Recent Patents on Anti-Cancer Drug Discovery - Volume 18, Issue 2, 2023

The use of antibody-drug conjugates is expected to transform the management of human malignancy. Antibody-drug conjugates for cancer treatment are designed to deliver anticancer drugs to tumor cells. The main components of such conjugates are a monoclonal antibody that binds to a tumor antigen, an anticancer drug to inhibit tumor cell growth and a linker that serves to conjugate the antibody and drug. The antibody-drug conjugates developed and approved for breast cancer treatment are ado-trastuzumab emtansine, (fam)-trastuzumab deruxtecan-nxki and sacituzumab govitecan. The mechanisms of action, clinical uses and toxic effects of these antibody-drug conjugates are discussed.

Background: Lung cancer is one of the major killers among different kinds of cancer. Being a silent developer, the earliest detection and treatment of lung cancer is a challenging task. The existing therapeutic agents have lower efficacy. Nanotechnology can overcome the challenges posed by conventional approaches to ensure reliable diagnosis and treatment. Objectives: Various patents on nano diagnosis and nano delivery aspects of lung cancer were analyzed to compile the information in a nutshell. The increasing trend of patents on nano-based solutions for lung cancer opens new opportunities. Methods: Google patent and Science Citation Index Expanded data sources were used to obtain relevant literature on nano-detection and nano-drug delivery for lung cancer. Various keywords were used to ensure the inclusion of recent and most relevant information in each section. The gist of the patent is described with suitable subsections. Results: Thorough review of recent patents on nanotechnology-based theranostics of lung cancer was conducted. Nanotechnology-based diagnosis and treatment of lung cancer overcome the drawbacks of traditional treatments with better stability, targeted drug delivery, controlled sustained drug release, ease of membrane transport, and better therapeutic efficacy/safety ratio to obtain optimized clinical results. Further, it is cost-effective and accurate. Conclusion: Overall, the application of nanotechnology in lung cancer treatment and diagnosis is a futuristic approach. Furthermore, NPs-based in vitro and in vivo detection and nano drug delivery to lungs need to be rigorously pursued for a sustainable solution.

Background: Cancer is the biggest killer that threatens human health. Poor bioavailability and strong drug resistance of cancer drugs are common defects. In recent years, drug delivery therapy based on nanotechnology has become a focused research area, and nano drug delivery system has been widely studied in cancer treatment. Objectives: Based on the articles and patents published on the application of nano drug delivery systems in cancer treatment in the past five years, this paper summarizes the types of nano drug delivery systems and their advantages and limitations in cancer treatment in order to provide a reference for future anticancer research on nano drug delivery systems. Methods: This perspective summarizes the types of nano drug delivery systems and their advantages and limitations in cancer treatment in recent five years, and proposes the development direction of nano drug delivery systems in the future. Results: Based on the review of articles and patents, we found that the nano drug delivery system is mainly divided into encapsulated nano drug delivery system and covalently bound nanoprodrug delivery system. Its advantages in cancer treatment are mainly reflected in enhancing drug stability, improving bioavailability, reducing toxicity and better application in cancer diagnosis. However, nano drug delivery system is a new field of science, some of these drug delivery systems might have high toxicity and low bioavailability; the off-target phenomenon often occurs, and most studies are just focused on the early stage, its mechanism of action, clinical efficacy and patient tolerance, and the toxicity of treatment remains to be further investigated. Conclusion: This perspective systematically summarizes the types of nano drug delivery systems and their advantages and limitations in cancer treatment based on the published articles and patents obtained in the last five years. Future research on nano drug delivery system should consider the potential risks, and stable and efficient nano drug delivery systems should be designed to treat cancer by changing or functionalizing the nanomaterial.

