Recent Patents on Anti-Cancer Drug Discovery - Volume 11, Issue 4, 2016

Background and Objective: Methods of local or loco-regional anticancer treatment are of the utmost importance because the therapeutic ‘power’ is applied directly to the disease site. Consequently, general toxicity is minimized. Hyperthermia, that is, a sustained increase of intratumoral temperature up to 45oC, has been investigated as a perspective treatment modality alone and/or in combination with ionizing radiation or chemotherapy. Still, the surrounding tissues can be damaged by the external heat. Method: Development of new materials and devices gave rise to methods of inducing hyperthermia by a high frequency magnetic or electromagnetic field applied to the tumor with exogenous nanosized particles captured within it. The idea of this approach is the release of local heat in the vicinity of the magnetic nanoparticle in a time-varying magnetic field due to transfer of external magnetic field energy into the heat. Therefore, tumor cells are heated whereas the peritumoral non-malignant tissues are spared. Results: This review analyzes recent advances in understanding physical principles that underlie magnetic hyperthermia as well as novel approaches to obtain nanoparticles with optimized physico-chemical, toxicological and tumoricidal properties. Special focus is made on the construction of devices for therapeutic purposes. Conclusion: The review covers recent patents and general literature sources regarding magnetic hyperthermia, the developing approach to treat otherwise intractable malignancies.

Effective therapies against metastatic pancreatic cancer remain limited, and despite treatment, many will ultimately progress. Previously, few options were available for second line therapy in metastatic pancreatic cancer. Liposomal encapsulated irinotecan, in combination with leucovorin-modulated fluorouracil, was found to significantly increase overall survival in patients who have progressed after gemcitabine- based therapy in a large, international, randomized clinical trial (NAPOLI-1). We reviewed the background of systemic therapy for metastatic pancreatic cancer, examined putative mechanisms for the success of encapsulated drugs, and identified recent patent applications on the use of liposomal irinotecan in pancreatic cancer. The landmark NAPOLI-1 trial established a second-line option for those with metastatic pancreatic cancer refractory to gemcitabine chemotherapy, but effective therapies with long duration of response are still lacking. Alternative techniques targeting key driver genes in pancreatic cancer and novel methods of early detection and targeting drugs are currently being explored. How liposomal irinotecan can be integrated into chemotherapy regimens, including neoadjuvant or first line combinations, are currently being tested in clinical trials and covered by several new patent applications.

Background: Cancer is a heterogeneous disease, which is based on an intricate network of processes at different spatiotemporal scales, from the genome to the tissue level. Hence the necessity for the biomedical and pharmaceutical research to work in a multiscale fashion. In this respect, a significant help derives from the collaboration with theoretical sciences. Mathematical models can in fact provide insights into tumor-related processes and support clinical oncologists in the design of treatment regime, dosage, schedule and toxicity. Objective and Method: The main objective of this article is to review the recent computational-based patents which tackle some relevant aspects of tumor treatment. We first analyze a series of patents concerning the purposing the purposing or repurposing of anti-tumor compounds. These approaches rely on pharmacokinetics and pharmacodynamics modules, that incorporate data obtained in the different phases of clinical trials. Similar methods are also at the basis of other patents included in this paper, which deal with treatment optimization, in terms of maximizing therapy efficacy while minimizing side effects on the host. A group of patents predicting drug response and tumor evolution by the use of kinetics graphs are commented as well. We finally focus on patents that implement informatics tools to map and screen biological, medical, and pharmaceutical knowledge. Results and Conclusions: Despite promising aspects (and an increasing amount of the relative literature), we found few computational-based patents: there is still a significant effort to do for allowing modelling approaches to become an integral component of the pharmaceutical research.

Background: Non-small cell lung cancer is the leading cancer-related cause of death. Objective: We review the latest therapies for NSCLC with EGFR and ELM4-ALK mutations as well as the most relevant studies and promising patents. Method: A literature search of PubMed database was carried out to identify recent Clinical Trials using EGFR therapies and novel patents involving diagnosis and therapies on NSCLC. We conducted a search to find new therapy strategies, new biomarkers, and selected five patents we find relevant. Results: Over the last few years, identification of cancer harboring epidermal growth factor receptor mutations (EGFR) or chromosomal rearrangements of anaplastic lymphoma kinase (ALK) led to new ways in classifying and treating NSCLC. On the other hand, acquired resistance are a constantly challenge in the management of patients with these mutations and new drugs options are in development to improve and amplify treatment strategies. Conclusions: Currently, EGFR TKIs (e.g.: erlotinib, gefitinib, osimertinib) and ALK inhibitors (crizotinib, ceritinib, alectinib) provided a new face for advanced NSCLC outcomes. To understand the disease molecular profile is mandatory to define the best approach for each patient.

