Frontiers in Clinical Drug Research - Anti-Cancer Agents

Solid tumors grow within a complex microenvironment composed of diverse cell types such as fibroblasts, endothelial cells, mast cells, macrophages and immune cells that are attracted by tumor cell derived factors and embedded in an extracellular matrix. Molecular and cellular interactions between epithelial cells and cells surrounding the tumor stroma promote growth, invasion and spread of tumors. To delay or impede tumor growth, the tumor microenvironment (TME) is increasingly being explored as a potential therapeutic target for which novel strategies are developed.

This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed.

Cladribine (2-CdA, 2-chlorodeoxyadenosine) is a purine nucleoside analog of high efficacy in lymphoid and myeloid malignancies. In contrast to other purine nucleoside analogs, 2-CdA is equally cytotoxic to both proliferating and quiescent cells. In addition, recent data indicates that a combination of 2-CdA with other cytotoxic agents and monoclonal antibodies shows synergistic proapoptotic and cytotoxic activity on lymphoid and myeloid neoplastic cells. Cladribine is the drug of choice in the treatment of hairy cell leukemia. It is also useful in other lymphoid and myeloid neoplasms, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and non-Hodgkin lymphoma. In addition, 2-CdA has been found to be effective in Sezary syndrome and mycosis fungoides. Moreover, several investigations have revealed that the agent is active in acute myeloid leukemia, Langerhans cell histiocytosis, and systemic mastocytosis. This chapter will summarize the current status of 2-CdA in the treatment of hematologic malignancies.

Human chromosome ends are capped by telomeric DNA composed of long arrays of (TTAGGG)n repeats. During each cell division, telomeric DNA is shortened by 50-100 bp. This attenuation of chromosome ends results in a loss of coding sequences and end-to-end chromosomal fusions, leading to chromosomal instability and aberrations. Therefore, telomere shortening is a critical event that acts as a mitotic clock to measure cellular life span. Telomerase, a ribonucleoprotein composed of a catalytic subunit (TERT), an RNA template (TERC), and the dyskerin protein, elongates telomeric sequences in germ cells and immature precursors such as hematopoietic stem cells. Telomerase is activated by multiple signaling pathways and its activity is regulated at the levels of gene transcription and translation, as well as post-translational modifications, trafficking, and assembly of the protein. Telomerase is upregulated in most cancer cells, including hematologic malignancies. Telomere shortening and telomerase activation are correlated with the prognosis and aggressiveness of various hematologic tumors. Therefore, targeting telomerase may be an attractive therapeutic strategy for hematologic malignancies. In fact, several strategies of telomerase inhibition, such as G-quadruplex-interacting agents, catalytic/reverse transcriptase inhibitors, oligonucleotides, and immunotherapy, have been developed as therapeutic methods.

Lung cancer is one of the most commonly diagnosed malignancies and the leading cause of cancer-related mortality in North America. The heterogeneity of nonsmall cell lung cancer (NSCLC) and the importance of linking new, targeted agents to the appropriate disease subtype require an individualized approach to treatment. In patients with epidermal growth factor receptor (EGFR) mutations, EGFR tyrosine kinase inhibitors (EGFR-TKIs) provide a highly effective treatment option, with improved toxicity compared with standard chemotherapy. Newer irreversible EGFRTKIs have additional advantages and are able to overcome the resistance seen with the older reversible agents. A number of clinical trials using EGFR-TKIs are showing promising results, including a superior side-effect profile and improved quality of life when compared with standard chemotherapy. Studies using EGFR-TKIs will aid in determining the optimal positioning of these therapies. With improvements in both testing and access to treatment, targeted use of EGFR-TKIs may greatly improve outcomes in NSCLC.

Tumors of the Central Nervous System (CNS) are the most common solid tumors in children, and represent a heterogeneous group of diseases. Progress has been made in understanding the biology of some histologic tumor subtypes and a number of involved cell signaling pathways have been identified. As a consequence, molecularly targeted therapies are being evaluated as part of the therapeutic armamentarium against these diseases. Targeting key signaling pathways in pediatric brain tumors is an attractive idea since aberrant signaling pathways may be specific to tumor cells. Pediatric tumors are different from their adult counterparts and offer unique challenges. In addition to the unique pharmacokinetic properties of the CNS (blood-brain barrier and blood-tumor barrier), treatment of children with brain tumors is aimed at the developing brain, which may be more susceptible to effects of therapy, and the effects of signal inhibitors on the post-natal developing brain are largely unknown. Despite these obstacles, inhibitors of signaling networks involving sonic hedgehog, epidermal growth factor receptor, plateletderived growth factor receptor, BRAF, Notch, and others are under clinical investigation and have the potential to bring exciting management alternatives for pediatric CNS tumors in the near future. This article reviews pediatric brain tumors with signaling pathways implicated in their tumorigenesis and current efforts to target them.

Since ancient times, natural products have been recognized as a source for remedies. In particular, the natural products which contain anti-tumor properties have gained increasing attention. Although there has been great scientific and technological progress in synthetic chemistry, anti-cancer drugs that are derived from natural products still make an enormous contribution to drug discovery and clinical application. In the following chapter, three types of anti-tumor natural products will be introduced in detail.