Frontiers in Anti-Cancer Drug Discovery

Gastric cancer is the second leading cause of cancer related-death worldwide. In 2008, it was estimated 990.000 new cases and 738.000 related-deaths. Considering the poor prognosis of advanced gastric cancer, new therapeutic regimens with acceptable toxicity have been pursued. Interesting insights have emerged from the investigation of human epidermal growth factor receptor 2 (HER2) as a potential therapeutic target. HER2 is a transmembrane tyrosine kinase receptor which is activated through dimerization, leading to a cascade of events that involves the activation of molecular pathways concerning regulation of cell proliferation, differentiation and survival, including the MAPK and PI3K pathways. The importance of addressing HER2 as a therapeutic target is underscored by consistent molecular and pathological findings: upregulated HER2/neu relates to carcinogenesis and is found in both primary tumours and metastasis. HER2 over-expression has been reported in breast, stomach, lung, salivary gland, ovary, colon, prostate and pancreatic cancers. In the particular case of breast cancer, recognition of the molecular signature of HER2 over-expression is widely used to tailor therapeutics involving molecular therapies with antibodies targeting HER2, therefore establishing HER2 status as a prognostic factor and a predictor of response to therapy. However, the correlation between the expression of HER2 and the prognosis of gastric cancer is still controversial. HER2 over-expression is currently estimated to occur in about 7-34% of gastric cancers. In this behalf, it is important to stress the recent development of validated methods in identifying HER2 overexpression in gastric cancer. In this chapter the authors will address the molecular mechanisms of HER2's oncogenicity, the assessment of HER2 over-expression and its clinico-pathological significance, resistance mechanisms and future perspectives emanating from clinical trials in this regard.

Cancer development is a dynamic and long term process which involves many complex factors through critical steps of initiation, promotion and progression, leading to an uncontrolled growth of cancerous cells throughout the body. It is believed that dietary constituents derived from plant sources have the ability to modify the process of carcinogenesis thus relating the food stuffs, beyond their basic nutritional benefits, to disease prevention. The concept of nutritional approach to disease prevention and therapy has thus given way to the popularity of bioactive components of food known as nutraceuticals. Nutraceuticals may range from isolated nutrients, herbal products, dietary supplements and special diets to genetically engineered ‘designer’ foods and processed products such as cereals, soups and beverages. Phenolic nutraceuticals derived from fruits, wines, vegetables and spices have been the subject of considerable scientific research in the last few decades for their chemopreventive action against cancer. These include curcumin (from the spice turmeric), resveratrol (from red grapes and red wine), epigallocatechin-3-gallate (EGCG, from green tea), ellagic acid and delphinidin (from pomegranate juice) and genistein (from soybean). Several mechanisms of pleiotropic action have been identified for the anti-cancer properties of these dietary agents, including induction of cell-cycle arrest and apoptosis, targeting the inflammatory and oxidative pathways and modulating the activities of signaling molecules critical to cellular growth and proliferation. The regulation of cancer cell growth by dietary nutraceuticals involves multiple molecular targets and thus unlike drugs these may have the advantage of simultaneously influencing various pathways that go awry in a complex multifactorial disease like cancer. Accumulating evidence in literature, based on epidemiological and laboratory (both in vitro and in vivo) studies, reveals the properties of dietary phenolics that can form the basis of their consideration as lead molecules in the synthesis of novel anti-cancer drugs and to further explore their role as pharmacologically active natural adjuvants to standard chemotherapeutic approaches. The underlying sections of this chapter will specifically focus on how nutraceuticals modulate the essential cellular pathways and thus affect the survival, proliferation, invasion, angiogenesis, and metastasis of the tumor.

Human diet comprises of polyphenolic compounds called the flavonoids which are universally present as constituents of food plants. The flavonoid derivatives found in many of our spices and plants have applications for prevention of diseases and as therapeutic agents in traditional medicines mainly in Asia. The flavonoid composition is most likely the key for the potential health benefits. The lower risks of colon, prostate and breast cancers in Asian population could be related to their vegetable and fruit rich diets containing many flavonoid derivatives. The question is whether these flavonoids mediate the protective effects of diets rich in these foodstuffs by acting as natural chemopreventive and anticancer agents. The current study summarizes the most recent advances providing new insights into the factors, regulation and molecular mechanisms underlying the promising anticarcinogenic activity of dietary flavonoids, their potential interactions with proteins and other dietary components.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutics that are generated by covalent attachment of cytotoxic agents to monoclonal antibodies via linkers. It is generally believed that following antibody binding to the antigen and ADC internalization, release of toxic payload would produce cytotoxic effects in tumor cells in relatively selective manner. The clinical development of ADCs was not feasible until several critical prior developments took place, including development of recombinant therapeutic monoclonal antibody production, advancement of linker technology, and discovery of potent cytotoxic agents.