Background: Topoisomerases are a set of nuclear enzymes that play a vital role in handling of topological consequences of DNA during various genetic activities necessary for vitality of cell. Inhibition of these enzymes consequently leads to the blockage of ligation step of the cell cycle which generates single and double strand breakage in DNA strand. Introduction of these breaks subsequently leads to programmed cell death (Apoptosis). Objective: In the past several years, topoisomerases have become one of the most expedient and strategic molecular targets for anticancer drugs and numerous patents have been filed and published on topoisomerase inhibitors. This review compiles the patent literature up to 2016 embracing topo I and II inhibitors as well as dual inhibitors which are structurally adjacent to camptothecin (CPT), natural products such as lamellarins and synthetic trisubstituted pyridines. The present assemblage can be extremely advantageous for the medicinal chemists who are in crave for the development of potential anticancer agents targeting topoisomerases. Conclusion: Recent patents indicated that some of the nitrogen containing heteroaromatic compounds have immense potential to inhibit topoisomerase enzyme. In particular, fused N-Heterocycles can be anticipated for their promising therapeutic potential alone or in combination with other anticancer agents. Naphthyridinone and indenoisoquinoline derivatives, described in the preceding sections of this review, are endowed with significant potency against topoisomerase I which clearly indicates the need of preclinical and clinical studies to place them in forefront as potential future drug candidates.

Background: Epigenetics is a biomedical novelty in drug design and disease control whose mechanisms play a significant role in transferring environmental signals to determine patterns of gene expression. Systematic identification of the main trends in epigenetics patenting activity provides insights into fundamental building blocks of this research field and policy guidance to funding agencies. Objective: The review aims at providing a comprehensive overview of the research and development trend in epigenetics by mapping the knowledge structure in patent landscape. Methods: Citation-based patent network analysis was performed to visualize the technological landscape. We focus on identifying the structure of the knowledge networks to study the technological trajectories. Patents that play an integral part in the dissemination and bridging of the technical knowledge are located and ranked. The latent topics in patent documents are highlighted by means of a topic modeling technique. Results: Visualization of the patent network results in four main clusters. The first two clusters deal with the inhibition of histone deacetylase (HDAC). The third cluster covers inventions related to DNA methylation, which represents an epigenetic signaling tool that cells use to control gene expression. The fourth cluster encompasses computing systems and data mining techniques for identifying combinations of genetic and epigenetic attributes related to health and lifestyle improvements. Conclusion: We are in the growth period of gathering knowledge on various mechanisms of epigenetic regulation. There is enormous potential for improving healthcare through better understanding of the interrelationships between epigenetic control of gene expression and compounds that trigger these modifications.

Background: Recent studies have shown that the high mortality of patients with colorectal cancer (CRC) is related to its ability to spread the surrounding tissues, thus there is a need for designing and developing new drugs. Objective: Here, we proposed a combinational therapy strategy, an inhibitory peptide in combination with miRNA targeting, for modulating CRC metastasis. In this study, some of the recent patents were also reviewed. Methods: After data analysis with GEO2R and gene annotation using DAVID server, regulatory interactions of differentially expressed genes (DEGs) were obtained from STRING, GeneMANIA, KEGG and TRED databases. In parallel, the corresponding validated microRNAs (miRNAs) were obtained from mirDIP web server and a miRNA-DEG regulatory network was also reconstructed. Clustering and topological analyses of the regulatory networks were performed using Cytoscape plug-ins. Results: We found the HOXB family as the most important functional complex in DEG-derived regulatory network. Accordingly, an anti-HOXB7 peptide was designed based on the binding interface of its coactivator, PBX1. Topological analysis of miRNA-DEG network indicated that hsa-miR-222 is one of the most important oncomirs involved in regulation of DEGs activities. Thus, this miRNA, along with HOXB7, was also considered as the potential target for inhibiting CRC metastasis. Molecular docking studies exhibited that the designed peptide can bind to desired binding pocket of HOXB7 in a highaffinity manner. Further confirmations were also observed in Molecular dynamics (MD) simulations carried out by GROMACS v5.0.2 simulation package. Conclusion: In conclusion, our findings suggest that simultaneous targeting of key regulatory genes and miRNAs may be a useful strategy for prevention of CRC metastasis.

