Recent Patents on Anti-Cancer Drug Discovery - Volume 9, Issue 2, 2014

A large number of mostly recent reports show enhanced expression of the multi-functional protein nucleolin (NCL) on the surface of activated lymphocytes, angiogenic endothelial and many different types of cancer cells. Translocation of NCL at the external side of the plasma membrane occurs via a secretory pathway independent of the endoplasmic reticulum-Golgi complex, requires intracellular intact actin cytoskeleton, and seems to be mediated by a variety of factors. Cell surface NCL serves as a binding partner of several molecules implicated in cell differentiation, adhesion, and leukocyte trafficking, inflammation, angiogenesis and tumor development, mediating their biological activities and in some cases, leading to their internalization. Accumulating evidence validates cell surface NCL as a strategic target for treatment of cancer, while its property of tumor-specific uptake of targeted ligands seems to be useful for the development of non-invasive imaging tools for the diagnosis of cancer and for the targeted release of chemotherapeutic drugs. The observation that cell surface NCL exists in complexes with several other proteins implicated in tumorigenesis and angiogenesis suggests that targeting cell surface NCL might trigger multi-inhibitory effects, depending on the cell type. This review summarizes papers and patents related to the redistribution and the biological functions of cell surface NCL, with emphasis on the potential importance and advantages of developing efficient anti-cell surface NCL strategies.

Due to the high heterogeneity of breast cancers, numerous recent patents describe improved methods of detection and classification which promise better patient prognosis and treatment. In particular, there has been a shift towards more effective genetic screening to identify specific mutations associated with breast tumours, which may lead to “personalised medicine” with improved outcomes. Two challenging areas of breast cancer research involve the development of treatments for the highly aggressive triple negative breast cancer subtype as well as the chemotherapy-resistant cancer stem cell subpopulation. In addition, despite numerous recent advances in breast cancer treatment in woman, male breast cancer remains poorly understood and there are limited therapies available which are developed specifically for men. This review serves to report on important developments in the treatment of breast malignancies patented in the past two years as well as to highlight the current gaps in the field of breast cancer therapeutics and areas which require further study.

Tubulin is one of the most useful and strategic molecular targets for anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites in the β-tubulin subunit. By interfering with microtubule function in vitro, these agents arrest cells in mitosis, eventually leading to cell death, by both apoptosis and necrosis. So far, three binding domains have been identified a) the colchicine site close to the α/β interface, b) the area where the vinca alkaloids bind, and c) the taxane-binding pocket. This review compiles the patent literature up to 2013 and offers a detailed account of all the advances on Tubulin inhibitors (lead molecules) along with in depth knowledge about the number of novel scaffolds, modified analogs and derivatives of the lead molecules. Colchicine binding site remains the most explored site indicated by the patent survey as majority of the patents revolves around phenstatin and combretastatin based molecules where the key structural feature for tubulin inhibition is an appropriate arrangement of the two aromatic rings at an appropriate distance and optimal dihedral angle maximizing interactions with tubulin. A brief account of promising tubulin inhibitors in stages of clinical development and some strategies for the development of potent molecules overcoming the problem of drug resistance have also been discussed.

Background: During the past 10 years, dramatic progress has been made in the development of effective lung cancer drugs in China. However, little is known about their patents. Objective: To summarize and analyze lung cancer patents or potential drug candidates issued in China over the last 10 years, and thus help researchers and developers to understand the current situation and potential candidates of lung cancer drug patents in China. Methods: Data were obtained from China Intellectual Property Right Net (CNIPR), a website maintained by the Intellectual Property Publishing House (IPPH) subordinate to the State Intellectual Property Office (SIPO), and analyzed by bibliometric methods. Results: A total of 707 lung cancer drug patents have been granted in China over the past 10 years. These patents include synthetic compounds, traditional Chinese medicines (TCM), combinations of synthetic compounds and TCM, biological products and medical apparatus. Current TCM approaches focus primarily on alteration of natural product rather than whole herb treatments, and there is an effort to modify TCM components and natural products to achieve optimal cancer targeting effects. The patents on synthetic lung cancer drug compounds in China mainly focus on well-known targets, such as EGFR, which comprises 93% of patents for validated targets. Conclusion: There has been a surge in lung cancer patents filed in China in recent years due to advancements in the Chinese pharmaceutical industries, improved practices that protect intellectual property rights, and a growing demand for lung cancer drugs. Therefore, there are great opportunities for obtaining lung cancer drug patents, particularly patents on active ingredients from TCM in China.

Eosinophils play important roles in allergic diseases as well as during helminth infection. As multifunctional leukocytes, eosinophils have also been indicated in anti-cancer immunity. Published studies have suggested an association between allergic conditions and a trend of decreased risk in numerous malignances. Moreover, eosinophil infiltration in tumor tissue is considered an independent prognostic factor. Eosinophils are often recruited to tumor sites, where eosinophil granule proteins and cytokines are released upon activation, which in turn damage and kill tumor cells. In the last decade, a number of patents based on potential cancer therapy using eosinophilic cytokines have been awarded. In this article, we review the current findings on epidemiology, experimental models, clinical pathology, and molecular mechanisms involved in the response of eosinophils towards cancer. Moreover, we discuss promising targeted therapies with eosinophilic cytokines as a novel perspective to combat cancer.

Background and Purpose: Aim of this research is to study the in vivo degradation and biocompatibility in rabbits and the dose distribution of novel iodine-125 seed strands connected using magnesium alloy AZ31. Method: Thirtythree New Zealand rabbits were divided into three Groups (A, B, and C). All rabbits in Groups A and C were implanted with VX2 tumors. For Group A, radioactive iodine-125 seed strands were implanted into the VX2 tumors. For Group B, non-radioactive iodine-125 seed strands were implanted into thigh muscle. Rabbits in Group C were used as controls. Displacement of the seed strands was assessed using X-ray and CT. Blood and urine samples were collected from all groups to measure changes in magnesium ion concentrations. The changing effect of alloy AZ31 tube according to dose distribution of iodine-125 was evaluated using the Monte Carlo method. Results: In Groups A and B, 14 days after implantation, majority of the magnesium alloy tubes were fragmented, and 28 days after implantation, the magnesium alloy tubes were completely degraded. Small differences in dose distribution were observed between bare iodine-125 seeds and iodine-125 seed strands. Conclusions: Our results suggest that these novel iodine-125 seed strands connected using magnesium alloy AZ31 are promising anti-cancer drug for brachytherapy due to the rapid degradation of connective materials and even distribution of seed doses in tumors. Some recent patents are also outlined in this article.

Background and Purpose: A number of recent patents related to 125I seed and osteopontin have been awarded. In this study, we developed a new in vitro model to study the radiobiological effects of 125I seeds on cancer cells. Methods: We placed 125I seeds in a cell culture plate with cells seeded on a transwell chamber to evaluate the effects of 125I seeds on cell motility. We placed 125I seeds in a transwell chamber with cells seeded on the cell culture plate to study cell proliferation, apoptosis, and to perform western blot. Results: We used SK-Hep-1 liver cancer cells to evaluate the effectiveness of our model, and investigated the role of osteopontin in the therapeutic effects of 125I seeds. We found that 125I seeds inhibited the cell proliferation and motility in this model while osteopontin reduced these effects. We also measured the effects of 125I seeds on apoptosis. Furthermore, when treated with 125I seeds, we detected changes in several signaling pathways that are involved in the proliferation and invasion of cancer cells. Conclusions: The model can be used to assess the biological effects of 125I seeds in vitro. Osteopontin may be involved in the 125I seed-induced inhibition of SK-Hep-1 cells.