Topics in Anti-Cancer Research

Docetaxel has until recently been the only agent with a small survival benefit for metastatic castration-resistant prostate cancer (CRPC). To improve the clinical outcome in CRPC, numerous classes of drugs targeting specific pathways involved in hormone action, bone metabolism, angiogenesis, apoptosis and immune response have recently been investigated for efficacies either as single agents or in combination with docetaxel. Of note, some novel agents or vaccines including cabazitaxel, sipuleucel-T and abiraterone have received US governmental approval to treat patients with CRPC on the evidence of significant improvement of overall survival in CRPC. From the viewpoint of the complex mechanisms implicated in prostate cancer progression, effective therapeutic strategies should be developed by multifaceted approaches, such as the composition of novel agents targeting key molecules, cytotoxic chemotherapy, and immunotherapy. Recently patented molecules (e.g., N-cadherin, AR splicing variants, PCGEM-1, ELR-CXC chemokine antagonist, dual inhibitor of MET and VEGF) have strong potential as therapeutic options for CRPC. Here, we review the newest evidence of novel agents and patented compounds and methods for the purpose of future use in CRPC.

Resistance to death receptor ligands (such as FasL and TRAIL) and anticancer treatments is a hallmark of cancer cells. Alteration of sphingolipid (SL) metabolism is frequently observed in cancer cells and may contribute to resistance to stress-induced apoptosis. Ceramide, a biologically active sphingolipid, antagonizes cell growth and promotes apoptosis and non-apoptotic forms of cell death. The intracellular levels of ceramide are highly regulated via complex metabolic pathways. Sphingomyelin synthases (SMS) 1 and 2 convert ceramide to sphingomyelin (SM), a ubiquitous phospholipid in mammals. A growing body of evidence in the literature indicates that SMSs likely modulate cell growth and sensitivity to stress-induced apoptosis. On one hand, complete and sustained inhibition of SMS activity likely alters membrane composition and properties through membrane SM depletion, perturbing intracellular signaling pathways and cancer cell growth and conferring partial resistance to death receptor ligands. On the other hand, different patents & reports point to anti-apoptotic functions for SMSs. In patients with chemoresistant leukemia, a decreased intracellular ceramide level was associated with a higher SMS activity. Thus, SMSs and cofactors may constitute original pharmacological targets to treat malignant diseases. This chapter gives an overview on how SM biosynthesis putatively modulates cancer cell death and growth.

The Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway mediates cellular responses to different growth signals and is frequently deregulated in cancer. There are three Raf kinases-A-Raf, B-Raf, and C-Raf; however, only B-Raf is frequently mutated in various cancers. The most common B-Raf mutation involves a substitution of a glutamic acid residue to a valine moiety at codon 600. Subsequently, the MAPK pathway is constitutively activated, even in the absence of any growth signals. Although early attempts to target Ras have not yielded any viable drug candidates, many novel compounds inhibiting the activities of B-Raf and MEK have been developed and investigated in clinical trials in recent years and have shown promising result. The first MEK inhibitor (CI-1040) lacked efficacy in clinical trials, but its low toxicity encouraged the search for novel compounds-now there are over a hundred open clinical trials employing various B-Raf and MEK inhibitors. Several of these trials are now in Phase III. In this chapter, we will discuss new patents and patent applications related to inhibitors of the Ras/Raf/MEK/ERK pathway and some recent clinical trial results.

Inappropriate phosphoinositide 3-kinase (PI3K) signaling is one of the most frequent occurrences in human cancer and is critical for tumor progression. Various genetic mutations and amplifications have been described affecting key components of this pathway, with implications for tumorigenesis and also for resistance to targeted agents. Emerging preclinical research has significantly advanced our understanding of the PI3K pathway and its complex downstream signaling, 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 chapter 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.

Recent results obtained from research on the intermediary metabolism of tumor cells have uncovered the biochemical reprogramming that takes place upon malignant transformation. Many features have been highlighted that are currently being exploited for specific chemotherapy. Many more will become available shortly as a consequence of the recognition of potentially useful targets for treatment. General interest in this area can be gauged by the number of recent patents that have been deposited, or are in the process of application. Because the metabolic subversion that is a hallmark of cancer cells involves disruption of its homeostasis, the regulatory pathways dealt with in this chapter were broadly divided into those that encompass the main stages of the cell cycle and its various regulatory mechanisms and those that involve the aerobic glycolysis typical of cancer cells. It becomes apparent that both, the cell cycle and the intermediary metabolism are interconnected and rely on reactions many of which are dependent on kinases and phosphatases. Kinases and phosphatases are responsive to cellular redox signaling and may have a key role in determining whether cells progress towards malignant transformation as a result of continuous oxidative stress. The data discussed here underline aspects of the signaling pathways that lend themselves to specific inhibition by natural and synthetic compounds. The mitochondria and its role in programmed cell death is briefly commented, but special emphasis is placed on biochemical regulation at the level of chromatin structure, particularly the reactions that involve acetylation and deacetylation of histones. Within this context, inhibitors that act on histone deacetylases are discussed as promising alternatives to available treatments.

