Recent Patents on Anti-Cancer Drug Discovery - Volume 7, Issue 1, 2012

The journal is gaining considerable interest by researchers in oncology, medicinal chemistry and pharmacology involved in drug design and discovery, and anti-cancer drug therapy. The Impact factor of the journal is increasing , as are the number of pages published per issue, and is at present 2.368 (JCR, Thomson-Reuters, 2010). In this current issue, various approaches in the field of cancer therapy with extensive coverage of patents are presented. Metabolic therapy of acute lymphoblastic leukemia by L-asparaginase was reported by Scotti et al. The article summarizes the biotechnological production of asparaginase which is known as an antitumor enzyme particularly by Helicobacter pyroli. The mechanisms of antitumor effect have been discussed. This property is attributed to its significant glutaminase activity. Recently, Jaccard and Hermine [1] reported the use of L-asparaginase effectiveness in extranodal natural killer (NK)/T-cell lymphoma while Pallem et al. studied the solid state fermentation using Fusarium oxysporum for the production of a tumor inhibitory enzyme, L-asparaginase [2]. Recent US20110275590 invention discloses the asparagine and glutamine and their analog compositions for the treatment of different kinds of cancers. The role of amino acids for the diagnosis of tumors and metastases was also described. The chemotherapeutic agent, L-asparaginase hydrolyzes L-asparagine to aspartate and ammonia and depleting L-asparagine from the serum and inhibiting tumor growth. L-Asparaginase is used mainly in the treatment of Acute Lymphoblastic Leukemia (ALL) and shows some activity against other hematological cancers including acute non-lymphocytic leukemia [3]. The administration of asparagine synthetase (ASNS) antagonist, L-asparaginase (L-ASP) and a pegylated L-ASP resulted in a decrease in cell proliferation of leukemia, ovarian cancers, melanomas, renal cancers, breast cancers, brain cancers, and other cancers [4]. Wong in his article discusses recent developments and patents reported for the IGF signallling pathway and the outcome of IGF-IR in in vivo and in vitro future novel molecular therapeutics. The vital role of insulin-like growth factor (IGF) and the IGF-1 receptor (IGF-IR) in many cancers and initial clinical trial's results for compounds are also discussed. Zhao et al. reviewed the increase of insulin-like growth factor I receptor (IGF-IR) and removal of tumor suppressor phosphatase and tensin homolog (PTEN) in Trastuzumab resistance but these mechanisms have not been defined [5]. IGFs play a vital role in regulating cell proliferation, differentiation and apoptosis. A method of predicting efficacy of an IGF-1 R antagonist therapy for cancer in a patient was described in WO2011083391. Cancer patient for insulin growth factor 1 receptor (IGF-1R) antagonist therapy and patient with a concentration of free IGF-1 or insulin/IGF binding protein 1 were selected to determine the ratio that is equal to or more than a determined value [6]. Huang et al. studied that reduction in IR-B expression is the important factor to the altered IR-A: IR-B ratio revealed in breast cancer. Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) attributes to tumorigenesis and essential resistance to anti-IGF1R therapy [7]. Kung et al. studied different strategies for the particular inhibition of IGF-1 R possessing effective anti-tumor property in multiple myeloma cell growth. The method and composition of chemotherapeutic agent and an insulin-like growth factor receptor-1 (IGF-1R) inhibitor used for the inhibition of tumor cell growth were covered in this invention [8]. Fialho et al. discussed in their article comprehensive recent patents reported on the role of attenuated strains of live bacteria such as Salmonella, Mycobacterium, Listeria, and Clostridium etc. as anti-cancer agents. The anti- cancer property of microbial products i.e. peptides, proteins, enzymes, immunotoxins, antibiotics and secondary metabolites was extensively covered in this review article. Recently, methods and administration of new attenuated Listeria bacterium composition as vaccine for entry into nonphagocytic cells and cell-to-cell spread for inducing immune responses and in the treatment of cancer, infectious diseases, autoimmune diseases, allergies, and other hyperproliferative diseases were disclosed [9]. An invention disclosing the methods for treatment of the DNA vaccines comprising polyubiquitinated human Fra-1 protein, and IL-18, such as human IL-18 against cancer cells was recently published. The polynucleotide construct is incorporated in doubly attenuated aroA- dam- Salmonella typhimurium [10]. Singh and Wallecha in 2011 reported the Listeria monocytogenes based cancer vaccine in clinical trials through antigen presenting cells (APC) and mechanism of targeting the tumor by the immune system [11]. Mechanism of action of antagonists of growth hormone- releasing hormone (GHRH) and other growth factor analogs for inhibition of the growth of experimental cancers was described by Stepien et al. The synthesis of potent growth hormonereleasing hormone antagonists, mechanism of action and its antineoplastic action were also reviewed. New methodology for the treatment of cancer by administering IGF-II