Recent Patents on Anti-Cancer Drug Discovery - Volume 19, Issue 2, 2024

mRNA emerged as an attractive therapy modality with the development of mRNA structure engineering techniques and delivery platforms. mRNA therapeutics, applied for vaccine therapy, protein replacement therapy, and chimeric antigen receptor (CAR) T cell-based therapy, has shown huge potential in treating a wide range of diseases, such as cancer and rare genetic diseases, with successful and exciting preclinical and clinical progress. In mRNA therapeutics, a potent delivery system is key to the success of its application for disease treatment. Herein, different types of mRNA delivery strategies, including nanoparticles produced from lipid or polymer materials, virus-based platforms, and exosome-based platforms, are mainly focused.

Background: Cannabis use for tumor treatment has been explored in several areas, and its potential for tumor remission is currently being studied after the discovery of the endogenous cannabinoid.Objective: The study aimed to conduct a critical patent review to identify and explore the latest advances and therapeutic strategies using Cannabis to treat cancer.Methods: The research was carried out in the free and online database Espacenet, using the descriptors "cancer" and "Cannabis or cannabidiol" in the title or abstract. A total of 95 patents were identified for preliminary evaluation in the database. Six duplicate patents were excluded, 12 referring to traditional Chinese medicine and 36 with a title in disagreement with the scope of this review. In addition the final selection involved 21 patents that were in line with the objective of the study.Results: As observed in the reading of patents, the interest of pharmaceutical industries and researchers and the development of new products to fight cancer have increased in recent years. The main cannabinoids present in the patents are tetrahydrocannabinol, cannabidiol, and hemp. Moreover, the patents were classified and the main applicant countries were the United States followed by Japan, with a higher filing rate in 2019 and, mainly by the industry.Conclusion: In conclusion we can say that, the importance of parliamentary approval in the cultivation and investments that, in addition to bringing innovation to the industrial sector, enriches research in the area, contributing to the creation of new medicines.

Background: Chlorogenic acid (CA, United States Patent No. 10772340), a natural biologically active food ingredient, displays potent antitumor activity against a variety of cancer cells. However, the mechanism underlying its anticancer effect is not well elucidated.Objective: In the present study, we hope to dissect the mechanism underlying the anticancer effects of CA in pancreatic cancer cells.Methods: The cytotoxicity of CA in pancreatic cancer cells was determined by MTT assay. Flow cytometry was performed to evaluate the cells apoptosis, while a clonogenic assay was carried out to check the colony formation of cancer cells. Transwell assay was performed to assess the cells migration and invasion. The protein expression of AKT/GSK-3β/β-catenin signaling pathway was detected by Western Blot.Results: Our data indicated that CA inhibited the proliferation of PANC-28 and PANC-1 cells in a dose and time-dependent manner. CA was able to inhibit colony formation, migration, and invasion ability and trigger apoptosis in PANC-28 and PANC-1 cells. Further study showed that CA down-regulated the expression of AKT, p-AKT(Thr308), p-GSK-3β(Ser9), β-catenin, N-cadherin, and vimentin while enhancing the expression of cleaved-caspase 3 and cleaved-caspase 7 in PANC-28 and PANC-1 cells.Conclusion: Our study provides significant evidence that CA is able to inhibit the growth of pancreatic cancer via the AKT/GSK-3β/β-catenin signaling pathway.

