to identify the maximum tolerated dose. Mice were treated on a weekly dosing schedule and toxicity was evaluated at day 35 as a composite of: evaluation of bladder histology with Hematoxylin and Eosin (H&E) staining by a board-certified pathologist, blood chemistry measurements, complete blood counts, as well as body weight measurement. Secondly, we assessed the efficacy of the nanoparticles through a tumor prevention experiment where MB49 bladder cancer cells were instilled in the murine bladder and shortly after treated with intravesical: 1.) Saline, 2.) Gemcitabine, or 3.) NaCl-NPs for 1 hour (n=18 per group). Mice were monitored for tumor development with 3D bladder ultrasound. In additional, overall survival (OS) was assessed. Results: The dose escalation study showed that there was no local or systemic toxicity in the NaCl-NP treated mice, even at the highest concentration (2700ug/ml). The tumor prevention study showed that mice treated with NaCl-NPs had a significant 2.55 fold reduction in tumors that developed at 4 weeks compared to saline (22% vs 56% respectively, p <0.05). This reduction was similar to that seen with intravesical gemcitabine, which is clinically, a standard of care intravesical chemotherapy. We also found an improvement in overall survival in the NaCl NP group with 70% of mice alive at 60 days compared to the other treatment groups (65% gemcitabine; 40% saline). Conclusions: Our findings suggest that NaCl-NPs could provide a safe and effective alternative therapy for preventing recurrence of NMIBC following transurethral resection of bladder tumors. This opens avenues for safer treatment protocols that can mitigate the side effects commonly seen in the management of early-stage bladder cancer.

Nivolumab and Ipilimumab Acting as Tormentors of Advanced Tumors by Unleashing Immune Cells and Associated Collateral Damage.

Combining immune checkpoint inhibitors, specifically nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), holds substantial promise in revolutionizing cancer treatment. This review explores the transformative impact of these combinations, emphasizing their potential for enhancing therapeutic outcomes across various cancers. Immune checkpoint proteins, such as PD1 and CTLA4, play a pivotal role in modulating immune responses. Blocking these checkpoints unleashes anticancer activity, and the synergy observed when combining multiple checkpoint inhibitors underscores their potential for enhanced efficacy. Nivolumab and ipilimumab harness the host's immune system to target cancer cells, presenting a powerful approach to prevent tumor development. Despite their efficacy, immune checkpoint inhibitors are accompanied by a distinct set of adverse effects, particularly immune-related adverse effects affecting various organs. Understanding these challenges is crucial for optimizing treatment strategies and ensuring patient well-being. Ongoing clinical trials are actively exploring the combination of checkpoint inhibitory therapies, aiming to decipher their synergistic effects and efficacy against diverse cancer types. This review discusses the mechanisms, adverse effects, and various clinical trials involving nivolumab and ipilimumab across different cancers, emphasizing their transformative impact on cancer treatment.

The Anticancer Activities of Natural Terpenoids That Inhibit Both Melanoma and Non-Melanoma Skin Cancers.

The prevalence of two major types of skin cancer, melanoma and non-melanoma skin cancer, has been increasing worldwide. Skin cancer incidence is estimated to rise continuously over the next 20 years due to ozone depletion and an increased life expectancy. Chemotherapeutic agents could affect healthy cells, and thus may be toxic to them and cause numerous side effects or drug resistance. Phytochemicals that are naturally occurring in fruits, plants, and herbs are known to possess various bioactive properties, including anticancer properties. Although the effects of phytochemicals are relatively milder than chemotherapeutic agents, the long-term intake of phytochemicals may be effective and safe in preventing tumor development in humans. Diverse phytochemicals have shown anti-tumorigenic activities for either melanoma or non-melanoma skin cancer. In this review, we focused on summarizing recent research findings of the natural and dietary terpenoids (eucalyptol, eugenol, geraniol, linalool, and ursolic acid) that have anticancer activities for both melanoma and non-melanoma skin cancers. These terpenoids may be helpful to protect skin collectively to prevent tumorigenesis of both melanoma and nonmelanoma skin cancers.

