Recent Patents on Anti-Cancer Drug Discovery - Volume 8, Issue 3, 2013

Cancer is the main cause of death in developing countries. Its development requires multiple steps in which the occurrence of certain events determines the state transition from a normal to a tumor cell. These events are related to the loss of mechanisms that control various biological processes, which results from the accumulation of genetic alterations, including mutations, chromosomal rearrangements, and variations in gene copy number, as well as from epigenetic alterations. In general, chemotherapeutic agents used for toxicity treatments have shown limited antitumor activity, with a high recurrence rate. This has prompted major research efforts to identify novel effective and selective anti-tumor compounds. In this article, we review recent patents that protect the antitumor properties of natural compounds and related molecules derived from plants, animals, or microorganisms. We consider their structure, mechanism of action, molecular targets and, in some cases, the clinical trial phase reached. We also report on various natural agents that appear to prevent cancer development.

Glioblastoma is the most common, aggressive and lethal brain tumor in adults. However, current therapeutic protocols have low success rates and average overall survival is less than 15 months. The resistance to therapy is largely a result of the remarkable cellular and phenotypical heterogeneity that characterizes this type of tumor. The discovery of a subpopulation of cells exhibiting stem cell properties within the tumor bulk has profound implications for therapy as increasing evidence indicates that these cells, glioblastoma stem cells (GSCs), are responsible for the origin, maintenance and recurrence of the glioblastomas. These findings highlight the need to characterize GSCs in order to find novel treatments directly targeted specifically against them. In this review, we summarize the current knowledge regarding this issue, including some recent and relevant patents.

Kinase inhibitors are among the fastest growing class of anti-cancer therapies. One family of kinases that has recently gained attention as a target for treating malignant disorders is the Tec kinase family. Evidence has been published that one member of this family; the Bmx kinase, may play a role in the pathogenesis of glioblastoma, prostate, breast and lung cancer. Bmx has also shown potential as an anti-vascular therapy in combination with radiation or as a sensitizer to chemotherapeutic agents. Therefore, several companies such as Pharmacyclics, Avila Therapeutics, Merck and Co., Metaproteomics, IRM, and Moerae Matrix have developed compounds or peptides that function as Bmx kinase inhibitors. These companies have subsequently been issued patents for these inhibitors. Additionally, it has been shown that current clinical stage EGFR inhibitors can irreversibly inhibit Bmx, suggesting these compounds might be rapidly moved to clinical trials for other malignancies. This review will discuss current patents issued since 2009 that contain data specifically on inhibition of the Bmx kinase, and will also discuss the scientific literature that suggests their potential application as therapeutics in the treatment of the aforementioned malignancies.

Solid tumors contain several different types of malignant cells. This cellular heterogeneity complicates therapy for at least two reasons. First, each subpopulation may respond differently to a given treatment. Second, cancer cells are plastic, and thus may convert from a therapy-sensitive to a therapy-resistant cell type represented by another subpopulation. Therefore, successful therapies will have to target numerous malignant cell types, not just the rapidly proliferating cells as most standard treatments do. Immunotherapies with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) are particularly promising approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells. Here, we discuss several patents associated with exceptionally effective bsAbs of the tandem single-chain variable fragment (taFv) class and untangle a part of the complex network of patents directly or indirectly related to CARs. Furthermore, we speculate on the future of bsAbs and CARs for both treatment and prevention of solid tumors such as prostate cancer.

Based on the analysis of more than 270 patents and scientific articles, this state-of-the-art review presents Ganoderma lucidum, a medicinal basidiomycete mushroom with immunomodulatory and anti-cancer effects. Cultivation methods for the commercial production of G. lucidum fruit bodies and mycelia are summarized, with main active compounds of triterpenoids, polysaccharides, and proteins, often found in forms of proteoglycans or glycopeptides. Pharmacological effects with emphasis on anti-cancer and immunomodulatory functions are presented, separately for spores and dry mycelia, and for the groups of triterpenoids, polysaccharides, proteins and glycoproteins. Patents disclosing preparation methods of extracts and purified pharmaceutical isolates are reviewed, and examples of anti-cancer formulations, used as pharmaceuticals or nutraceuticals, are given. The review suggests that according to the present understanding, the anti-cancer activity of G. lucidum may be attributed to at least five groups of mechanisms: (1) activation/modulation of the immune response of the host, (2) direct cytotoxicity to cancer cells, (3) inhibition of tumor-induced angiogenesis, (4) inhibition of cancer cells proliferation and invasive metastasis behaviour, and (5) carcinogens deactivation with protection of cells. Although, the data from recent in vitro and in vivo studies demonstrate promising anti-cancer effects, a need is identified for further (1) isolation and purification of compounds, with deeper understanding of their individual and synergistic pharmacological effects, (2) molecular level studies of the antitumor and immuno-supportive mechanisms, (3) well designed in vivo tests and controlled clinical studies, and (4) standardisation and quality control for G. lucidum strains, cultivation processes, extracts and commercial formulations.

