Recent Patents on Anti-Cancer Drug Discovery - Volume 1, Issue 2, 2006

Targeting tumor angiogenesis to treat cancer has been the focus of intense research in recent decades. The resulting increase in our knowledge of cancer biology has lead to the development of several new classes of investigational agents that inhibit the angiogenic process. While many clinical trials on antiangiogenic compounds have had disappointing results, the recent approval of the first effective drug targeting tumor vessels has revived interest in further drug development for angiogenesis inhibitors. Of the plethora of new patents for antiangiogenic compounds, only a few describe compounds that will become effective and non-toxic therapies for patients with cancer. This review examines representative patents related to cancer angiogenesis in the context of our current knowledge of the biological processes leading to tumor vascularization and explores the future of multi-targeted therapy and nanoformulation technology in the field of angiogenic therapy.

Cytotoxic nucleoside analogues are clinically important anticancer drugs. The newer member of this family, gemcitabine, has shown great activity in solid tumors and thus enlarged the spectra of malignancies treated by this family of molecules. However, the clinical use of nucleoside analogues is limited by important side-effects and primary or acquired drug resistance, and there is an unmet medical need for the development of new molecules and technologies allowing a suitable treatment of cancer patients with these agents. In this article we will review literature data and patents concerning (i) the recent development of some novel nucleoside analogues, (ii) oral formulations for cytotoxic nucleoside analogues, (iii) strategies to circumvent acquired resistance to nucleoside analogues, and (iv) gene therapy strategies used to increase cytotoxicity of nucleoside analogues.

Thymidine phosphorylase (TP), also known as platelet derived endothelial cell growth factor (PD-ECGF), is an enzyme involved in thymidine synthesis and degradation and exerts an angiogenic activity, whereas N4 pentyloxycarbonyl- 5'-deoxy-5-fluorocytidine, commonly called capecitabine (CAP), is a TP-activated oral fluorpyrimidine, which generates 5-fluorouracil (5-FU) within tumours. In addition to its classic antitumour activity, recent studies suggest that CAP may act as an antiangiogenetic molecule. Assessment of tumour microvessel density as expressed by endothelial cell TP positivity may identify the most vascularized and hence CAP-sensitive tumours. This review summarizes: (i) the biochemical and tissue expression of TP; (ii) the pharmacological profile of CAP as an anti-cancer compound and the central role of TP in its activation; (iii) the potential antiangiogenetic role of TP-activated CAP in tumours.

Increasing evidence suggests that four-stranded tetraplex structures spontaneously form under physiological conditions and these alternate DNA structures are likely to form in vivo. Alternate G-quadruplex DNA structures that may form in regulatory elements of oncogenes or G-rich telomere sequences are potential targets for cancer therapy since these sequence-specific structures are proposed to affect gene expression and telomerase activation, respectively. Small molecule compounds that specifically bind tetraplexes may be used to regulate cell cycle progression by modulating promotor activation or disrupting telomere maintenance, important processes of cellular transformation. In this review, we summarize the current research developments and associated patents that bear relevance to understanding the mechanism and clinical application of tetraplex binding molecules as anti-cancer agents.

Cancer is a complex multifactorial disease requiring combinations of several therapeutic modalities to treat it effectively. Despite advances in the field of prevention and treatment of cancer, morbidity and mortality remain high, especially for tumors that cannot be completely removed, as well as for those that are highly recurrent or highly metastatic. Surgery, radiotherapy and chemotherapy, alone or in combination, are currently the prevalent treatment modalities. Yet, in order to treat metastases more effectively, the immune response must be recruited. In this review, we will focus on recent patents in the field of cancer that have concentrated on combining chemotherapy or radiotherapy strategies with immunotherapy, in order to eradicate the primary tumor as well as its metastases.