and IGF-IIE binding new proteins and an additional therapy such as a growth hormone and growth hormone releasing hormone pathway modulator or epidermal growth factor receptor inhibitor as an additional therapy was discussed in the invention by Dransfield, Cohen, Adams and Cosgrove [12]. Colorectal cancer, breast cancer, prostate cancer and lung cancer are suppressed by new polypeptides and nucleic acids disclosed in the recent invention. The methodology involved use of a non-cytotoxic protease, Targeting Moiety, and translocation domain which inhibits secretion/transmission of growth hormone from cancer cell [13]. Papadia et al. studied the role of antagonists of the growth hormone-releasing hormone (GHRH) i.e. JMR-132 and MZ-J-7- 118 in the inhibition of epithelial ovarian carcinoma involving endocrine, autocrine and paracrine mechanisms [14]. Pozsgai et al. reported the results of a novel antagonist of growth hormone releasing hormone on cell proliferation and on the key cell signaling pathways in nine different breast cancer cell lines. The studies showed that a MIA-602 is promising against a wide range of in vitro breast cancers [15]. Borgres et al. reviewed the hot topic area of recent advances and patents in the area of hyperthermic methods, external radiofrequency devices, hyperthermic enhancers or perfusions, heating applications to the target site by catheter and injection of magnetic , ferroelectric particles and magnetic nanoparticles (mNPs) used for cancer therapy. Kurkayev discloses the use of nanoparticles dimensions of 0.5-200nm in the treatment of cancer. Nanoparticles are obtained from the destruction of SiO2 heterocrystal mineral from quartzite, sphene, leukoxen and rutilated quartz [16]. Systems and methods for inducing hyperthermia with mechanical index above a threshold level for cavitation and below a threshold level for cavitation in human body for cancer therapy have been disclosed [17] Studies on a combined thermal model embedded with gold nanoshells for laser hyperthermia treatment of tumors were recently published [18]. Li et al. emphasized on the recent patents on new matrix metalloproteinases MMPs, matrix metalloproteinases inhibitors (MMPIs), and cancer and developments in MMPs research area for cancer therapy. Authors review the patents on MMPIs in preclinical or clinical trials for the period 2005-2010 and future implication on further design & advancement of MMPIs. Heteroaryl substituted indole compounds as MMP-13 inhibitors disclosed in this invention will be valuable for treating tumor metastasis and solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid , lymphomas, sarcomas, and leukemia [19]. Recent studies showed that the mRNA expression of matrix metalloproteinases (MMPs) i.e. MMP1, MMP2, MMP7, MMP13, MMP14, MMP16, MMP19, and MMP25 was suppressed by cancer inhibitors NME, DRG1, IL10 in breast cancer cells [20]. Agrawal et al. comprehensively discussed anti-telomerase cancer therapy, immunotherapy, small molecule inhibitors, RNA interfernec (RNAi), eighty nine approaches and patents related to the inhibition of RNA (HTR) constituent of telomerase and telomerase reverse transcriptase (HTERT) component of telomerase. The expression of ALT-associated proteins and mRNAs in human osteosarcoma OS cell lines was discussed. Expression of all the mRNAs involved in telomere maintenance mechanisms (TMMs) including human telomerase reverse transcriptase, promyelocytic leukemia proteins and other related proteins was analyzed by genome expression arrays [21]. Preparation and compositions of novel organic compounds i.e. heterobicyclic carboxamides are used as inhibitors for protein kinases associated proliferative diseases, particularly tumor diseases are disclosed in the recent patent [22]. The albumin fusion proteins composition was disclosed to be useful for the cure of metastatic melanoma, malignant melanoma, renal cell carcinoma and metastatic renal cell carcinoma [23]. The paper by Ramon A. de Mello et al. reviews the role of vascular endothelial growth factor (VEGF) proteins in current pathologic tumoral angiogenesis and later phase development of antiangiogenic agents in lung cancer. HIF-1α and VEGF expression in non-small cell lung cancer cells was reported to be enhanced. In vitro and in vivo tumor angiogenesis was observed to be enhanced through over expression of HPV-16 E6 and E7 oncoproteins in NSCLC cells [24]. The review on current existing cancer therapy approaches involving molecular and genetic actions to determine the pathogenesis of adrenocortical carcinoma (ACC) for further development of diagnosis and treatment of this rare tumor was studied by Hubalewska-Dydejczyk. MicroRNA expression may be in future an important diagnostic biomarker and therapeutic target for the prognosis of adrenocortical carcinoma (ACC). The compounds acting as selective inhibitors of rock protein are described to be effective for the treatment or reducing of proliferative diseases or disorders such as melanoma, breast cancer, colon cancer, pancreatic cancer, and adrenocarcinoma and adrenocortical [25]. Similarly, Singh et al. in their recent submitted paper discussed the existing perceptive of miRNAs in adrenocortical tumors, and diagnosis. The changes in miRNA expression may be related to adrenocortical tumors [26].