Recent developments in several areas are rekindling interest and empowering progress in improving therapeutic cancer vaccines. These advances have been made in target selection, vaccine technology, and approaches for reversing the immunosuppressive mechanisms exploited by cancers. Studies on diverse tumor antigens have revealed target properties, including high cell specificity and adequate immunogenicity, to affect clinical efficiency. Therefore, one of the principal goals of cancer vaccinology is the development of efficient therapeutic cancer vaccines that are capable of eliciting an effector as well as memory T cell response specific to tumor antigens. Neoantigens, which arise from mutated proteins in cancer cells, are cancer-specific and may be highly immunogenic. However, the vast majority of these are distinctive to each patient’s cancer and hence require the development of personalised therapies. Novel immunotherapeutic strategies are focused on breaking immune tolerance to tumor antigens, improving the immunogenicity of tumor vaccines, in addition to overcoming mechanisms of tumor escape. However, current developments and patents in cancer immune therapies, together with associated technologies, are significant. Supreme achievements in immune inhibitor-centered therapies and neo-antigen identification tools envisage probable improvements in cancer vaccines with respect to treatments of malignancies. Antibody modulation of T cell function through checkpoint blockade or co-stimulatory activation may restore survival, proliferation, and effector function. Thus, these tumor-infiltrating T cells with genetically engineered therapeutic vaccines have the potential to act as curative cancer immune therapeutics. In this review, target tumor antigens employed in recent years in the development of therapeutic cancer vaccine approaches are described, and the patents involved in the process are highlighted.

Identifying cancer genomes has provided acuity into somatically altered genes athwart tumors, transformed our understanding of biology, and helped us design therapeutic strategies. Though the action of most cancer cells remains furtive yet many features of cancer surpass their genomes. Consequently, the characterization of tumor genome does not affect the treatment of many patients. Strategies to know the circuity and function of cancer genes provide corresponding methods to explicate both non-oncogene and oncogene deficiencies. The emerging techniques specify that the therapeutic targets produced by non-oncogene deficiencies are much grander than the mutated genes. In the present review, a framework of the long-drawn-out list of cancer targets viz. synthetic lethal targets, oncogene dependence, response to DNA damage, tumor suppressor rescue, metabolic susceptibility, protein-protein interaction, cell state or master regulators, targeting immune cells, fibroblasts, etc. giving innovative prospects for clinical translation, are discussed.

Background: The high heterogeneity of ovarian cancer (OC) brings great difficulties to its early diagnosis and prognostic forecast. There is an urgent need to establish a prognostic model of OC based on clinicopathological features and genomics. Methods: We identified hypoxia-related differentially expressed genes (DEGs) between OC tissues from The Cancer Genome Atlas (TCGA) and normal tissues from the Genotype-Tissue Expression (GTEx). LASSO Cox regression analysis was applied for building a prognostic model in the TCGA-GTEx cohorts, and its predictive value was validated in the GEO-OC cohort. Functional enrichment analysis was performed to investigate the underlying mechanisms. By constructing a hypoxia model of the SKOV3 cell line and applying qRT-PCR, we investigated the relationship between hypoxia with two novel genes in the prognostic model (ISG20 and ANGPTL4). Results: Twelve prognostic hypoxia-related DEGs were identified, and nine of them were selected to establish a prognostic model. OC patients were stratified into two risk groups, and the high-risk group showed reduced survival time compared to the low-risk group upon survival analysis. Univariate and multivariate Cox regression analysis demonstrated that the risk score was an independent risk factor for overall survival. The biological function of the identified prognostic hypoxia-related gene signature was involved in immune cell infiltration. Low expression of ISG20 was observed in the CoCl2-mimicked hypoxic SKOV3 cell line and negatively correlated with HIF-1α. Conclusion: Our findings showed that this hypoxia-related gene signature could serve as a satisfactory prognostic classifier for OC and will be beneficial to the research and development of targeted therapeutic strategies.