Abstract 7275: GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation

Abstract As a tumor suppressor, p53 can prevent tumor development through multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumor cell death and rapid tumor progression. The oncogenic Y220C mutation is the ninth most frequent p53 missense mutation in cancer. Y220C mutation creates a narrow, hydrophobic pocket on the surface of the p53 DBD that reduces its thermal stability. As a result, the Y220C mutation causes a rapidly unfold of the p53 protein under physiological conditions, abrogates p53 signaling and drives tumorigenesis. There are approximately 100,000 new Y220C mutation cancer cases per year worldwide with limited treatment choices. The initial clinical evaluation of PC14586 that can restore missense-mutant p53 protein has seen efficacy in patients harboring p53 Y220C mutation even though there is still room for improvement. Here we report a brain-penetrable, highly potent p53 Y220C reactivator which has great in vitro activity as well as induce tumor shrinkage in multiple tumor models at a much lower systematic exposure comparing to PC14586. In vitro, GS-P-328 could bind to p53 Y220C protein with a single nM potency and potently induce cell death in a wide range of p53 Y220C tumor cells while have no anti-proliferative effects with p53 WT cells. GS-P-328 is also active in patient-derived cell (PDC) models in various tumor background including SCLC, gastric, ovarian and colon. In vivo, GS-P-328, at approximately 1/3 of systematic exposure comparing to a leading clinical reactivator, causes tumor shrinkage in multiple CDX models. GS-P-328 could induce MDM2/p21 upregulation in cell systems. In vivo, GS-P-328 could induce 2 fold and more increase in MDM2/p21 protein levels in tumor tissues at approximately 1/3 of plasma concentrations comparing to PC14586. More importantly, in a NUGC3-luc intracranial model, GS-P-328 could strongly inhibit growth of cancer cells in the mouse brain. GS-P-328 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GS-P-328 is now under IND-enabling study and P1 study is planned in early 2025. Citation Format: Meng Liu, Kaijun Geng, Biao Lu, Yuanfeng Xia, Fanglong Yang. GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation [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 7275.

Abstract 772: Investigation of gender disparity in liver tumor formation using a hydrodynamic tail vein injection mouse model

Abstract The incidence of hepatocellular carcinoma (HCC), the major form of liver cancer, is 4 times higher in men than in women. This gender disparity is difficult to study since it is believed to be multifactorial, due in part to differences in risk factors, behaviors, and hormones. The liver is a sexually dimorphic organ that is extremely susceptible to interactions with estrogens and androgens. Estrogen has been proven to have a protective effect against HCC with a demonstrable gender-related hormonal effect on the growth of HCC, though the underlying mechanisms are not fully understood. The hydrodynamic tail vein injection (HTVI) mouse model allows for the induction of liver tumors in the host. Eliminating the social and behavioral aspects of the gender disparity will allow us to determine what role estrogen plays in tumor development. In our study, a gender disparity in tumor development was observed between 6-week-old male and female FVB/NJ mice injected via HTVI of plasmids expressing c-MET, a mutated beta-catenin (b-Cat) and Sleeping Beauty transposon. HTVI of a Luciferase and Sleeping Beauty transposon expressing plasmid showed no significant difference in photon flux by bioluminescence imaging between male and female mice 24 hours after injection. When imaging was repeated one week after injection, the photon flux reduced by an order of magnitude in both male and female mice with the female mice showing more uniform reduction than the male mice. Similar luciferase gene copy number was detected in the liver tissue of male and female mice. These data suggest that there appears to be no gender difference in the transient expression and stable integration of the transfected plasmid. Plasma alpha-fetoprotein (AFP) was used to monitor tumor formation in the mice that were injected with c-MET and b-Cat without luciferase as luciferase is immunogenic. The male mice had significantly higher AFP levels at 3.5 weeks, 8 weeks, and 12 weeks post-injection than the female mice. At termination, the liver weight confirmed that female mice had much lower tumor burden than the males. We are currently using quantitative PCR to confirm similar copy number of exogenous c-MET and b-Cat inserted in the tumor cell genome and using RT-qPCR and Western blotting to determine whether the transgene expression is different in tumors from male and female mice. To determine whether estrogen played a role in preventing tumor development and progression in female mice, six-week-old male and ovariectomized female mice have been injected with the same oncogene plasmid combination plus the sleeping beauty. Interestingly, AFP levels between male and ovariectomized female mice were comparable when measured at 3 weeks. We will present our findings at the meeting. Citation Format: Araceli Bernal, Morgana McLaughlin, Ankur Tiwari, Francisco Cigarroa, LuZhe Sun. Investigation of gender disparity in liver tumor formation using a hydrodynamic tail vein injection mouse model [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 772.

