Frontiers in Anti-Cancer Drug Discovery

DNA topoisomerases are promising targets in the development of cancer therapeutics. They are comprised of a large number of structurally diverse compounds and function by trapping the DNA-enzyme covalent complex, resulting in DNA strand breaks that can ultimately lead to cancer cell death. Topoisomerases are broadly classified as type I and type II. Type I enzyme (hTopoI) transiently breaks the DNA strands one at a time, while type II enzyme (hTopoII) forms a dimeric enzyme molecule that transiently breaks both DNA strands in the double helix in concert. Camptothecin was first isolated from a tree Camptotheca acuminate, which showed evidence of hTopI poisoning. Irinotecan and topotecan, two camptothecin analogs designed to be soluble, are widely used in clinical practice. Because of the instability of these analogs, however, other hTopoI inhibitors are being introduced that are more potent and stable. Drugs that interfere with hTopoII are typically classified by their mechanism of action. Poisons (including etoposide and doxorubicin) stabilize the covalent TopoII-5´ phosphotyrosyl DNA intermediate or cleavable complex. hTopoII catalytic inhibitors inhibit the enzymatic activity of hTopoII by disrupting the enzymatic recognition of DNA without causing DNA breaks. Recently described hTopoII catalytic inhibitors include aclarubicine, which is successfully used in clinical oncology practice. A series of 9-aminoacridine compounds with hTopoII inhibitor activity have shown promise in inhibiting pancreatic cancer cell proliferation in vivo and have been shown to induce apoptosis. On the basis of the hypothesis that targeting both hTopoI and hTopoII might increase overall anti-tumor activity and overcome resistance, compounds with dual inhibitor activity have been described and are under investigation. In conclusion, the area of topoisomerase inhibitors in cancer therapeutics is evolving and development of dual inhibitors, catalytic inhibitors of hTopoII, and specific inhibitors of hTopoII α isoforms will help to identify more potent compounds with fewer side effects.

The classic BCR/ABL-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), essential thrombocythaemia (ЕТ) and primary myelofibrosis (PMF), originate from a stem cell-derived clonal myeloproliferation represented with variable hematopoietic cell lineages and the possibility to convert to PMF and progress into acute myeloid leukemia. Their molecular pathogenesis has been associated with persistent and acquired gain-of-function mutations in the Janus kinase 2 (JAK2) and thrombopoietin receptor (MPL) genes. Furthermore, familial MPNs have an autosomal dominant inheritance with decreased penetrance. Additionally, mutations in TET2, IDH1/2, EZH2, and ASXL1 genes which appear to affect the epigenome of MPN patients have been described. The transforming growth factor-beta (TGF-β) signaling pathway has a defined role in regulating normal hematopoiesis and is frequently dysregulated in hematologic malignancies. During hematopoiesis, the TGF-τ potently inhibits proliferation and stimulates cell differentiation and apoptosis. MPNs are resistant to normal homeostatic regulation by TGF-τ mainly due to mutations or deletion of members of TGF-τ signaling pathways or deregulation by oncoproteins. Despite the heterogeneity and genetic complexity of MPNs, the improvement in understanding of their pathogenetic mechanism of myeloid transformation, coupled with the increasing availability of agents acting as tyrosine kinase inhibitors, facilitated the development of therapeutics capable of suppressing the constitutive activation of the JAK/STAT pathway. In addition, advances in the TGF-τ signaling area enable targeting it for the treatment of hematologic malignancies. In this chapter we will discuss new insights in the molecular pathomechanism of MPN, the new innovative JAK inhibitor drugs and potential therapeutic strategies by targeting TGF-τ signaling as well as the potential combinatory use of JAK inhibitors and TGF-τ signal transduction modulators for the treatment of BCR/ABL-negative MPNs.

Although advances have been made in reducing mortality rates and improving survival, cancer is still the second world cause of death among men and women. Such an unfavorable prognosis is a consequence of its complex genetic nature that makes it difficult to diagnose and treat. Moreover, due to inherent ability of cancer cells to acquire resistance to cytotoxic agents, most therapies eventually fail, resulting in resumption of disease progression. Therefore, the call for the discovery of less toxic, more selective, and more effective agents to treat cancer has become most urgent. At this moment, molecular targeted therapy looks most promising. Small-molecule and antibody therapeutics against targets implicated in PI3K-Akt pathway such as EGFR (e.g., cetuximab, gefitinib), erbB2 (trastuzumab, lapatinib), mTOR (sirolimus, temsirolimus), in tumor angiogenesis such as VEGFR (bevacizumab, sunitinib) and αvβ3 integrin receptors (cilengitide) as well as against other tyrosine kinases such as Abl (imatinib, nilotinib), have delivered clinical efficacy in certain disease settings. The emergence of these therapies has led to an era of treatments increasingly aimed at certain patient populations, and this has implications for the development of future novel treatments. However, cancer cells could develop the resistance to anti-cancer drugs in molecular targeted therapy, like in conventional chemotherapy, by several mechanisms. Resistance mechanisms include increased DNA damage repair, reduced apoptosis, altered drug metabolism and site of action, increased energy-dependent efflux of hydrophobic anticancer agents that enter cells. The latter refers to multi-drug resistance (MDR) which is one of the major and most common obstacles for the effective treatment of cancer. The most frequent mechanism underlying MDR is overexpression of P-glycoprotein (P-gp)/MDR1/ABCB1 which acts as an efflux pump for various hydrophobic anticancer drugs. Among them are anticancer drugs of previous generations (such as anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins), of new generation (e.g., imatinib, nilotinib, everolimus), as well as other tumor signal transduction inhibitors currently undergoing clinical investigation (aurora B kinase inhibitor AZD1152). The most striking feature of ABCB1 is its remarkable spectrum of substrates. Namely, ABCB1 recognizes and mediates the transport of thousands of substrates without specified structural determinants. Therefore, anti-ABCB1 therapy represents a significant step forward in cancer therapy. However, many things remain to be clarified, such as how to use anti ABCB1 therapeutics, what is the biological consequence of ABCB1-blockade, etc. We know that tumors are very diverse and plastic entities, able to adapt to various conditions. Lessons that we have learned in cancer research, taught us that the diversity of signal networks underlying tumor growth could eventually overcome our efforts in finding efficient therapeutic approaches. In this chapter, we present a reflection of new anti-cancer therapeutic strategies driven toward specific molecular targets, their benefits and limitations.