Background: Doxorubicin is a significant drug for the treatment of breast cancer, but its cardiotoxicity is an obvious obstacle. Previously, we confirmed that ruthenium complex (Δ-Ru1) and doxorubicin (Δ-Ru1/Dox) combination had a synergistic effect in MCF-7 cells, but its biological effect in vivo is unknown. Purposes: To find a way to overcome the toxicity of doxorubicin and build MCF-7 xenograft tumor mouse model to test whether this potential combination has better efficacy and less toxicity. Methods: The tumor model of nude mice was established to verify the synergistic antitumor effect of the drug combination in vivo. H staining was used to detect the toxicity of major organs in mice. Sirius red staining and transmission electron microscopy were used to detect cardiotoxicity. Prussian blue was used to measure iron accumulation in heart tissue. TUNEL staining was used to detect the antitumor effect in vivo. Immunohistochemical staining was used to detect the expression of iron death-related pathway proteins. High-throughput sequencing techniques were used to determine the molecular mechanism of ferroptosis. Results: Histopathological analysis of tumor tissues indicated that the Δ-Ru1/Dox combination significantly promoted tumor cell apoptosis. Doxorubicin damaged cardiac tissue by inducing fibrosis and iron accumulation, but it was reversed by the Δ-Ru1/Dox combination treatment. Further exploration found that doxorubicin could regulate iron accumulation in the ferroptosis pathway and the expression of lipid peroxidation-related proteins, including upregulation of Tf, DMT1, and HO-1, and downregulation of Nrf2, SLC7A11, and GPX4. Conclusion: Δ-Ru1/Dox combination synergistically inhibits tumor growth, and it can significantly reduce and alleviate the toxic side effects of doxorubicin, especially cardiac injury.

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers, associated with a high rate of mortality. A disturbance between cell proliferation and cell death is one of the cancer hallmarks including HCC. Cell proliferation is mainly controlled by the cell cycle. The arrest of the cell cycle is one of the important targets of anticancer agents. Objectives: The present study tries to clarify the exact role of some natural products such as daidzein (DAZ) and alcoholic chicory leaf extract (CE), as possible regulators of cell cycle and apoptosis. Methods: HCC in rats was induced using diethylnitrosamine (DENA). Ninety rats were allocated and divided equally into nine groups, treated with CE, DAZ, a combination of both, and sorafenib with non-treated control groups. Results: Treatment with CE, DAZ, and their combination significantly downregulated hepatic tissue expression of cyclin D1/CDK4 axis as well as cyclin A/CDK2 axis. The suggested therapeutic protocol inhibited the proliferation and dampened Bcl-2 expression. Furthermore, the efficiency of combining CE and DAZ demonstrated a potency comparable to sorafenib in terms of cyclin D/CDK4 axis expression, as well as; this combination protocol was more potent in revealing a potentiated inhibitory effect on cyclin A and Ki-67 expression. Conclusion: Treatment with DAZ or CE alone, or in combination, could possess an inhibitory effect on hepatocarcinogenesis via cell cycle arrest, inhibition of proliferation through suppression of Ki-67 expression, and apoptosis induction, mediated by downregulation of Bcl-2.

Background: Tumor metastasis is a main cause of death in patients with breast cancer. The cross-talk between cancer-associated fibroblasts (CAFs) and tumor cells plays an important role in promoting tumor invasion and metastasis. It is important to develop a novel delivery system to inhibit tumor development by simultaneously targeting both CAFs and tumor cells. Objectives: The main objective of this research was to prepare nanoparticles to inhibit tumor proliferation and migration by blocking the cross-talk of tumor-CAFs. Additionally, a novel “MCF- 7+NIH/3T3” mixed cell model was established to mimic the tumor microenvironment (TME). Methods: In this study, the pH-responsive nanoparticles (MIF/DOX-sul-HA NPs) based on sulfated hyaluronic acid (sul-HA) polymers were prepared for co-delivery of doxorubicin (DOX) and mifepristone (MIF). The effects of anti-proliferation and anti-metastasis of MIF/DOX-sul-HA NPs were investigated both in vitro and in vivo. Results: The results showed that MIF/DOX-sul-HA NPs were nearly spherical in shape with narrow particle size distribution and pH-responsive drug release, and could be taken up by both MCF-7 and NIH/3T3 cells. Compared with MCF-7 cells alone, the anti-tumor effect of single DOX was weak in the “MCF-7+NIH/3T3” mixed cell model. MIF/DOX-sul-HA NPs exhibited strong effects of anti-proliferation and anti-metastasis than the free single drug. Conclusion: The sul-HA nanoparticles for co-delivery of DOX and MIF could be a promising combined therapy strategy for the treatment of breast cancer.

