Recent Patents on Anti-Cancer Drug Discovery - Volume 6, Issue 2, 2011

BREAST CANCER Breast carcinoma is the commonest cancer in women globally, in both developed and developing countries, and also the leading cause of malignancy-associated deaths [1]. The GLOBOCAN project estimated that there were 1.38 million newly diagnosed breast cancer cases worldwide in 2008, and that the disease accounted for more than 458,000 deaths [2]. In the United States of America alone, cost of medical care for cancer patients in 2010 was estimated to be US$125 billion [3]. Of this, US$16.5 billion would be used in the management of patients with breast cancer. The figure is expected to rise to US$20.5 billion by 2020. The direct cost of medical and nursing care of cancer patients contributes to less than half of the economic burden of cancer [4, 5]. The major impact comes from indirect morbidity and mortality costs and the loss of productivity. Several factors are well established to be associated with a greater risk of breast cancer [6]. Mutations in the BRCA1 and BRCA2 genes significantly increase the incidence of breast cancer. Early menarche, an older age at first full-term pregnancy and late menopause are known to increase a woman's risk of developing breast cancer, and suggest the importance of hormonal status in this malignancy. Exposure to ionising radiation has also been linked to an elevated risk of breast cancer. In contrast, a healthy diet, limitation of alcohol intake, and regular physical activity may help in the primary prevention of this disease [7]. Early diagnosis and advancement in treatment modalities are important strategies in the management of breast cancer patients. Analysis of survival trends of women with breast cancer during the period 1996 to 2005 showed a large improvement, with a relative risk of 0.94 [3]. Clinical breast examination and screening by mammography have been shown to reduce patient mortality [8-12]. However, there are conflicting reports that question the effectiveness of screening programmes [13, 14]. Indeed, in 2009, the US Preventive Services Task Force recommended reducing the frequency of screening by mammography from once a year to once every two years, and restricting the use of biennial screening to women in the 50 to 74 age group [15]. Overdiagnosis, false positives and associated problems must always be borne in mind in the assessment of breast cancer screening programmes [16, 17]. TARGETS FOR TREATMENT OF BREAST CANCER Depending on the stage and other clinicopathological considerations, current breast cancer treatment may involve surgery, radiotherapy, chemotherapy and systemic adjuvant or neoadjuvant therapy. Much effort has been put into the discovery of novel strategic targets and anticancer drugs that may be able to significantly improve patient prognosis. Recognition of the key role of hormonal regulation in breast cancer led to targeting of the oestrogen receptor using tamoxifen and other selective oestrogen receptor modulators, resulting in improved patient survival [18-21]. A complementary approach using aromatase inhibitors such as anastrozole and letrozole to block oestrogen biosynthesis has also been demonstrated to be clinically effective [22, 23]. Overexpression of epidermal growth factor receptor 2 (ERBB2) is predictive of worse clinical outcome in breast cancer patients [24]. Targeting the ERBB2 receptor using trastuzumab, a recombinant humanised monoclonal antibody that binds to the receptor, has produced dramatic results in patients with HER2-positive breast cancer [25-27]. Lapatinib, an inhibitor of HER2 and epidermal growth factor receptor signalling, has also been shown to reduce disease progression [28, 29]. In recent years, heparan sulphate proteoglycans have emerged as a potential therapeutic target for breast carcinoma [30]. Changes in the glycosaminoglycan moiety per se or in the expression levels of proteoglycans have been shown to regulate tumour growth and disease progression [31-35]. The compound phosphomannopentaose sulphate, which inhibits the heparanase enzyme, has been demonstrated to reduce breast cancer growth and distant spread to draining lymph nodes [36]. Other possible strategies that capitalise on the biological roles of heparan sulphate proteoglycans for cancer treatment include disruption of the biosynthesis of these molecules, and using antibodies or prodrugs to bind to the molecules [37-40]. In this issue, Mohanraj and Oh examine the potential targeting of the insulin growth factor system for cancer treatment, while Lai et al. review the possible exploitation of metallothioneins for this purpose. Raju et al. provide evidence that novel pyrazole derivatives possess anti-cancer activities. Potential treatment options for aggressive triple negative breast tumours are reviewed by Teng et al. It is hoped that continual research efforts would lead to improvements in clinical outcome for breast cancer sufferers, thereby reducing the personal and societal impact of this disease. ACKNOWLEDGEMENTS Work in the author's laboratory is supported by Grant BMRC/10/1/21/24/636.....