Роль клеточного иммунитета в развитии злокачественных новообразований у лиц, подвергшихся хроническому облучению

Some long-term effects of radiation could be related to changes in the immune system resulting from radiation exposure. Immunity disorders caused by radiation can influence carcinogenesis. Cellular immunity factors were investigated in peripheral blood of workers chronically exposed to occupational combined radiation (external gamma-rays and internal alpha-particles), with malignant neoplasms diagnosed after blood samples were taken or without them, and in the control group. The aim of this study was examine effects of radiation on the cellular immunity status in individuals chronically exposed to ionizing radiation who had malignant neoplasms developed after blood sampling. The relative and absolute number of lymphocyte subpopulations (total T-cells, T-helpers, T-cytotoxic, total B-cells, NK-cells, NKT-cells and activated T-cells) was detected by flow cytofluorometry. The absolute number of T-cells was significantly reduced in workers chronically exposed to occupational combined irradiation, with or without malignancies, compared to the control, which may contribute to tumor progression at an early stage of its onset. At the same time, workers without malignancies had a significant increase in the relative number of T-cytotoxic lymphocytes, which may be a factor preventing tumor development. A significant increase in the relative number of natural killer cells (NK cells) was detected in individuals with malignant neoplasms chronically exposed to occupational combined irradiation, compared with the control, which may indicate enhanced antitumor defense that developed in response to exposure to tumor antigens. In addition, a significant decrease in the absolute and relative number of T- and B-lymphocytes was found in the group of workers with malignant neoplasm, compared with the control. A significant increase in the relative number of T-helpers was found in both groups of workers. Since the role of T-helpers in the antitumor response is ambiguous, additional research on types of T-helpers is planned to clarify the results of the present study

Role of cellular immunity in malignant tumors development in individuals chronically ex-posed to ionising radiation

Some long-term effects of radiation could be related to changes in the immune system resulting from radiation exposure. Immunity disorders caused by radiation can influence carcinogenesis. Cellular immunity factors were investigated in peripheral blood of workers chronically exposed to occupational combined radiation (external gamma-rays and internal alpha-particles), with malignant neoplasms diagnosed after blood samples were taken or without them, and in the control group. The aim of this study was examine effects of radiation on the cellular immunity status in individuals chronically exposed to ionizing radiation who had malignant neoplasms developed after blood sampling. The relative and absolute number of lymphocyte subpopulations (total T-cells, T-helpers, T-cytotoxic, total B-cells, NK-cells, NKT-cells and activated T-cells) was detected by flow cytofluorometry. The absolute number of T-cells was significantly reduced in workers chronically exposed to occupational combined irradiation, with or without malignancies, compared to the control, which may contribute to tumor progression at an early stage of its onset. At the same time, workers without malignancies had a significant increase in the relative number of T-cytotoxic lymphocytes, which may be a factor preventing tumor development. A significant increase in the relative number of natural killer cells (NK cells) was detected in individuals with malignant neoplasms chronically exposed to occupational combined irradiation, compared with the control, which may indicate enhanced antitumor defense that developed in response to exposure to tumor antigens. In addition, a significant decrease in the absolute and relative number of T- and B-lymphocytes was found in the group of workers with malignant neoplasm, compared with the control. A significant increase in the relative number of T-helpers was found in both groups of workers. Since the role of T-helpers in the antitumor response is ambiguous, additional research on types of T-helpers is planned to clarify the results of the present study.