Vacuolar-type ATPases are multicomponent proton pumps involved in the acidification of single membrane intracellular compartments such as endosomes and lysosomes. They couple the hydrolysis of ATP to the translocation of one or two protons across the membrane. Acidification of the lumen of single membrane organelles is a necessary factor for the correct traffic of membranes and cargo to and from the different internal compartments of a cell. V-ATPases are also involved in the regulation of pH at the cytosol and, possibly, extracellular milieu. The inhibition of V-ATPases has been shown to induce apoptosis as well as cell cycle arrest in tumor cells; therefore, chemicals that behave as inhibitors of this kind of proton pumps have been proposed as putative treatment agents against cancer and many have been patented as such. The compounds filed in patents fall into five major types: plecomacrolides, benzolactone enamides, archazolids, chondropsins and indoles. All these have proved to be apoptosis inducers in cell culture and many are able to reduce xenograft tumor growth in murine models. The present chapter will summarize their general structure, origin and mechanisms of action and put them in relation to the patents registered so far for the treatment of cancer.

Recently, the field of oncology has witnessed the introduction of several effective chemotherapeutic agents. Still, not all cancers respond to the use of conventional chemotherapy and thus combination therapy is an emerging weapon in the battle against cancer. There is emerging evidence in support of the use of Monoclonal antibodies (MoAbs) in cancer therapy. The mechanisms behind their efficacy are multifaceted; they can kill tumor cells through antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis as well as target ligands or growth factor receptors favoring tumor growth. The interaction of the Fc domains of antibodies with the Fcγ (gamma) receptors is an essential prerequisite for biological response to antibodies, including ADCC. This interaction is strongly regulated and is largely dependent upon receptor conformation and number. It is accepted that germ-line single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) have the potential to predict the outcome of therapy. The possibility of predicting patients response to monoclonal antibody therapy is of particular importance, as response rates are moderate, with the risk of serious side effects all at a high financial cost. This patent chapter provides an insight into the role of Fcγ receptors (FcγRs) genetic variation in Monoclonal Antibody-based anti-cancer therapy.

Renal cell carcinoma (RCC) is one of the most common cancers in the United States. Recent achievements in translational research have led to significant developments in treatment strategies for this malignancy. RCC is a richly vascular neoplasm. A better understanding of disease biology has helped in the development of anti-angiogenic therapy. Vascular endothelial growth factor (VEGF) is the most important molecular target in the treatment of RCC. Patents have been filed for anti- VEGF and other molecular pathways involved in the pathogenesis of RCC. This chapter provides an overview of angiogenesis in RCC, important anti-angiogenic drugs for treating RCC and some developmental drugs and patents which might shape the treatment of RCC in future.

Tumors are dependent upon neovascularization to feed their massive demand for nutrients and oxygen. To uphold the nutrient influx, cancer cells produce growth factors and activators that stimulate and shape the blood vessel network around the tumor. Therapies aimed at reducing the blood flow to the cancer cells can slow down tumor growth and reduce metastasis. This chapter focuses on tumor neovascularization as a target for anti-cancer therapy. An overview of long standing and novel anti-angiogenic agents is given, which includes antibodies directed against vascular growth factors and angiotensin II, pharmaceutical compounds and natural metabolites, and combination therapy. The relevant patents are discussed. Anti-angiogenic therapy has every potential of becoming indispensible, as a supplement to chemo- and radiation-cancer therapy.

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. Targeting tumor endothelial cells has gained much attention with the notion that tumors can be starved to death by cutting the lifeline of tumor cells, i.e. vascular endothelial cells. In this regard, the inhibition of angiogenesis represents a new approach to cancer therapy and several agents and approaches are in different stages of clinical development. A paradigm shift is expected in the treatment of malignancies because of the recent introduction of mechanism-based systemic therapies that may be more specific, less toxic, and more effective. These inhibitors were recently shown to constitute a new modality for cancer treatment. In this chapter, we will review the recent angiogenesis inhibitors-related patent literature. This review will cover specifically the discovery and development disclosures of endogenous inhibitors. The scope of this chapter is to give the reader a well structured patent literature overview of agents targeting different steps of the angiogenic process. Finally, we have summarized the key attributes of the emerging endogenous angiogenesis inhibitors that make them a potent antitumor agents.