Background: Multidrug resistance (MDR) of cancer cells is a major obstacle to efficient cancer chemotherapy. Combination therapy is expected to enhance the anticancer effect and reverse MDR. Numerous patents involve different kinds of nanoparticles for the co-delivery of multiple chemotherapeutics, but the FDA has approved none.Objective: In this study, oxymatrine (OMT) and glycyrrhizin (GL) were co-loaded into phytosomes as the core of nanocarriers, and the shell was cross-linked with chitosan (CS) and hyaluronic acid (HA) with the capability for the controlled, sequential release and the targeted drug uptake.Methods: Phospholipid complexes of OMT and GL (OGPs) were prepared by a solvent evaporation technique and could self-assemble in an aqueous solution to form phytosomes. CS and HA were sequentially coated on the surface of OGPs via electrostatic interactions to obtain CS coated OGPs (CS-OGPs) and HA modified CS-OGPs (HA-CS-OGPs), respectively. The particle size and zeta potential were measured to optimize the formulations. In vitro cytotoxicity and cellular uptake experiments on HepG2 cells were performed to evaluate the anticancer activity.Results: OGPs were obtained with nano-size around 100 nm, and CS and HA coating on phytosomes could change the particle size and surface potential. The drug loading of OMT and GL showed that the nanocarriers could maintain a fixed ratio of 1:1. The in vitro release experiments indicated the release of OMT and GL was pH-dependent and sequential: the release of OMT from CS-OGPs and HA-CS-OGPs was significantly increased at pH 5.0 compared to the release at pH 7.4, while GL exhibited sustained released from CS-OGPs and HA-CS-OGPs at pH 5.0. Furthermore, in vitro cytotoxicity and cellular uptake experiments on HepG2 cells demonstrated that the co-delivery system based on phytosomes had significant synergistic anti-tumor activities, and the effects were enhanced by CS and HA modification.Conclusion: The delivery of OMT and GL via HA-CS-OGPs might be a promising treatment to reverse MDR in cancer therapy.

Introduction: Maintenance therapy aimed to strengthen the first-line chemotherapy and improve quality of life is needed for gastric cancer (GC). Currently, many clinical studies have confirmed the important role of fluoropyrimidine in the maintenance stage. Our team has created patented prescriptions "Fuzheng jiedu Quyu Method" recipe (FJQR), which was considered as an adjuvant therapeutic scheme (reduce toxicity and increase the efficacy of chemotherapy). This study aimed to evaluate the efficacy and safety of FJQR combined with fluoropyrimidine as a maintenance treatment in HER-2 negative GC patients.Methods: We performed the analysis of 129 patients with HER-2 negative GC who entered the maintenance stage in our hospital and Tianjin Cancer Hospital between January 2018 and December 2020. Out of the 129 eligible patients, 64 were categorized into the maintenance treatment group with FJQR+fluoropyrimidine, and 65 patients were assigned to the control group if they received fluoropyrimidine alone. Capecitabine was orally 1000mg/m², Qd, half an hour after meals, and FGQR was 15g Bid after capecitabine. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), overall remission rate (ORR), quality of Life (QOL), TCM syndrome and safety.Results: The mPFS in the treatment group was significantly prolonged compared with the control group (6.3 vs. 5.0 months, p = 0.03), while the mOS was not substantially improved (11.4 vs. 10.5 months, p = 0.38). Gastrointestinal symptoms and pain became better in the treatment group. The number of distant metastatic organs, first-line chemotherapy cycles, and lymph node metastasis were independent risk predictors for PFS. Blood stasis syndrome may be the protective factor. In terms of safety, treatment-related adverse events (AEs) in the treatment group were relatively lighter, and the incidence of grade III-IV AEs could be significantly reduced.Conclusion: FJQR and fluoropyrimidine have synergistic effects as maintenance treatment in HER-2 negative GC, with good efficacy and safety.

Background: Laryngeal squamous cell carcinoma (LSCC) is the most common cancer of head and neck cancer. Y-box binding protein-1 (YBX1) has tumor-promoting effects in some types of cancers. However, its role in LSCC remains unknown. This study set out to identify the role of YBX1 in LSCC.Methods: Bioinformatics analysis of the Gene Expression Omnibus (GEO) database and our cohort data were used to explore the association of YBX1 expression with clinicopathological factors in LSCC. Then, cells with stably or transiently transfected with plasmid or siRNA were constructed to assess the effect of loss and gain of YBX1 on the biological phenotypes of LSCC cells in vitro. In addition, subcutaneous xenograft and orthotopic liver tumor mouse models were constructed for validation. The interrogated miRNA databases and subsequent luciferase reporter assays were used to confirm the miR-382-5p target of YBX1. At last, KEGG enrichment annotation from TGCA data was used for downstream analyses of miR-382-5p/YBX1 and verified by PCR and Western immunoblotting.Results: The results showed that significant upregulation of YBX1 in LSCC tumors was correlated with advanced TNM stage and poor prognosis. Knockdown of YBX1 markedly impaired the proliferative, invasive, and migratory activity of Tu212 cells. We confirmed that miR-382-5p targets YBX1 to mediate LSCC progression both in vitro and in vivo. We further confirmed that miR-382-5p/YBX1 modulated the Ras/MAPK signaling axis to regulate the progression of LSCC.Conclusion: Together, our results indicated that YBX1 is an important promoter of LSCC progression. And miR-382-5p/YBX1/RAS/MAPK signaling pathway can be perceived as a promising target in the treatment of LSCC.

