Novel insights into the role of aptamers in the fight against cancer

Certain guanine-rich (G-rich) DNA and RNA molecules can associate intermolecularly or intramolecularly to form four stranded or "quadruplex" structures, which have unusual biophysical and biological properties. Several synthetic G-rich quadruplex-forming oligodeoxynucleotides have recently been investigated as therapeutic agents for various human diseases. We refer to these biologically active G-rich oligonucleotides as aptamers because their activities arise from binding to protein targets via shape-specific recognition (analogous to antibody-antigen binding). As therapeutic agents, the G-rich aptamers may have some advantages over monoclonal antibodies and other oligonucleotide-based approaches. For example, quadruplex oligonucleotides are non-immunogenic, heat stable and they have increased resistance to serum nucleases and enhanced cellular uptake compared to unstructured sequences. In this review, we describe the characteristics and activities of G-rich oligonucleotides. We also give a personal perspective on the discovery and development of AS1411, an antiproliferative G-rich phosphodiester oligonucleotide that is currently being tested as an anticancer agent in Phase II clinical trials. This molecule functions as an aptamer to nucleolin, a multifunctional protein that is highly expressed by cancer cells, both intracellularly and on the cell surface. Thus, the serendipitous discovery of the G-rich oligonucleotides also led to the identification of nucleolin as a new molecular target for cancer therapy.

Antibodies and related products are the fastest growing class of therapeutic agents. By analysing the regulatory approvals of IgG-based biotherapeutic agents in the past 10 years, we can gain insights into the successful strategies used by pharmaceutical companies so far to bring innovative drugs to the market. Many challenges will have to be faced in the next decade to bring more efficient and affordable antibody-based drugs to the clinic. Here, we discuss strategies to select the best therapeutic antigen targets, to optimize the structure of IgG antibodies and to design related or new structures with additional functions.

Cancer is one of the leading causes of death in the United States along with heart disease. The hallmark of cancer treatment has been conventional chemotherapy. Chemotherapeutic drugs are designed to target not only rapidly dividing cells, such as cancer cells, but also certain normal cells, such as intestinal epithelium. Over the past several years, a new generation of cancer treatment has come to the forefront, i.e, targeted cancer therapies. Like conventional chemotherapy, targeted cancer therapies use pharmacological agents that inhibit growth, increase cell death and restrict the spread of cancer. As the name suggests, targeted therapies interfere with specific proteins involved in tumorigenesis. Rather than using broad base cancer treatments, focusing on specific molecular changes which are unique to a particular cancer, targeted cancer therapies may be more therapeutically beneficial for many cancer types, including lung, colorectal, breast, lymphoma and leukemia. Moreover, recent advances have made it possible to analyze and tailor treatments to an individual patient's tumor. There are three main types of targeted cancer therapies; 1) monoclonal antibodies, 2) small molecule inhibitors and 3) immunotoxins. This review will discuss these three classes of targeted therapies in detail, as well as the biology behind targeted cancer therapies.