Background: Lymphoid Enhancer-Binding Factor-1 (LEF1) was previously reported to contribute to a variety of malignancies, including Hepatocellular Carcinoma (HCC). However, its role in HCC is poorly understood. Objectives: To explore the role of LEF1 in HCC, including its prognostic and drug-targeting value. Methods: The LEF1 expression and patient characteristics were investigated. The associations between clinical characteristics and LEF1 were analyzed using both univariate and multivariate logistic regression. Cox regression and Kaplan-Meier curves were used to explore the clinicopathological factors related to overall survival in patients with HCC. A nomogram to predict the survival rate was constructed and validated. The Kyoto Encyclopedia of Genes and Genomes database (KEGG) was used to explore the function of LEF1. Gene Set Enrichment Analysis (GSEA) was also performed using The Cancer Genome Atlas dataset. Furthermore, compounds that may have the potential to be targeted drugs in the treatment of LEF1-overexpressing HCC were identified using the Comparative Toxicogenomics Database (CTD), patents about these drugs in HCC were also reviewed through Worldwide Espacenet® and Patentscope®. Results: Increased expression of LEF1 was significantly associated with high histological grade of HCC (odds ratio (OR) = 2.521 for grade (G) 2 vs. G1, OR = 2.550 for G3 vs. G1, OR = 7.081 for G4 vs. G1, all P < 0.05). A Kaplan–Meier survival curve showed that HCC patients with LEF1 overexpression had a poor prognosis compared with those with normal LEF1 expression (P = 0.025). Multivariate Cox regression analysis revealed that LEF1 is an independent prognostic factor for the overall survival of patients with HCC (Hazard Ratio (HR) = 1.095; P = 0.04). The constructed nomogram to predict the survival rate produced a statistically significant prediction (area under the curve (AUC) = 86.68). In addition, Gene Ontology (GO) and KEGG analysis of genes co-expressed with the protein showed that LEF1 was associated with transcriptional regulation. GSEA suggested that the cell cycle, the WNT signaling pathway, and the NOTCH signaling pathway may be the key pathways regulated by LEF1 in HCC. Furthermore, the Comparative Toxicogenomics Database (CTD) identified nine compounds that may have the potential to be targeted drugs in the treatment of LEF1-overexpressing HCC. Patent reviews suggested that these drugs may show some efficacy in HCC, but whether these drugs interact with LEF1 and improve the prognosis for patients with HCC remains to be explored. Conclusion: LEF1 is a latent prognostic molecular biomarker of HCC. The cell cycle, and WNT and NOTCH signaling pathways are regulated by LEF1 in HCC. LEF1 could be a potential drug target for HCC.

Background: SV-BR-1-GM, derived from a patient with grade 2 (moderately differentiated) breast cancer, is a GM-CSF-secreting breast cancer cell line with properties of antigen-presenting cells. SV-BR-1-GM and next-generation versions are covered by several pending and granted patents. Methods: We report findings from an open-label phase I, single-arm pilot study with irradiated SV-BR-1-GM cells in 3 breast and 1 ovarian cancer subjects. Inoculations were preceded by lowdose intravenous cyclophosphamide and followed by interferon-alpha2b injections into the SVBR- 1-GM inoculation sites. We assessed both cellular and humoral immune responses, and measured expression levels of SV-BR-1-GM HLA alleles. Results: Treatment was generally safe and well tolerated. Immune responses were elicited universally. Overall survival was more than 33 months for three of the four patients. As previously reported, one patient had prompt regression of metastases in lung, breast, and soft tissue. Following cessation of treatment, the patient relapsed widely, including in the brain. Upon retreatment, rapid tumor response was again seen, including complete regression of brain metastases. Consistent with a role of Class II HLA in contributing to SV-BR-1-GM’s mechanism of action, this patient allele-matched SV-BR-1-GM at the HLA-DRB1 and HLA-DRB3 loci. We are in the process of developing next-generation SV-BR-1-GM, expressing patient-specific HLAs. Patent applications were filed in various jurisdictions. Thus far, one is granted, in Japan. Conclusion: A whole-cell immunotherapy regimen with SV-BR-1-GM cells induced regression of metastatic breast cancer. We develop intellectual property based on SV-BR-1-GM’s predicted mechanism of action to develop additional whole-cell immunotherapies for cancer patients.