Background: Giant cell tumor of bone (GCTB) is a locally aggressive bone tumour aggravated by stromal cell proliferation and metastasis.Objective: We investigated the mechanism of action of human chorionic gonadotropin (HCG) in mediating GCTB proliferation and invasion.Methods: The expression of HCG was quantified using quantitative real-time PCR. After the primary stromal cells were isolated and identified, the function of HCG in GCTB was estimated using the cell counting kit-8, flow cytometry, scratch experiment, transwell assay, Western blot, and immunofluorescence. Moreover, the mechanism of HCG was assessed through western blotting.Results: HCG expression was decreased in clinical tissue samples from patients with GCTB. We validated that HCG repressed stromal cell proliferation, migration, invasion, autophagy, and epithelial- mesenchymal transition (EMT) and promoted cell apoptosis in GCTB. We also verified that HCG repressed the autophagy and EMT of stromal cells through the Smad signaling axis in GCTB. HCG inhibited the transduction of the Smad signaling pathway by restraining the binding of the TGF-β II receptor to ligand Activin A.Conclusion: HCG restrained the Smad signaling pathway by antagonizing TGF-β signaling in GCTB. HCG may serve as a useful patent to treat GCTB.

Background: As a pentacyclic triterpenoid, OA (oleanolic acid) has exhibited antiinflammatory, immunomodulatory and antitumor effects. VEGFR-2 (vascular endothelial cells receptor-2) tyrosine kinase activity could be inhibited by apatinib, a small-molecule antiangiogenic agent.Objective: Thus, this study sought to investigate the mechanism underlying the synergistic antitumor activity of combined OA and apatinib patent.Methods: Through CCK8 (Cell counting kit 8 assay), flow cytometric and western blotting techniques, we conducted in vitro studies on apatinib and OA effects on cell proliferation and apoptosis in H22 cell line. H22 tumor-burdened mice model was established in vivo, while the related signaling pathways were studied via pathological examination, western blotting and qPCR (quantitative polymerase chain reaction).Results: Growth of H22 cells in vitro and in vivo could be inhibited effectively by apatinib and OA. Thus, OA repaired liver function and inhibited oxidative stress induced by apatinib.Conclusion: OA can treat apatinib induced liver injury in H22 Tumor-burdened mice by enhancing the suppresssive effect of apatinib on the growth of tumor.

Background: The purpose of this study was to explore the expression profiles of lipid metabolism-related genes in patients with Colorectal Cancer (CRC).Methods: The lipid metabolism statuses of CRC patients from The Cancer Genome Atlas (TCGA) were analyzed. Risk characteristics were constructed by univariate Cox regression and minimum Absolute contraction and Selection Operator (LASSO) Cox regression. A histogram was constructed based on factors such as age, sex, TNM stage, T stage, N stage, and risk score to provide a visual tool for clinicians to predict the probability of 1-year, 3-year, and 5-year OS for CRC patients. By determining Area Under Curve (AUC) values, the time-dependent Receiver Operating characteristic Curve (ROC) was used to evaluate the efficiency of our model in predicting prognosis.Results: A novel risk signal based on lipid metabolism-related genes was constructed to predict the survival of CRC patients. Risk characteristics were shown to be an independent prognostic factor in CRC patients (p <0.001). There were significant differences in the abundance and immune characteristics of tumor-filtering immune cells between high-risk and low-risk groups. The nomogram had a high potential for clinical application and the ROC AUC value was 0.827. Moreover, ROC analysis demonstrated that the nomogram model was more accurate to predict the survival of CRC patients than age, gender, stage and risk score.Conclusion: In this study, we demonstrated a lipid metabolism-related genes prognosis biomarker associated with the tumor immune micro-environment in patients with CRC.