Background: Recent patent of licochalcone B (LCB) as an antiinflammatory agent has been developed. Emerging evidence shows that LCB may be a promising alternative compound with anti-cancer activities. However, the anticancer mechanism of LCB in MCF-7 cells has not been fully investigated. Objective: We aimed to unearth the anti-cancer effect and mechanism of LCB in MCF-7 cells. Method: Cell proliferation activity and cell-cycle progression were determined by sulforhodamine B assay and flow cytometry, respectively. The mRNA and protein levels of cell cycle-related proteins and apoptosis-associated proteins were examined by RT-qPCR and western blot, respectively. Mitochondrial membrane potential (MMP) was measured by flow cytometry after JC-1 staining. Results: We found that LCB inhibited MCF-7 cells proliferation in a concentration- and time-dependent manner. Moreover, LCB-treatment led to S phase arrest in MCF-7 cells, which could be elucidated by the decreased mRNA and protein levels of Cyclin A, Cdk2 and Cdc25 A, and the increased protein level of p21. LCB also induced such apoptosis morphology as phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Moreover, LCB led to the loss of MMP, resulting in the release of cytochrome C. The above apoptotic events were supported by the fact that LCB upregulated the mRNA and protein levels of Caspase 3, Caspase 9 and Bax, and downregulated the mRNA and protein level of Bcl-2, which was triggered by the increased p53 protein level in LCB-treated MCF-7 cells. Conclusion: These findings suggested that LCB could be a promising agent for treatment of human breast cancer.

Background: Gene therapy is a promising approach for the treatment of various cancers. However, most viral vectors used for this purpose carry risks, including potential integration into the host genome. Objective: We addressed this issue in the present study by constructing an episomal lentiviral vector using the β-interferon matrix attachment region to express the microRNA -145(miR-145), and examining the effect of miR-145 overexpression on human esophageal carcinomas (EC) cells. Some recent relevant patents are also discussed. Method: Expression levels of miR-145 and the marker protein enhanced green fluorescent protein (EGFP) in infected ECA109 and EC9706 human esophageal carcinoma cells were detected by quantitative PCR and flow cytometry, respectively. Cell proliferation and apoptosis were assessed by Cell Counting Kit-8 and flow cytometry, respectively. Plasmid rescue experiments and fluorescence in situ hybridization were used to determine the episomal status of the transfected vector. Results: We found that EGFP and miR-145 were highly expressed in EC cells, and miR-145 overexpression inhibited cell proliferation and induced apoptosis. Moreover, the lentiviral vector did not integrate into the host genome, but was maintained episomally at lower copy numbers. Conclusion: Taken together, our results demonstrate that miR-145-expressing episomal lentiviral vectors are a promising tool for gene therapy in the treatment of EC.

Background: Ribonucleotide Reductase (RNR) is an important anticancer chemotherapy target. It has main key role in DNA synthesis and cell growth. Therefore several RNR inhibitors, such as hydroxyurea, have entered the clinical trials. Based on our proposed mechanism, radical site of RNR protein reacts with hydroxyurea in which hydroxyurea is converted into its oxidized form compound III, and whereby the tyrosyl radical is converted into a normal tyrosine residue. Objective: In this study, docking and molecular dynamics simulations were used for proposed molecular mechanism of hydroxyurea in RNR inhibition as anticancer agent. Method: The binding affinity of hydroxyurea and compound III to RNR was studied by docking method. The docking study was performed for the crystal structure of human RNR with the radical scavenger Hydroxyurea and its oxidized form to inhibit the human RNR. hydroxyurea and compound III bind at the active site with Tyr-176, which are essential for free radical formation. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2. To confirm the binding mode of inhibitors, the molecular dynamics (MD) simulations were performed using GROMACS 4.5.5, based upon the docked conformation of inhibitors. Results: Both of the studied compounds stayed in the active site. The results of MD simulations confirmed the binding mode of ligands, accuracy of docking and the reliability of active conformations which were obtained by AutoDock. Conclusion: MD studies confirm our proposed mechanism in which compound III reacts with the active site residues specially Tyr-176, and inhibits the radical generation and subsequently inhibits the RNR enzyme.