The IGF system plays a major role in growth, development and maintenance of homeostasis in normal cells and also contributes towards proliferation of malignant cells. Any disruption in the IGF system has its implications on growth retardation, atherosclerosis, insulin resistance and cancer. Imbalances in the IGF axis are known to contribute towards the progression of breast cancer. Due to the ubiquitous nature of the components of the IGF system, targeting specific members of the axis has gained attention over the past decades. The most elaborately investigated component as a therapeutic target in the system is the IGF-IR and studies have been pursued to inhibit IGF-IR by the administration of monoclonal antibodies and tyrosine kinase inhibitors. Very recently, a novel cell death receptor that binds specifically to IGFBP-3 was identified. It has also been shown that the IGFBP-3/IGFBP-3 receptor may be impaired in breast and prostate cancer. In this review, we present the mechanisms used to target the IGF system in various diseased states, emphasizing on breast cancer. We further discuss currently available therapeutic approaches and summarize the latest patents published in the field of IGF-I/IGF-IR and IGFBP-3/IGFBP-3R systems.

Breast cancer is a disease that has plagued many women globally. The rapid rise in the incidence rate has prompted the rigorous search to understand its etiology and find better management strategies for this disease. Metallothionein (MT) belongs to a family of metal-binding proteins where dysregulated expression of this protein has been observed in invasive breast ductal carcinomas. Since its discovery in equine kidney, functions of MT have extended beyond the initial role of heavy metal detoxification to promoting tumorigenesis. MT, which was reported to be highly expressed in many tumors including breast cancers, is known to regulate key processes such as cell proliferation, apoptosis and even chemoresistance. In this patent review, we shall evaluate the roles of 10 functional isoforms of MT in breast neoplasia and discuss the utility of MT isoforms as biomarkers for prognosis. Strategies targeting MT for treatment could provide alternatives to overcome this dreaded disease which has claimed the lives of many women.

In search of synthetic chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multistage carcinogenesis, we synthesised a series of novel 1-(4-methoxybenzyl)-3-cyclopropyl-1H-pyrazol-5-amine derivatives 9(a-h) by a nucleophilic substitution reaction and characterized by 1H and 13C nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. These novel compounds were evaluated for their efficacy in inhibiting VERO normal and MCF-7 breast cancer cells proliferation by trypan blue exclusion assay, MTT assay, [3H] thymidine incorporation assay and DNA fragmentation analysis. Among the series, some compounds exhibited interesting growth inhibitory effects against cell lines. From the Structure-Activity Relationship studies, it has been revealed that, both novel patented compounds and therapeutic protocols of N-terminal pyrazole ring structures play key role in the antiproliferative activity.

Triple negative breast cancers, defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2/EGFR2/ERBB2), are increasingly gaining attention for its intricate relationship with basal-like and BRCA1-linked breast carcinomas, and its lack of effective tailored therapies. Triple negative breast tumors usually account for 10-20% of all breast cancers in Asian populations, similarly in Caucasian populations (10-23%), but occur at much higher frequencies in individuals of African descent (20-47%). In addition, triple negative breast cancers are usually of high histological grade and are accompanied by aggressive clinical behavior with shorter time to recurrences and death, and preference for metastasis to the brain and lungs. In this report, we would like to review recent patents and the relationship between triple negative and basal-like breast cancers, as well as BRCA1-linked breast carcinomas. Specifically, potential treatment modalities and current innovations that are designed for the predictive and prognostic values of triple negative breast tumors will be discussed.

