Tumor progression is usually ensured by more than one proliferative mechanism. When one of these is shut down by a specifically targeted drug, other mechanisms may emerge. While these events may lead to treatment failure, they may also become an opportunity for researchers to identify novel targets to be further explored. In a paper recently published in the journal Oncology (“BDNF/TrkB content and interaction with gastrin-releasing peptide receptor blockade in colorectal cancer,” Vol. 79, pages 430�, 2011; DOI: 10.1159/000326564) Roesler and colleagues describe a novel potential drug-target in colorectal cancer.
Colorectal cancer (CRC) is the fourth most common cancer in men and the third in women worldwide. It is a frequent cancer, with more than 1 million new cases every year and a poor survival rate. Rapid increases in CRC incidence have been observed mainly in emerging economies. These increases are attributed to changes in diet, life style, and patterns of physical activity. In Western countries, only 55% of the patients are alive 5 years after diagnosis, with most patients dying from metastatic disease.
Although a number of treatment options are available for CRC patients, including surgery, chemotherapy and biologic therapies targeting two different mechanisms — angiogenesis (bevacizumab) and epidermal growth factor receptors (cetuximab and panitumumab) — new treatment options are required to improve survival rates.
The search for novel targets led Dr. Rafael Roesler at the Federal University of Rio Grande do Sul (UFRGS) Brazil, Dr. Gilberto Schwartsmann, and graduate student Caroline Brunetto de Farias, among others, to investigate whether a brain-derived protein known to be involved in tumor growth, metastasis and drug resistance in a number of cancers, including some non-neurological cancers, could also be found in CRC.
The team led by Dr. Roesler found that the brain protein, known as brain-derived neurotrophic factor (BDNF), is present in greater amounts in colorectal tumors when compared to the normal tissue of the same patient. BDNF’s receptor, a tropomyosin receptor kinase B (TrkB), is also found in CRC.
The study also shows that BDNF is potentially involved in CRC progression and CRC resistance to drugs targeted at another protein known as the gastrin-releasing peptide, or GRP. By blocking GRPR (which is GRP’s receptor) with RC-3095, an antagonist molecule that inhibits proliferation in colorectal cancer cells, expression levels of BDNF may increase. Dr. Roesler and colleagues observed that when levels of BDNF were higher RC-3095-treated colorectal cells still proliferated, indicating that BDNF inhibits the anti-proliferative effects of RC-3095. On the other hand, blockage of BDNF receptor TrkB rescues the anti-proliferative effects of RC-3095. These findings suggest that BDNF is associated with a compensatory response mechanism aimed at maintaining higher proliferative levels characteristic of tumor progression.
The study provides the first evidence of BDNF and TrkB presence in colon cancer and “offers new insights into their potential contribution to tumor progression and resistance to some types of antitumor drugs” said Dr Roesler.
The research was funded by the National Council for Scientific and Technological Development (CNPq); the National Institute for Translational Medicine (INCT-TM); the UFRGS/HCPA university hospital research fund (FIPE/HCPA); the South American Office for Anticancer Drug Development; and the Children’s Cancer Institute (ICI-RS).
Other researchers working on the study include Denis B. Rosemberg, Tiago E. Heinen, Patricia Koehler-Santos, Ana Lucia Abujamra, Flávio Kapczinski, Algemir L. Brunetto, Patricia Ashton-Prolla, Luise Meurer, Maurício R. Bogo, and Daniel C. Damin.