Background: Ribosome-inactivating proteins (RIPs) have been reported to exert antitumor and anti-virus activities. A recent patent CN202011568116.7 has developed a new method to prepare Momordica anti-HIV protein of 30 kDa (MAP30). MAP30 is a type I RIP, which kills various tumor cells through the N-glycosidase activity and irreversibly inhibits protein synthesis.Objective: To assess the potential role of MAP30 in inducing apoptosis of human hepatocellular carcinoma HCC-LM3 cells and elucidate the molecular mechanism of MAP30.Methods: CCK-8 assay was used to assess the proliferation of HCC-LM3 cells. Flow cytometry was used to measure the cycle, the level of ROS and apoptosis in HCC-LM3 cells. Western blots was used to measure protein levels.Results: Treatment with MAP30 reduced survival and proliferation of human liver cancer HCCLM3 cells in a dose-dependent manner. PI staining showed cell cycle arrest in G0/G1 phase. Furthermore, MAP30 increased the level of ROS in HCC-LM3 cells in 24 h treatment. To further confirm the role of MAP30 in inducing cell apoptosis, immunoblotting was carried out to detect the change of apoptosis-related proteins including PARP poly (ADP-ribose) polymerase (PARP- 1), Casepase3 and Cleaved-Caspase9. We found that PARP-1 and Caspase-3 were downregulated, whereas Cleaved-Caspase9 was up-regulated in HCC-LM3 cells treated with MAP30.Conclusion: This study indicated that MAP30 has the potential to be a novel therapeutic agent for human hepatocellular carcinoma.

Introduction: Circular RNAs (circRNAs) are important biological molecules associated with the pathogenesis of multiple cancers.Objective: This work aimed to investigate the function and molecular mechanism of circ_0070203 in high-grade serous ovarian cystadenocarcinoma (HGSOC).Methods: circRNA microarray was conducted to detect the circ_0070203 expression in HGSOC tissues. Bioinformatics analysis was used to find the binding sites between circ_0070203, miR- 370-3p and TGFβR2. Real-time quantitative reverse transcription PCR (RT-qPCR) was executed to detect the expressions of circ_0070203, miR-370-3p and TGFβR2 in HGSOC tissues and SKOV3 cells. Dual-luciferase reporter gene assay was used to validate the relationships between miR-370-3p and circ_0070203 or TGFβR2. Besides, transwell assays were conducted to assess the migrative, invasive abilities of ovarian cancer (OC) cells. Western blotting was adopted to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins. The related patents were also studied during the research.Results: Circ_0070203 and TGFβR2 were upregulated, while miR-370-3p was downregulated in FIGO stage III-IV HGSOC tissues and SKOV-3 cell lines. circ_0070203 overexpression changed the expression of other EMT-related proteins and enhanced the migrative, invasive abilities of OC cells, while silencing circ_0070203 worked oppositely. Mechanistically, circ_0070203 could upregulate TGFβR2 expression in OC cells via sponging miR-370-3p.Conclusion: Circ_0070203 could promote the epithelial-mesenchymal transition, invasion, and metastasis of HGSOC via regulating the miR-370-3p/TGFβR2 axis. Our findings provided a potential biomarker for HGSOC therapy.

Background: Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been proven a long-lasting treatment effect in pulmonary adenocarcinoma, most patients still progressed within one year due to the acquired resistance. Complex mutations of rare rare sites after acquiring resistance are rarely reported in pulmonary adenocarcinoma.Case Presentation: A 62-year-old woman was diagnosed with pulmonary adenocarcinoma with stage IV. Genetic testing at the initial treatment showed EGFR L858R positive. After being treated with gefitinib, persistent 2 years disease progression occurred due to drug resistance. The genetic testing showed that EGFR L858R was eliminated, while a rare rare complex mutation of L861Q/G719X appeared. After 160 mg furmonertinib was treated for 1 month, the primary tumor regressed and the intracranial lesions disappeared. The patient has achieved progression-free survival (PFS) for more than 20 months.Conclusion: Pulmonary adenocarcinoma with rare rare complex mutations in EGFR induced by gefitinib resistance and disease progression might benefit from furmonertinib treatment.

The patent describes novel useful compounds, such as PI3K protein kinase inhibitors, in particular as PI3K delta (δ) and/or gamma (γ) protein kinase modulators. The present disclosure also provides methods for preparing PI3K protein kinase inhibitors, pharmaceutical compositions containing them, and methods of treatment, prevention, and amelioration of PI3K kinase-mediated diseases, and disorders.