Ribonucleotide Reductase (RNR) plays a critical role in DNA synthesis, and is a well-recognized target for cancer chemotherapeutic and antiviral agents. RNR inhibition precludes DNA transcription and repair, from which results cell apoptosis. Many regulation checkpoints concerning RNR activity have been unravelled through the last two decades, with potential use to inhibit enzyme activity. This was accomplished by researchers from different but complementary areas from which several and different inhibitors have resulted. The volume of these studies has generated over 5000 articles since the discovery of RNR in 1960. Some of these compounds have already been approved by FDA and EMEA for the treatment of specific types of cancer, as it is the case of gemcitabine, fluoromethylene and hydroxyurea. This chapter summarizes patents and papers during the period 1958-2012 dealing with the present understanding of ribonucleotidereductase biochemistry, mechanism of action and the most relevant data concerning RNR inhibition. Special attention is given to the inhibitors that have been patented and are currently in clinical use.

Glioblastoma multiforme (GBM) is the most common malignant intrinsic brain tumor in adults. Especially in this disease, qualitative and quantitative aspects render the dysregulated epidermal growth factor receptor (HER1/EGFR) an outstanding therapeutic target. A variety of therapeutic compounds was developed to target HER1/EGFR among which the clinically most advanced agents are small molecule tyrosine kinase (TK) inhibitors. Unfortunately, clinical studies examining their therapeutic efficacy have so far failed to document a major therapeutic break-through in the setting of GBM. Thus, the targeted approach against HER1/EGFR likely requires a synergistic drug combination strategy to ultimately become successful in this disease. This patents chapter focuses on innovative therapeutic strategies combining HER1/EGFR-targeted TK inhibitors with novel agents which for the most part have not been evaluated for the treatment of GBM yet but which constitute interesting candidates for further evaluation in this setting.

Cancer is a disease which brings about a huge sense of terror. It has therefore, been a threat to human beings globally. Many organic and metallo chemotherapeutics are currently available in the market for the treatment of different sorts of cancers, but, still there is no drug which can curb this disease at late stages completely and worse, most drugs exhibit severe side effects. The choice for cancer treatment seems to be nanodrugs, which are effective at much lower concentrations and with much less side effects. Nanodrugs are the magic bullets, designed to be selective for tumor tissue and to act only on cancer cells. Nanodrugs are macromolecules or nanoparticles that function as targeted carrier systems to deliver active anticancer drug exclusively at the site of cancer. The well known anticancer chemotherapeutics cisplatin, carboplatin, 5-fluorouracil, bleomycin, paclitaxel, doxorubicin, vinblastin and topotecan etc., but also novel drugs including nucleic acids and proteins can be incorporated into these delivery systems. Drugs become active only at the site of cancer cells. A consideration of the unique properties of nanodrugs seems to bring about a revolution in cancer treatment which is the urgent need of time. The present chapter describes the huge diversity of nanodrugs and highlights the few principles of their mechanisms. Moreover, the superiority of nano anticancer modalities in comparison to the conventional chemotherapeutic anticancer drugs will be discussed. Recent patents in the field have been discussed under different sections of the chapter. Recent rocketing developments in the field will be introduced and emphasis has been laid on future perspectives.

DNA topoisomerase is one of drug targets in cancer therapy. Camptothecin is a plant alkaloid derived from the Chinese tree Camptotheca acuminate. It has been demonstrated that the plant alkaloid camptothecin (CPT) and its analogs caused DNA damage by specifically targeting DNA topoisomerase, effectively devastating a broad spectrum of tumors. Although the anti-tumor activities of CPT and its analogs have been intensively studied for nearly fifty years, recent advances in drug delivery systems of CPT have considerably improved this drug’s efficiency and prevented drug resistance. However, CPT and its analogs showed extremely low water solubility, inactivation of carboxylate salt, undesired interaction with human serum albumin and short half-life, therefore, the development of new and effective CPT-derived products is ongoing. In this chapter, we will summarize the current status of CPT-derived anticancer drugs in literatures, patents and highlight their clinical application.

Cancer, a leading cause of death, can be prevented by different nutrients, in accordance to epidemiological and experimental data. Cancer chemoprevention might involve different dietary substances, which can counteract genetic damage and modulate the acquisition of a neoplastic phenotype. Critical to this process is redox cellular homeostasis, with antioxidants and essential biomolecules being the most promising functional compounds of the diet. Nutritional interventions require accurate biomarkers in order to evaluate their appropriateness. Such parameters may be biological targets involved in the oncogenetic process, and biochemical changes deriving from the organic response to tumors, which can be considered as endpoints of dietary interventions. This chapter reviews the patents on recent progress in the development of redox-related anticancer nutritional interventions involving lipophilic compounds, and of scientificbased biological markers for evaluating them.