The antitumour enzyme L-asparaginase (L-asparagine amidohydrolase, EC 3.5.1.1, ASNase), which catalyses the deamidation of L-asparagine (Asn) to L-aspartic acid and ammonia, has been used for many years in the treatment of acute lymphoblastic leukaemia. Also NK tumours, subtypes of myeloid leukaemias and T-cell lymphomas respond to ASNase, and ovarian carcinomas and other solid tumours have been proposed as additional targets for ASNase, with a potential role for its glutaminase activity. The increasing attention devoted to the antitumour activity of ASNase prompted us to analyse recent patents specifically concerning this enzyme. Here, we first give an overview of metabolic pathways affected by Asn and Gln depletion and, hence, potential targets of ASNase. We then discuss recent published patents concerning ASNases. In particular, we pay attention to novel ASNases, such as the recently characterised ASNase produced by Helicobacter pylori, and those presenting amino acid substitutions aimed at improving enzymatic activity of the classical Escherichia coli enzyme. We detail modifications, such as natural glycosylation or synthetic conjugation with other molecules, for therapeutic purposes. Finally, we analyse patents concerning biotechnological protocols and strategies applied to production of ASNase as well as to its administration and delivery in organisms.

The insulin-like growth factor (IGF) family and the IGF-1 receptor (IGF-1R) play an important role in cancer. This intricate and complex signaling pathway provides many opportunities for therapeutic intervention, and several novel therapeutics aimed at the IGF-1R, particularly monoclonal antibodies and small molecule tyrosine kinase inhibitors, are under clinical investigation. This article provides a patent overview of the IGF signaling pathway and its complexity, addresses the justification for the use of IGF-1R-targeted therapy, and reviews the results of in vivo and in vitro novel therapeutics. Over the past year, the completion of several phase I, II, and III trials have provided interesting new information about the clinical activity of these novel compounds, particularly CP-751,871, IMC-A12, R1507, AMG-479, AVE-1642, MK-0646, XL-228, OSI-906, and BMS-754807. We review the important preliminary results from clinical trials with these compounds and conclude with a discussion about future therapeutic efforts.

This review intends to provide a comprehensive coverage of the various patents, published or issued, since 2007 on live or attenuated bacteria as potential anticancer agents, as well as microbial products including toxins, enzymes, antibiotics, various proteins and peptides as well as other small molecular weight products. Below is a list of such published/ issued patents and a summary of the main contents of many such patents.

Some of the antagonists of growth hormone-releasing hormone (GHRH) are able to inhibit the growth of various experimental human cancers. The antitumor effects of first antagonists seemed to be dependent mainly on the disruption of pituitary secretion of growth hormone (GH), followed by the reduction in the levels of circulating insulin-like growth factor (IGF)-1, an important growth factor for cancer cells. It seems obvious, that growth hormone deficiency (GHD) induced by GHRH antagonists with all its complications, could limit the beneficial effects of GHRH antagonists therapy, and decrease patients' quality of life. The discovery of local autocrine/paracrine production of GHRH and other related growth factors in many tumoral tissues, in combination with the wide expression of GHRH receptors on cancer cells, directed the research to the synthesis of more potent GHRH antagonists. These compounds exert strong inhibitory effects directly on tumor growth, with scarce endocrine action. The receptor-mediated mechanisms comprise complex and still not completely understood effects on intracellular signaling pathways that are strictly related to human tumorigenesis. This review summarizes recent patents and latest observations on the antineoplastic role of GHRH antagonists in human tumors with emphasis on potential therapeutic applications in clinical oncology.

Cancer is one of the main causes of death in the world and its incidence increases every day. Current treatments are insufficient and present many breaches. Hyperthermia is an old concept and since early it was established as a cancer treatment option, mainly in superficial cancers. More recently the concept of intracellular hyperthermia emerged wherein magnetic particles are concentrated at the tumor site and remotely heated using an applied magnetic field to achieve hyperthermic temperatures (42-45°C). Many patents have been registered in this area since the year 2000. This review presents the most relevant information, organizing them according to the hyperthermic method used: 1) external Radio- Frequency devices; 2) hyperthermic perfusion; 3) frequency enhancers; 4) apply heating to the target site using a catheter; 5) injection of magnetic and ferroelectric particles; 6) injection of magnetic nanoparticles that may carry a pharmacological active drug. The use of magnetic nanoparticles is a very promising treatment approach since it may be used for diagnostic and treatment. An ideal magnetic nanoparticle would be able to detect and diagnose the tumor, carry a pharmacological active drug to be delivered in the tumor site, apply hyperthermia through an external magnetic field and allow treatment monitoring by magnetic resonance imaging.

