Recent Patents on Anti-Cancer Drug Discovery - Volume 15, Issue 3, 2020

Background: Breast cancer is the predominant form of cancer in women; various cellular pathways are involved in the initiation and progression of breast cancer. Among the various types of breast cancer that differ in their growth factor receptor status, PI3K/Akt signaling is a common pathway where all these converge. Thus, the PI3K signaling is of great interest as a target for breast cancer prevention; however, it is less explored. Objective: The present review is aimed to provide a concise outline of the role of PI3K/Akt/mTOR pathway in breast carcinogenesis and its progression events, including metastasis, drug resistance and stemness. The review emphasizes the role of natural and synthetic inhibitors of PI3K/Akt/m- TOR pathway in breast cancer prevention. Methods: The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results: PI3K/Akt/mTOR signaling plays an important role in human breast carcinogenesis; it acts on the initiation and progression events associated with it. Numerous molecules have been isolated and identified as promising drug candidates by targeting the signaling pathway. Results from clinical studies confirm their application in the treatment of human breast cancer alone and in combination with classical chemotherapeutics as well as monoclonal antibodies. Conclusion: PI3K/mTOR signaling blockers have evolved as promising anticancer agents by interfering breast cancer development and progression at various stages. Natural products and bioactive components are emerging as novel inhibitors of PI3K signaling and more research in this area may yield numerous drug candidates.

Background: Epidermal Growth Factor Receptor (EGFR) and members of its homologous protein family mediate transmembrane signal transduction by binding to a specific ligand, which leads to regulated cell growth, differentiation, proliferation and metastasis. With the development and application of Genetically Engineered Antibodies (GEAs), Nanobodies (Nbs) constitute a new research hot spot in many diseases. A Nb is characterized by its low molecular weight, deep tissue penetration, good solubility and high antigen-binding affinity, the anti-EGFR Nbs are of significance for the diagnosis and treatment of EGFR-positive tumours. Objective: This review aims to provide a comprehensive overview of the information about the molecular structure of EGFR and its transmembrane signal transduction mechanism, and discuss the anti-EGFR-Nbs influence on the diagnosis and treatment of solid tumours. Methods: Data were obtained from PubMed, Embase and Web of Science. All patents are searched from the following websites: the World Intellectual Property Organization (WIPO®), the United States Patent Trademark Office (USPTO®) and Google Patents. Results: EGFR is a key target for regulating transmembrane signaling. The anti-EGFR-Nbs for targeted drugs could effectively improve the diagnosis and treatment of solid tumours. Conclusion: EGFR plays a role in transmembrane signal transduction. The Nbs, especially anti- EGFR-Nbs, have shown effectiveness in the diagnosis and treatment of solid tumours. How to increase the affinity of Nb and reduce its immunogenicity remain a great challenge.

Background: In the last decade, the proposed Cancer Stem Cell (CSC) hypothesis has steadily changed the way cancer treatment is approached. CSCs may be the source of the heterogeneous non-tumorigenic cell population included in a neoplasm. Intratumor and intertumoral heterogeneity is a well-known phenomenon that massively entangles the diagnosis and treatment of cancer. The literature seems to suggest that heterogeneity develops progressively within tumor-initiating stem cells. CSCs harbor genetic and/or epigenetic alterations that allow them to differentiate into multiple tumor cell types sequentially. Objective: The CSC hypothesis, cellular therapy, and the most recent patents on CSCs were reviewed. Methods: PubMed, Scopus, and Google Scholar were screened for this information. Also, an analysis of the most recent data targeting CSCs in pediatric cancer developed at two Canadian institutions is provided. The genes involved with the activation of CSCs and the drugs used to antagonize them are also highlighted. Results: It is underlined that (1) CSCs possess stem cell-like properties, including the ability for self-renewal; (2) CSCs can start carcinogenesis and are responsible for tumor recurrence after treatment; (3) Although some limitations have been raised, which may oppose the CSC hypothesis, cancer progression and metastasis have been recognized to be caused by CSCs. Conclusion: The significant roles of cell therapy may include an auto-transplant with high-dose treatment, an improvement of the immune function, creation of chimeric antigen receptor T cells, and the recruitment of NK cell-based immunotherapy.