Cellular receptors for the Epidermal Growth Factor (EGF-R) are members of the ErbB receptor family and are considered important targets for the experimental treatment of human cancer. Monoclonal antibodies as well as small tyrosine kinase inhibitors (TKIs) have been developed and have undergone extensive evaluation in preclinical and clinical studies based on the general idea that EGF-R plays a critical role on the growth and survival of human tumors. This assumption has been derived by the successful development of BCR/ABL tyrosine kinase inhibitors in human chronic myeloid leukemia as well as on the activity of therapy with monoclonal antibodies (mAb) in breast cancer and lymphoproliferative diseases. It is now becoming clear that factors regulating sensitivity to kinase inhibitors may differ from monoclonal antibodies and that the molecules targeted by interfering drugs must be prioritaire for growth and survival of those specific tumors in order to achieve valuable results. In this article, we will describe the signal transduction pathways regulated by EGF-R and the principal pharmacological and biotechnological agents directed against EGF-R. We will discuss the significance of targeting the EGF-R driven survival pathways and the compensatory intracellular survival mechanisms that counteract the specific EGF-R inhibition and are the cause of the poor clinical results derived from study based on the use of these agents. We will describe new multipotent TKIs that target also other members of ErbB family (i.e. ErbB2) blocking one of the compensatory mechanism that can be triggered in cancer cells. Moreover, we will report new patent on bispecific mAbs that bind EGF-R and immune effectors in order to increase the immunological function of this agent that could be the basis of the different clinical results achieved with the use of TKI and mAbs. Finally, we will propose a pharmacological model able to make cancer cells dependent on EGF-R for their survival and proliferation and we will discuss the relevance of patenting also new therapeutical strategies and not only the simple drug.

Angiogenesis, the formation of new blood vessels from preexisting microvasculature, is a highly regulated process. Angiogenesis is controlled by both positive and negative factors thus providing several targets for drug discovery. The inhibition of angiogenesis represents a new approach to cancer therapy and several agents and approaches are in different stages of clinical development. These inhibitors were recently shown to constitute a new modality for cancer treatment. In this article, we will review angiogenesis inhibitors-related patent literature for the years 2000-2005. This review will cover specifically the discovery and development disclosures of endogenous inhibitors. The scope of this review is to give the reader a well-structured patent literature review of these agents targeting different steps of the angiogenic process. Finally, we have summarized the key attributes of the emerging endogenous angiogenesis inhibitors that make them potent antitumor agents.

Somatostatin (SS) was originally discovered as a hypothalamic neurohormone which inhibits growth hormone secretion. The synthesis of the first two metabolically stabilized and more potent SS analogs, octreotide and lanreotide leads to the establishment of applications for them and to introduction into routine therapies. The effectiveness of octreotide or lanreotide in controlling symptoms and GH/IGF-I hypersecretion in acromegalic patients, both preoperatively and postoperatively is well proven. Similarly, these drugs are also very effective in the treatment of TSH-secreting adenomas. The introduction of these drugs into therapy of the functional neuroendocrine tumors of the gastrointestinal tract was a crucial step in the treatment. Octreotide and lanreotide are the drugs of choice in the treatment of patients with: VIPoma, glucagonoma and carcinoid syndrome. Somatostatin receptor scintigraphy with OctreoScan has been recommended as the best imaging technique in these tumors in the localization and staging procedure. SS analogs, coupled to radioisotope or cytotoxic drugs, create another class of SS molecules, very promising in the therapy of the endocrine glands tumors and in other tumors. Another class of SS analogs comprises hybrid molecules, which are chimera of sst2 agonist and D2 agonist, possessing more potent activity than these agonists, applied together.

Cancer is one of the most dreaded diseases with a complex pathogenesis, which threats human life greatly. Multidisciplinary scientific investigations are making best efforts to combat this disease and put to the identification of novel anticancer agents. Patent anticancer agents registered in China are therefore increasing dramatically during the past ten years, which will be reviewed briefly in this article. I. platinum complexes II. anthracycline analogs (including doxorubicin derivatives) III. quinoline analogs IV. podophyllotoxins analogs V. taxane analogs VI. camptothecin (CPT) analogs

Cisplatin, carboplatin and oxaliplatin continue to be among the most efficient anticancer drugs in world-wide clinical use so far. In particular, cisplatin has shown a remarkable therapeutic efficacy in a broad spectrum of solid tumors and outstanding activity against metastatic testicular germ-cell cancer with cure rates of about 90% of cases. Nevertheless, the dose-limiting severe toxic side-effects of platinum-based chemotherapy, the problem of inherent or therapy-induced resistance, the limited activity in a range of tumors, and the meager tumor selectivity are the motivation for tremendous efforts and inventions in the development of novel anticancer platinum drugs. This article reviews the most recent patents in this field of research, covering the following strategies in the design of promising anticancer platinum complexes: (i) synthesis of new anticancer platinum complexes, using combinatorial chemistry and high throughput synthesis and screening, (ii) activation of platinum complexes in the tumor tissue, (iii) accumulation of platinum complexes at the tumor site, (iv) novel platinum complexes, displaying activity against cisplatin resistant cells and as inhibitors of specific biological functions, and (v) direct derivatives of classical anticancer platinum drugs in clinical use.