The role played by oncogenes and tumor suppressors in the genesis of cancer is well established. Considering that cancer cells are a product of genetic disorders that alter crucial intracellular signaling pathways associated with the regulation of survival, proliferation, differentiation and death mechanisms it is not surprising that traditional antitumor approaches target specific molecular players whose action/expression is altered in cancer cells. However, because the physiology of normal cells is controlled by the same signaling pathways that are disturbed in cancer cells many cancer therapies also cause important side effects and multidrug resistance, the main causes of therapy failure. Since the pioneering work of Otto Warburg, over 80 years ago, the subversion of normal cellular metabolism by cancer cells has been highlighted by many studies. In recent years, the study of tumor metabolism has received considerable attention because metabolic transformation is now recognized as a crucial cancer hallmark and a direct consequence of disturbances in oncogenes and tumor suppressors. Far from being a completely understood phenomenon, metabolic transformation constitutes a challenge for researchers and a potential target for cancer therapies. In this chapter, we describe the anabolic and catabolic pathways of cancer cell metabolism, compare their functions and regulation with those of non-tumor cell metabolism and discuss some of the major questions in this field of investigation. We also discuss tumor metabolism and metabolic transformations from the perspective of oncogenes, tumor suppressors, miRNAs and protein signaling pathways. Finally, recent attempts to target metabolism as a treatment for cancer are discussed.

The ability of tumors to develop resistance to cytotoxic therapies has been a major obstacle in the clinical management of cancer. In addition, dose-limiting toxicity represents yet another impediment in the application of traditional therapeutics. To enhance the sensitivity of tumors to radio-therapeutics, researchers are increasingly turning to nitric oxide for its potential as a powerful adjuvant to existing therapies. Here, we review the aptitude of nitric oxide to serve as a radio-sensitizing, adjuvant therapeutic for the clinical management of cancer.

Cancer is a multistep process in which multiple genetic changes result in the transformation of normal cells into malignant cells. These genetic alterations are a result of various environmental or endogenous DNA-damaging agents. They can be inherited through germ cells or more commonly acquired as somatic mutations. Somatic mutations include point mutations, chromosomal translocations, deletions, inversions or amplifications. These genetic changes lead to the malignant transformation of normal cells through self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, replicative immortality, sustained angiogenesis, tissue invasion and metastasis. Characteristic genetic alterations have been identified in various types of cancers. This review focuses on the key molecular mechanisms underlying various human cancers.

Cytotoxic drugs are a diverse class of compounds that treat cancer primarily by killing cancerous cells that are rapidly growing and dividing along with cells that are meant for normal tissue function. A novel and suitable delivery system delivers the chemotherapeutic agents to cancerous tissues without harming healthy tissues and also retains these chemotherapeutic agents in the tumor area for a longer period of time that gives a boost to the therapy. Smaller size increases the surface area of the nanoparticles that enhances drug absorption or encapsulation and carries the drug into the blood in a shorter time period. In comparison with already existing delivery systems, nano sized delivery systems can penetrate much deeper into tumor tissue, generally taken up more efficiently by cells and reduce the toxicity of cancerous drug to healthy tissues. However, nanoparticulate systems are being researched throughout the world to increase the drug efficacy and to reduce toxicity. Thus, generally nanoparticulate systems work on passive targeting as well as on active targeting of the drug to the tumors. However, the research is still at a nascent stage and there is a need to understand the role of nano carriers in cancer treatment. This article summarizes various drug delivery technologies for chemotherapeutic agents, which are gaining more attention for better therapeutic response.

Cancer is a leading cause of mortality at global level, with recent advancements in research of anticancer drug therapy and diagnosis resulting in modest impacts on cancer therapy. Multifunctional or theranostic metallic nanoparticles gained attention in recent years as promising therapeutic paradigms, which provide attractive vehicles for diagnosis, and therapeutic delivery of diagnostic/active agents to tumor specific cells. Here, we discuss the cancer patho-physiology that acts as barrier in conventional chemotherapy and multidimensional aspects of metallic nanoparticles for effective cancer therapy, with particular focus on clinical stages. Keeping in mind the growing research in clinical application of metallic nanomedicines, toxicity and regulatory concerns related with these nanometric systems are also addressed in this review.