RNF213 inhibits migration in lung adenocarcinoma cell.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, and lung adenocarcinoma (LUAD) accounts for up to 40% of NSCLC. Ring finger protein 213(RNF213) has been demonstrated to suppress several cancers, including glioblastoma and breast cancer. Nonetheless, the role of RNF213 in LUAD has not been investigated. The expression of RNF213 in LUAD tissues was analyzed by western blotting, The Cancer Genome Atlas, Genotype Tissue Expression Project, and Gene Expression Omnibus databases. Prognostic value analysis was performed through the Kaplan-Meier Plotter database. We determined the role of RNF213 in LUAD cells through cell counting kit‑8 assay, migration, and invasion assay. The clinical roles of RNF213 were evaluated by immunohistochemical staining assay (IHC) and Kaplan-Meier survival analysis. RNF213 expression was reduced in LUAD, thus affecting the prognosis of LUAD. And RNF213 could suppress the migration and invasion of LUAD cells to prevent tumor development. the expression of RNF213 is positively correlated with the overall survival, providing a novel marker in the prognosis of LUAD patients.

Ultrahigh Enzyme Loading Metal-Organic Frameworks for Deep Tissue Pancreatic Cancer Photoimmunotherapy.

Protein drugs hold promise in treating multiple complex diseases, including cancer. The priority of protein drug application is precise delivery of substantial bioactive protein into tumor site. Metal-organic-framework (MOF) is widely considered as a promising carrier to encapsulate protein drug owing to the noncovalent interaction between carrier and protein. However, limited loading efficiency and potential toxicity of metal ion in MOF restrict its application in clinical research. Herein, a tumor targeted collagenase-encapsulating MOF via protein-metal ion-organic ligand coordination (PMOCol ) for refining deep tissue pancreatic cancer photoimmunotherapy is developed. By an expedient method in which the ratio of metal ion, histidine residues of protein and ligand is precisely controlled, PMOCol is constructed with ultrahigh encapsulation efficiency (80.3 wt%) and can release collagenase with high enzymatic activity for tumor extracellular matrix (ECM) regulation after reaching tumor microenvironment (TME). Moreover, PMOcol exhibits intensively poorer toxicity than the zeolitic imidazolate framework-8 biomineralized protein. After treatment, the pancreatic tumor with abundant ECM shows enhanced immunocyte infiltration owing to extracellular matrix degradation that improves suppressive TME. By integrating hyperthermia agent with strong near-infrared absorption (1064 nm), PMOCol can induce acute immunogenicity to host immunity activation and systemic immune memory production to prevent tumor development and recurrence.

Prevention of Colitis-Associated Cancer via Oral Administration of M13-Loaded Lipid Nanoparticles.

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease, is known to increase the risk of colitis-associated cancer (CAC). CAC has been found to be unresponsive to standard chemotherapy regimens, and the current treatments do not utilize effective small-molecule drugs and colon-targeted delivery systems. Previous studies indicated that the M13-nano-liposome (NL) formulation can effectively target the colon and reshape the gut microbiota in ex vivo cultures, generating altered microbial metabolites that can efficiently prevent chronic UC. In this study, we tested the cancer cell uptake ability of the NL formulation and investigated the potential of the M13-NL formulation to prevent CAC in the azoxymethane (AOM)-exposed IL10-/- mouse model. Our findings demonstrate that oral administration of M13-NL prevents tumor development in AOM-exposed IL10-/- mice, suggesting that M13-NL is a promising oral drug formulation for preventing CAC.

