Recent Patents on Anti-Cancer Drug Discovery - Volume 13, Issue 1, 2018

Background: Nucleic acid sensing is an essential strategy employed by the innate immune system to detect both pathogen-derived nucleic acids and self-DNA released by host apoptotic or necrotic cells. The presence of nucleic acids that gain access to the cytoplasm is perceived by mammalian cells as “stranger” or “danger” signals that trigger a myriad of immunological responses. Recent publications have highlighted the importance of nucleic acid sensing machinery as mediator of innate and adaptive immunity, and cGAS, STING and RIG-I agonists have been validated as immunooncology agents in cancer therapy. Objective: The crucial role of cGAS and STING in eliciting innate and adaptive immune responses provides a scientific rationale for using cGAMP and STING agonists both in human preventive vaccine and immunotherapy settings. Thus, search for natural and synthetic STING agonists and development of cyclic dinucleotides (CDNs)-based adjuvants were strongly intensified. Furthermore, with their ability to induce tumour cell death and lymphocyte cross priming, RIG-I ligands are among the most promising molecules for the development of new immunostimulatory adjuvants in cancer vaccines. Results: This work focuses on relevant recent patents (2010-2017) that entail the use of nucleic acid sensing machinery to elicit innate and adaptive immune responses, highlighting a new approach in immune-mediated cancer therapy. Several patents describe compositions and methods that may be used as immuno-oncology agents for the treatment of cancer patients. cGAS and/or STING pathways modulating compounds alone or in combination with pharmaceutical compositions are discussed. New approaches to improve DNA-vaccine induced adaptive immunity for cancer therapy through increasing the level of plasmid-mediated activation of innate immune signalling pathways are also discussed. In addition, a targeted selection of very recent clinical studies describing the employment of innate immunity targeting compounds is reported. Conclusion: It is highly relevant to deepen the study of the nucleic acid-sensing mechanisms to develop new pharmacological approaches to engage these pathways within the tumour microenvironment. Indeed, further clarification will be functional to develop advanced anticancer strategies or to design new vaccine formulations.

Background: Radiation therapy has become a common therapy for cancer patients and largely improved therapeutic outcomes. However, recurrence after radiation therapy is still a major unsolved concern of cancer patients. The Cancer Stem Cells (CSCs), a small sub-population with the capacity of self-renewal and differentiation into diverse types of cancer cells, are considered as strong drivers of metastasis, resistance, and recurrence. Objective: We overview the mechanisms behind the radiation resistance of CSCs, and introduce recent patents with the potential to overcome such an obstacle. In this review article, we will introduce those patented compounds as potential combinatory drugs for radiation therapy and present their specific molecular mechanisms. Method: From a thorough literature review on the mechanisms of radiation resistance exhibited by CSCs, several patents that have disclosed novel compounds or their specific applications for improving radiation therapy will be introduced with their developmental status and experimental results. Results: Recent studies have focused on revealing the molecular mechanisms of CSC contributing to radiation resistance and succeeded to discover that CSCs possess intrinsic and extrinsic resistance by preventing radiation-induced cellular damages and by adapting to the changes occurred by radiation exposure, respectively. Among currently discovered resistant mechanisms of CSCs, DNA repair and redox system directly decrease radiation-induced DNA breaks and relieve cellular stress caused by Reactive Oxygen Species (ROS). Indirectly, altered metabolism and cellular signaling may help CSCs adapt to the desolate microenvironment disrupted by radiation exposure. In order to overcome this obstacle on the road to the efficient cancer treatment, diverse therapeutic strategies using anti-sense oligonucleotides, small molecule inhibitors and antibodies have been tested and some of them actually showed an efficacy on improving current radiation therapy. Conclusion: Many agents that directly or indirectly sensitize CSCs have been developed and some of them are on clinical trial. We expect that they will be used to enhance clinical radiation therapy in the future.

Background: Adenosine is a purine, with an adenine group and a ribose sugar, formed endogenously by ATP catabolism both intracellularly and extracellularly. Among the medicinal features of adenosine and its receptors (A1, A2A, A2B and A3), anticancer activity has been an intense field of research. The anticancer potential of adenosine receptor ligands has been brought to the forefront of research and evidenced in innumerous research articles and patents. Objective: The present review focuses on the patent literature from 2002 onwards (2002-May 2017). Methods: Patents were searched and downloaded from the open access patent data bases and are available online. Results: A significant number of patents (65) have been published on adenosine receptor ligands claiming anticancer activity, or presenting new methods of preparation or treatment thereof, from 2002-2017 (May). From these, 35 were published highlighting the promising attributes of compounds/ methods to fight cancer. Most of the compounds act as adenosine A3 receptor agonists, while others act as antagonists for the other adenosine receptor subtypes. The signaling events triggered by activation of adenosine A3 receptor or by blockade of adenosine A1, A2A and A2B receptors can reverse an environment from being pro-cancer to an anti-cancer in the body. Conclusion: The promising anticancer effects mediated by adenosine receptor ligands put them in the forefront as new drug candidates. The present compilation can be worthy to medicinal chemists, pharmacologists, biochemists and other researchers focusing on the putative anticancer activity of adenosine receptor ligands.