In this book chapter, we will briefly introduce the history of ADC development and focus on the development and mechanisms of action of ADCs in oncological indications. In addition to covering present ADC therapies in clinical trials we will also offer possible future directions for ADC therapies, such as development of antibodies against new therapeutic targets, use of novel antibody and non-antibody-based platforms for the ADC development, use of novel linker designs for ADC generation, as well as development of novel payloads for antibody-based conjugates. As these development trends continue, future potential of ADC therapies to address the needs in oncology indications will be explored. Note that the information presented in this article represents publically available information. Any opinions expressed reflect the views of the authors and do not represent the policy of the U.S. Food and Drug Administration.

Virotherapy is the use of oncolytic or tumor-selective viruses to treat cancer. The replication of the virus inside a tumor can debulk the tumor mass and simultaneously, revert the immune suppressor environment that causes the immune escape of tumor cells. This therapeutic approach was discovered ten years ago but it has been renewed in the last decade with designed viruses. Adenovirus (Ad) is a nonenveloped DNA virus that infects broadly tumor cells and it has been frequently used in cancer gene therapy and virotherapy. A very high level of tumor-specific replication has been obtained with adenoviruses by replacing early viral gene promoters with tumorselective promoters. However, the complex Ad capsid interactions with blood proteins and cells and, also with liver and spleen macrophages result in rapid blood clearance and the prevention of systemic tumor targeting. To settle these problems, a new field is emerging where an oncolytic Ad genome is complexed to non-viral vectors to target tumors.

Phosphorylation and post-phosphorylation events are important regulators of cell signaling and protein activity. Important information about the peptidyl-prolyl isomerase Pin1 in the last decade has revealed a level of regulation beyond phosphorylation. Pin1 can interact with phosphorylated proteins and alter the isomerization state of the peptide bond involving serine/threonine-proline, which can bring about a change in their structure. Post-phosphorylation events, such as isomerization of the peptide bond, can lead to functional consequences e.g. increase in protein activity, turnover, dephosphorylation and ubiquitination on account of changes to the protein structure. Since levels of Pin1 are higher in tumor cells than in normal cells, Pin1 appears to be an attractive target for cancer therapy. Indeed, many studies have suggested that Pin1 inhibition could induce tumor cell death. The current literature and insights into use of Pin1 inhibitors as anti-cancer therapeutic agents and as adjuvants are reviewed.

Glioblastoma is the most common form of primary brain tumor. It remains one of the deadliest of human cancers. Despite work by dedicated clinicians and scientists over the past forty years, the median survival of the afflicted patients remains approximately 12-14 months.

A major challenge in the treatment of glioblastoma involves its inherently infiltrative and invasive properties. The tendency for the glioblastoma cells to microscopically extend beyond the region of gross anatomic abnormality renders complete surgical resection impossible. Further, glioblastoma infiltration into regions of the cerebrum where the blood-brain-barrier remains intact increases the probability of therapeutic failure. In these contexts, understanding the molecular mechanisms underlying the invasive nature of glioblastoma cells may afford opportunities for meaningful therapeutic development.

One of the central principles that emerged from the past decades of cancer research is that cancer cells subvert molecular circuitry inherent with the cell of origin. As differing aspects of these circuits are manifested during normal development, it comes as no surprise that the patterns of glioblastoma migration and invasion are highly reminiscent of those observed in astrocytes during development. These highly coordinated processes include establishment of cell polarity, directional cellular adhesion to the extracellular matrix, cytoskeletal rearrangement, and asymmetric detachment to the extracellular matrix. Our understanding of the factors that mediate these cues have led to novel therapeutic strategies.

This chapter will highlight our current understanding of the signaling pathways that mediate glioblastoma chemotaxis with special focus on pharmacologic inhibitors available for therapeutic interventions.

The anticancer agents share the distinction of having the lowest therapeutic indices among clinically utilized drug classes and hence antineoplastic chemotherapy is associated with dose-limiting toxicities. Moreover, many of the cytotoxic agents are characterized with pharmacokinetic problems, e.g., limited stability, fast elimination and low level of tissue penetration, further limiting their usefulness. The advances in our understanding of the tumor biology and microenvironment characteristics and the evolvement of nano-sized systems, suitable as drug-delivery platforms have conditioned immense research interest towards design and elaboration of tumor-targeted nano carriers. Based on the possibilities for ensuring tumor- or organ targeted delivery and triggered or controlled release nanocarriers allow for augmented and sustained anticancer activity of loaded agents, with a concomitant decreased systemic exposure and toxicity. Moreover, nano-carriers could also aid for improvement of the biopharmaceutical, stability and solubility characteristics of encapsulated drugs. The presented review gives a concise outline of the liposomes, polymeric micelles and related polymeric carriers, and molecular hosts as anticancer drug delivery platforms.