The traditional consensus that matrix metalloproteinases (MMPs) has correlation with various pathological and physiological processes led to the exploitation of a vast number of natural or synthetic broad-spectrum MMP inhibitors (MMPIs) for the prophylaxis or treatment of various MMP-related disorders, such as autoimmune, inflammatory, cardiovascular, neurodegenerative, respiratory diseases, and malignant cancer as well. Yet the unsatisfactory preclinical and/or clinical results motivated further investigation of the physiological roles of certain MMP subtypes. Despite the intricate and complicated MMP functions in normal physiology and disease pathology, the effort of designing specific inhibitors that can selectively target certain MMP family members for individualized therapy is ongoing and remains an arduous task. Success will rely on continued insight into the biological roles of these multifaced proteases. In our previous effort, we summarized various MMPIs that have entered preclinical or clinical trials as well as the patents in regard to MMPIs (Recent Pat Anticancer Drug Discov. 2010; 5(2): 109-41). In our on-going review, to illustrate the major challenges in MMP validation as druggable targets, we highlighted the physiological and pathological roles of representative MMPs, with an emphasis on description of the newly emerging MMPI-based patents, in particular, the inhibitors containing sulfonamide or sulfone motif. By analyzing the structural characteristics and selectivity profiles of these supplementary inhibitors, we hereby described their pharmaceutical application, and also expanded the strategies for potent MMPI design.

Telomerase, a specialised RNA-directed DNA polymerase extends and stabilises the telomeres at the ends of the eukaryotic chromosomes. The progressive loss of telomeres results in limited number of cell divisions and has been linked to the mechanism of human cellular ageing. Tumour cells marked by indefinite proliferation have stable telomere length maintained by telomerase. The differential expression of the telomerase enzyme in normal and cancer cells have led to the evolution of tumour specific anti-telomerase approaches which inhibit the telomerase enzyme activity so as to destabilise and shorten the telomeres leading to senescence in cancer cells. In the current review, we have selected nine tumour specific anti-telomerase approaches based on their mechanism of action or the target components of the human telomerase enzyme: Antisense-oligonucleotides, hammerhead ribozymes, dominant negative hTERT, reverse-transcriptase inhibitors, immunotherapy, G-quadruplex stabilisers, gene therapy, small molecule inhibitors and RNA interference. Recent research developments for each of the anti-telomerase approaches with the detailed analysis of specific granted patents from the perspective of different claims and downstream applications have been provided. A comprehensive list of patents for the different anti-telomerase approaches which includes information regarding the authors and institutional ownership along with the year of issue of the patent has also been provided.

Lung cancer is a highly prevalent disease worldwide. Currently, there are more than 150 million patients with lung cancer in the world, with more than 1 million new cases diagnosed per year. Tumoral angiogenesis is an important hallmark of this disease, but despite being extensively studied, the complete angiogenic mechanisms are not fully elucidated. Recent studies have reported a correlation between pharmacological inhibition of these angiogenic mechanisms and improvement of overall survival in lung cancer patients, mainly for those in advanced stages. The family of vascular endothelial growth factor (VEGF) proteins has critical roles in tumoral angiogenesis. An interaction between VEGF-A and VEGF receptor 2 (VEGFR-2) is the main pathway of activation and maintenance of angiogenesis. In tumors, this process is intimately correlative with progression and metastasis. Some studies suggested that serum levels of VEGF are higher in patients with lung cancer, especially in some types of non-small cell lung cancer (NSCLC). Other studies revealed that genetic polymorphisms of VEGF correlate with susceptibility, prognosis, and therapeutic response of some patients with NSCLC. This paper aims to review the impact of angiogenesis, especially on VEGF pathways, in NSCLC, and highlights the relevance of known and new patents disclosed of anti-angiogenic therapies in these patients.

Adrenocortical carcinoma (ACC) is a rare neoplasm with very poor prognosis despite the recent development of aggressive antitumor therapies. The cause of adrenal cancer remains elusive, but some molecular mechanisms could be responsible for its development. Target-specific therapies have been developed for a number of human malignancies and have resulted in therapeutic benefits in some cancer patients. However, these therapies are only effective in cases in which the corresponding targets are expressed in tumor tissues. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers, among which alterations of the IGF system, the Wnt pathway, p53 and molecules involved in cancer cell invasion properties and angiogenesis seem to be very promising. These molecular markers may not just play a role in the biology of these tumors and have prognostic implications, but can also be used as potential targets for treatment. The aim of this review is to summarize the genetic and molecular events implied in the pathogenesis of ACC and to highlight challenges to the development of anticancer agents in recent patents.

Full text available