Inappropriate PI3K signaling is one of the most frequent occurrences in human cancer and is critical for tumor progression. A variety of genetic mutations and amplifications have been described affecting key components of this pathway, with implications not only for tumorigenesis but also for resistance to targeted agents. Emerging preclinical research has significantly advanced our understanding of the PI3K pathway and its complex downstream signalling, interactions and crosstalk. This knowledge, combined with the limited clinical antitumor activity of mTOR complex 1 inhibitors, has led to the development of rationally designed drugs targeting key elements of this pathway, such as pure PI3K inhibitors (both pan-PI3K and isoform-specific), dual PI3K/ mTOR inhibitors, Akt inhibitors, and mTOR complexes 1 and 2 catalytic site inhibitors. This review will focus primarily on an analysis of newly developed inhibitors of this pathway that have entered clinical trials, and recently registered patents in this field.

A major challenge in cancer research is to discover drugs with high selectivity and minor side-effects. Tamoxifen has been widely used for more than 30 years in breast cancer treatment and prevention. Tamoxifen acts mainly via estrogen receptors (ER), but also displays anti-tumor activity in breast cancer negative to ERs, suggesting other targets. Actually, tamoxifen has effects on several transduction pathways and diverse ion channels. Despite the successful use of tamoxifen, this drug produces some non-desirable side-effects by acting on different targets. However, such nonspecificity of tamoxifen might be used to unravel new targets to inhibit tumor cell proliferation, to elucidate new mechanisms of action of tamoxifen and tamoxifen analogs, and finally, to design new more specific and potent drugs on the benefit of cancer patients. This review will briefly describe first the current and general aspects of tamoxifen and then will focus more deeply on various tamoxifen analogues and new uses of tamoxifen described in recent patents. We will describe the biological effects and the therapeutic targets of the new patented analogues, in order to offer an alternative panorama on tamoxifen-based chemotherapy.

Head and neck squamous cell cancers (HNSCCs) represent 4 to 5% of all solid malignancies. Despite improvements in diagnostic techniques, 60% of patients will present with locally advanced HNSCCs with a median survival of about 12 months and 5-year overall survival of approximately 10-40%. Recent clinical trials have altered the treatment landscape by refining existing forms of radiation, incorporation of IMRT, choice of chemotherapeutic agents, introduction of biological and targeted therapy, immunotherapy and gene therapy. Cetuximab, a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR), has recently been approved in combination with RT in patients with locally advanced HNSCCs. Antiangiogenic therapies and tyrosine kinase inhibitors (gefitinib and erlotinib) have also shown promise in the clinical trials. Vandetanib, an antagonist of both vascular endothelial growth factor receptor (VEGFR) and the EGFR is currently being tested in phase II trial. New patents on hypoxia-inducible factor 1 alpha, mesenchymal-epithelial transition factor, insulin-like growth factor or the PI3K/AKT/mTOR pathway, farnesyl transferase inhibitors have shown promise in the management of HNSCCs. Nevertheless, identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from them. However, increase in efficacy comes at the cost of increased toxicity. The current review focuses on insight into recent patents and updates on the clinical trials using new investigational agents in the management for HNSCCs.

Since the advent of hybridoma technology 35 years ago, research on monoclonal antibodies has developed enormously. Monoclonal antibodies of mouse origin were the first to be produced and continue to be the most popular affinity reagents for investigating the proteome of all organisms. For their adaptability to a variety of biological assays monoclonal antibodies are key tools for basic research as well as for diagnosis and therapy of human diseases. Recently, the expanding demand of high-quality antibodies with better specificities has resulted in a significant improvement in traditional hybridoma production methods. Owing to the ability of these affinity reagents to selectively target tumour cells, cancer has been a major focus of programmes for monoclonal antibody development. This review focuses on patents related to the advances made in the monoclonal antibody manufacture, showing how the traditional production techniques were turned into alternative, faster and more effective methods. Other patents are focussed on new technologies in which monoclonal antibodies are employed for the development of high-performance screening assays. A conclusive series of patents is related to monoclonal antibodies which find application to the diagnosis and the treatment of specific cancer diseases such as haematological malignancies and solid tumours.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets and therapeutic agents related to anti-cancer drug discovery.