Gastrointestinal stromal tumors (GISTs) owe their development to the activating mutations in mast/stem cell growth factor receptor (KIT) or platelet-derived growth factor receptor A (PDGFRA) oncogenes. Both these KIT and PDGFRA oncogenes are members of the type III transmembrane receptor tyrosine kinase family that stimulates intracellular signaling pathways controlling cell proliferation, adhesion, apoptosis, survival, and differentiation. The presence and type of KIT/PDGFRA mutations help to predict the imatinib mesylate therapy, a selective tyrosine kinase inhibitor. Moreover, there is reported a small proportion of wild-type GISTs for both KIT and PDGFRA genes, and tumors more often acquire secondary mutations on KIT, that results into imatinib resistance. New patents to the GISTs imatinib resistant have recently been introduced. At present, sunitinib, is prescribed as second line therapy for patients with imatinibresistant or imatinib-intolerant GIST, and a number of other drugs, such as masitinib and valatinib, are in the pipeline. The present research focuses on GISTs diagnostic, prognostic and therapeutic biomarkers and addresses the development of novel patents for the treatment of these patients.

The ubiquitin proteasome pathway is the most significant intracellular proteolytic pathway. The target proteins are usually ubiquitinated prior to degradation by the proteasome; however, ubiquitin-independent targeting mechanisms have also been reported (e.g., the antizyme-mediated degradation of ornithine decarboxylase). Aberrations in the components of the ubiquitin proteasome pathway are commonly observed in many cancers, and uncontrolled growth of cancer cells can result either from stabilization of oncoproteins (e.g., c-jun) or increased degradation of tumor suppressor proteins (e.g., p53). In addition, due to the pleiotropic functions of the ubiquitin proteasome pathway in cells, there is great interest in developing inhibitors to specifically block this pathway for cancer treatment. This review summarizes the recent literature and several patented inventions on the ubiquitin proteasome pathway with respect to its role in cancer development and treatment.

Self renewal, extensive proliferation and multilineage differentiation ability in vitro and in vivo make mesenchymal stem cells (MSCs) powerful tools for tissue engineering. Beyond their potential uses in regenerative medicine, an emerging field of research aims to utilize MSCs for anti-cancer treatment. These strategies are based on the remarkable ability of MSCs to localize and integrate into tumor stroma and deliver anti-cancer agents (US20100055167, US20120207725, US20120010499). Genetically engineered MSCs can specifically target different tumor types and locally secrete therapeutic proteins such as interferons α and β, interleukins 2 and 12 or chemokine CX3CL1 (US20110027239, US20120087901, WO2012071527). In addition, MSCs have also been engineered to deliver oncolytic viruses, for targeted chemotherapy using enzyme prodrug conversion or for inducing tumor cell apoptosis by delivering tumor necrosis factor-related apoptosis inducing ligand (TRAIL) (WO2012106281). The patent databases FPO and Delphion were used to locate patents that were published between 2005 and 2013. Here, we present the current progress and the most recent patents on MSC anti-cancer drug delivery systems and discuss future directions in the field.

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advances in research, diagnosis and treatment, lung cancer remains a highly lethal disease, often diagnosed at advanced stages and with a very poor prognosis. Therefore, new strategies for the prevention and treatment of lung cancer are urgently needed. The aim of the present study was to determine the anti-tumorigenic effects of docosahexaenoic acid monoacylglyceride (MAG-DHA), a newly patented DHA derivative in lung adenocarcinoma. Our results demonstrate that MAG-DHA treatments decreased cell proliferation and induced apoptosis in A549 human lung carcinoma cells whereas MAG-DHA treatment did not induce apoptosis of normal bronchial epithelial BEAS-2B cells. MAG-DHA decreased NFκB activation leading to a reduction in COX-2 expression level in both A549 cells and lung adenocarcinoma tissues. Furthermore, MAG-DHA treatment increased PTEN expression and activation concomitant with a decrease in AKT phosphorylation levels and enhanced apoptosis. Oral administration of MAG-DHA significantly reduced tumor growth in a mouse A549 xenograft model. Lastly, MAG-DHA markedly decreased COX-2 and enhanced PTEN protein expression in tumor tissue sections. Altogether, these data provide new evidence regarding the mode of action of MAG-DHA and strongly suggest that this compound could be of clinical interest in cancer treatment.