A NOVEL MSLN×4-1BB BISPECIFIC ANTIBODY FOR SOLID TUMOR

Abstract Background Mesothelin (MSLN) is a 70 KD glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein that is rarely expressed in normal tissues but overexpressed in a variety of cancers, including mesothelioma, ovarian cancer, pancreatic cancer and breast cancer et.al. 4-1BB is a member of the tumor necrosis factor receptor superfamily that functions as a co-stimulatory molecule. Agonistic antibodies bind to 4-1BB, triggering a signaling cascade leading to T-cell activation and expansion of cytotoxic CD8+ T lymphocytes. Here, we developed two bispecific antibodies (bsAbs) targeting both MSLN and 4-1BB with an intact Fc fragment from human IgG1 or IgG4, named HK013-G1 and HK013-G4 respectively. We suspected that HK013-G1 can simultaneously exert the cytotoxic effect of CD8+T cells and NK cells on tumor cells expressing MSLN to achieve better antitumor efficacy. Methods Both HK013-G1 and HK013-G4 were constructed by fused a single-chain variable fragment (scFv) targeting hu4-1BB to the C terminus of an anti-MSLA nanobody. And their affinity was optimized to making it highly effective in tumor localization. Next, we tested the killing ability of bsAbs-mediated PBMC or NK92 against tumor cells with different expression levels of MSLN in vitro. And the IFN-γ secretion was detected when CD8+T cells co-cultured with MSLN+ or MSLN- cells in the presence of antibodies. Also, the 4-1BB agonist activity of bsAbs was measured in a luciferase report gene assay. To confirm the safety of HK013-G1, non-specific activation of 4-1BB signal mediated by Fc receptor and CRS was evaluated in vitro. Finally, we compared the antitumor activity of two bispecific antibodies in both MC38/hMSLN and CT26/hMSLN tumor model and hepatotoxicity as well as cardiotoxicity was evaluated. Results Affinity-optimized HK013-G1 has an order of magnitude greater affinity for MSLN(KD≈10−9M) than 4-1BB (KD≈10−8M). HK013-G1 induced stronger PBMC against tumor cells than MOARb009 while HK013-G4 does not. Also, HK013-G1 could only mediate the killing of NK92 on MSLN-positive tumor cells. In co-cultured assay, HK013-G1 had superior ability to stimulate CD8+T cell secretion of IFN-γ than urelumab in the presence of MSLN. In luciferase reporter assay, the bsAbs-induced 4-1BB activation is dependent on expression level of MSLN. In addition, HK013-G1 was shown no stronger ability to inducing non-specific activation of 4-1BB signal mediated by Fc receptor and CRS in vitro. Compared with HK013-G4, HK013-G1 showed a more significant anti-tumor effect in both MC38/hMSLN and CT26/hMSLN tumor model. And, HK013-G4 showed significant hepatotoxicity in mice while HK013-G1 not. Moreover, HK013-G1 can protect mice against tumor re-challenge. Conclusions HK013-G1, an MSLN×4-1BB bsAb with human IgG1 Fc fragment, prevents tumor development by killing tumor cells directly via effector functions mediated by NK and cytotoxic T cells. More importantly, HK013-G1 showed no stronger toxic side effects both in vitro and in vivo. These results show that HK013-G1 has the potential to develop into a new clinical therapy for cancer types with MSLN expression.

Triterpenoids of Ganoderma lucidum inhibited S180 sarcoma and H22 hepatoma in mice by regulating gut microbiota

In order to explore effect of natural plant extracts on anti-tumor and prevent tumor development. The study assessed the antitumor effect of triterpenoids of Ganoderma lucidum (TGL) on S180 and H22 tumor bearing mice. A triterpene compound, 2α, 3α, 23-trihydroxy-urs-12-en-28-oic acid, was successfully isolated and purified from G. lucidum. S180 and H22 cells were subcutaneously inoculated in the left axilla of mice to establish a transplantable tumor model. After, the mice were orally treated with TGL and evaluated by tumor inhibition rate, organ index, and the serum index. The Bax and Bcl-2 proteins and gut microbiota was analyzed using western blot and 16S rDNA sequencing respectively. The results showed the tumor inhibition rates of TGL were higher than 40% in H22 and S180 tumor bearing mice. TGL had a protective effect on the spleen and thymus, and improved lipid peroxidation caused by the increased free radicals. TGL downregulated Bcl-2 and upregulated Bax. In particular, TGL treatment improved the reduction of gut microbiota richness and structure.