Background: Cancer is one of the leading causes of morbidity and mortality worldwide. Brain cancer is identified as one of the most formidable forms of cancer due to several hurdles posed by the anatomy and physiology of the brain on the therapeutic strategies employed for treating brain cancer. Poor prognosis and high relapse rate further aggravate the situation leading to the high mortality rate in brain cancer. Objective: The present review gives a brief insight on different aspects of brain cancer by elucidating its types, causative factors, associated symptoms, diagnostic techniques, treatment strategies and limitations of current treatment strategies. The review summarizes novel drug delivery based treatment strategies for tumor targeting. Methods: Conventional surgical or chemotherapy based strategies are less efficient for treating brain cancer. Surgery is risky because extracting the tumors can permanently damage the brain and alter the patient's ability to function. Sometimes, surgery cannot be performed because of the anatomical location of the tumor which is beyond the reach or near to any vital region. Drug based therapy requires heavy doses to cross the blood brain barrier leading to systemic toxicity. The review summarizes fifteen different patented technologies for targeting the drug substance specifically to the tumor site in the brain. Result: Targeted drug delivery strategies serve as an efficient tool for treating brain cancer. Conclusion: Novel strategies focused towards targeting drug substances specifically to brain tumor site would increase the therapeutic efficiency and reduce the toxicity of chemotherapeutics.

Background: Human dihydroorotate dehydrogenase (hDHODH, EC 1.3.5.2), a flavindependent mitochondrial enzyme involved in de novo pyrimidine biosynthesis, is a validated therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. However, human DHODH inhibitors have also been investigated as treatment for cancer, parasite infections (i.e. malaria) and viruses as well as in the agrochemicals industry. Objective: An overview of current knowledge of hDHODH inhibitors and their potential uses in diseases where hDHODH is involved. Method: This review focuses on recent advances in the development and application of hDHODH inhibitors, specifically covering the patent field, starting from a brief description of enzyme topography and of the strategies usually followed in designing its selective inhibitors. Results: The most important and well-described novelty is the fact that the discovery, in the autumn of 2016, that hDHODH inhibitors are able to induce in vivo myeloid differentiation has led to the possibility of developing novel hDHODH based treatments for Acute Myelogenous Leukemia (AML). Conclusion: The review will describe a variety of specific inhibitor classes and conclude on recent and future therapeutic perspectives for this target.

Background: Inflammasomes are recognized as key regulators in innate immunity from the pathogenic to endogenous danger signals. Although controlled activation of inflammasome is highly beneficial, dysregulation of inflammasome activation plays central role in various autoimmune, inflammatory disorders and aid in promoting various forms of cancers in humans such as breast cancer, fibrosarcoma, gastric carcinoma, and lung metastasis. NLRP3 inflammasome activation has been emerged as a topic of interest and is under profound investigation for its involvement in multiple forms of cancers. Objective: This review emphasizes an overview of the recent patents on NLRP3 inflammasome activation inhibitors with their relevant biological/pharmacological properties for the prevention and treatment of inflammation-associated cancer disorders. Methods: Data were obtained from online patent searchers such as World Intellectual Property Organization (WIPO®), Free Patent Online (FPO), Espacenet® and Google Patents. Results: Several NLRP3 inflammasome activation inhibitors were recently patented from naturally derived and synthetic agents mainly by academic researchers. Most of the claimed patents have been validated and confined to cell lines and animal models limiting their entry into clinical settings. Conclusion: The vigorous effort to discover and develop agents to specifically inhibit NLRP3 inflammasome activation, may pave the way to therapeutic intervention targeting inflammasome-regulated pathways that are involved in the pathogenesis of various forms of cancer.

Background: Metastases to the stomach are extremely rare and the metastatic pathway is not well understood. Objective: To present two unusual gastric metastases and a review of the literature regarding the pathway of Epithelial Mesenchymal Transition (EMT) in the metastatic cells. Method: The clinicopathological aspects of the two cases were presented in the light of the most recent patents. Data about patents were obtained from the online databases PubMed, World Intellectual Property Organization (WIPO) and Google patents. Results: In the first case, in a 73-year-old female, total gastrectomy was performed for a Gastric Cancer (GC) that was proved to be, based on the immunohistochemical features (positivity for mammaglobin and estrogen receptor and negativity for E-cadherin, β-catenin, CD44 and maspin), a metastasis from an invasive lobular carcinoma of the breast, that was later confirmed. In the second case, a 67-year-old female with invasive ductal carcinoma of the breast, which benefited from chemotherapy and mastectomy, presented a metachronous gastric adenocarcinoma with collision-type metastatic breast ductal carcinoma. The aggressiveness of the GC cells was induced through the E-cadherin/maspin pathway, while the CD44-related stem-like properties of the tumor cells induced the aggressiveness of ductal carcinoma. Conclusion: In females with breast cancer, a possible metastasis in the stomach should be taken into account. Maspin and VSIG1 are not involved in breast cancer histogenesis. The Wnt/β-catenin signaling is not involved in the lobular carcinoma progression. The CD44/HER2 positivity in ductal carcinoma cells might indicate high risk of distant metastasis and low response to chemotherapy.