Background: Receptor Tyrosine Kinases (RTKs) play critical roles in a variety of cellular processes including growth, differentiation and angiogenesis, and in the development and progression of many types of cancer. Mesenchymal-Epithelial Transition Factor (c-Met) kinase is one of the types of RTKs and has become an attractive target for anti-tumor drug designing. c-Met inhibitors have a broad prospect in tumor prevention, chemotherapy, biotherapy, and especially in tumor resistance. Objective: The purpose of this article is to review recent research progress of c-Met inhibitors reported in patents since 2015. Methods: A comprehensive Scifinder and Web of Science literature review was conducted to identify all c-Met inhibitors published in patents since 2015. Results: There are two kinds of c-Met inhibitors, one is from natural products, and the other one is of synthetic origin. Most of these c-Met inhibitors show potent in vivo and in vitro antitumor activities and have potential in the treatment of cancers. Conclusion: c-Met kinase inhibitors have emerged as an exciting new drug class for the treatment of all kinds of cancers, especially the Non-Small Cell Lung Cancer (NSCLC) with tumor resistance. More studies should be conducted on natural products to find novel c-Met kinase inhibitors.

Background: Vernonia cinerea (VC) is an important medicinal plant used in the indigenous system of therapy. In ethnomedicine, VC has demonstrated anticancer properties. However, the mechanisms of action VC is not known. Objective: To establish the anticancer mechanisms of ‘bioactive fractions of VC’ on human adenocarcinoma cells. Methods: The IC50 values of characterized VC extract and fractions in human adenocarcinoma and normal epithelial cells were determined using Sulforhodamine B (SRB) assay. Acridine Orange- Ethidium Bromide (AO-EB) assay/Hoechst 33342 assay, Comet assay, and Cell cycle analysis were used to determine apoptosis, genotoxicity, and cell cycle-specific changes in cancer cells, respectively. Rhodamine 123 (Rho-123) efflux assay and Mitoxantrone (MX) efflux assay were used to assess the inhibition of Multidrug Resistance (MDR) transporters. Results: The dichloromethane fraction of VC (VC-DM) imparted dose-dependent cytotoxicity in human adenocarcinoma cells with fewer effects in human normal epithelial cells. This ‘sesquiterpenoids’ enriched fraction (VC-DM) induced apoptosis, DNA damage, genotoxicity, and G2/M phase arrest in human adenocarcinoma cells. Interestingly, VC-DM significantly inhibited the functional activity of MDR transporters (ABCB1 and ABCG2) and caused ‘synergistic cytotoxic effects’ with anticancer drugs in human adenocarcinoma cells. Conclusion: The bioactivity guided fractionation of VC revealed that the specific ‘sesquiterpenoids enriched fraction’ (VC-DM) imparted cytotoxicity in human adenocarcinoma cells with fewer effects on normal cells. Mechanistic studies have shown that VC-DM induced apoptosis, DNA damage, genotoxicity, cell cycle arrest (G2/M), inhibited the functional activity of MDR transporters (ABCB1 and ABCG2), and produced ‘synergistic cytotoxic effects’ (combinatorial treatments with anticancer drugs) in human adenocarcinoma cells. Taken together, the findings of this study emphasize and validates VC-DM as a promising ‘anticancer agent’ against human adenocarcinomas, including those with a multi-drug resistant phenotype.

Background: Maintenance chemotherapeutic regimen with low toxicity is needed for metastatic colorectal cancer. A recent patent has been issued on the spleen-strengthening and detoxification prescription (JPJDF), a traditional Chinese herbal medicinal formula with anti-angiogenesis effect. The clinical effect of JPJDF on the maintenance treatment of advanced colorectal cancer has not been evaluated. Objective: This study aims to evaluate the effectiveness and safety of JPJDF in combination with fluoropyrimidine compared to fluoropyrimidine alone as maintenance therapy for metastatic colorectal cancer. Methods: We applied a prospective, randomized, double-blinded, single center clinical study design. A total of 137 patients with advanced colorectal cancer were recruited. Patients received either Fluoropyrimidine (Flu-treated group, n = 68), or Fluoropyrimidine plus JPJDF (Flu-F-treated group, n = 69) as maintenance treatment after 6-cycle of FOLFOX4 or FOLFORI induction treatment. The primary endpoints were Progression-Free Survival (PFS) and Overall Survival (OS). The secondary endpoints were safety, Performance Status (PS) score and other symptoms. Results: The endpoint of disease progression was observed in 91.7% of patients. The PFS was 5.0 months and 3.0 months in the Flu-F-treated and Flu-treated groups, respectively. The OS was 15.0 months and 9.0 months in the Flu-F-treated and Flu-treated groups, respectively. Some common symptoms, such as hypodynamia, anepithymia, dizziness and tinnitus and shortness of breath, were improved in the Flu-F-treated group. There was no significant difference in the common adverse reactions between the two groups. Conclusion: JPJDF and fluoropyrimidine have synergistic effect in the maintenance treatment of mCRC.