Therapeutic microRNA

Therapeutic potentials of microRNA have often been discussed and several functional studies explore strategies using antisense RNA against tumorigenic microRNA or replacing it. One recent publication in the magatine Cell shows the power of gene therapy utilizing inhibitory microRNA (http://www.cell.com/abstract/S0092-8674(09)00446-2). A characteristic feature of common tumor models is upregulation of specific and downregulation of general miRNA levels. Using a murine model for inducible liver tumors and human Hepatocellular carcinoma (HCC) cells the team around Joshua Mendell took advantage of the fact, that abundance of microRNA miR-26a is almost twice as high in unaffected tissue than in tumorous liver tissue. Through retroviral vectors it is possible to force expression of miR-26a and thus increasing its endogenic concentration leading to cell cycle arrest of tumor cells. Cellular proliferation is inhibited because miR-26a directly represses the expression of cell cycle control proteins Cyclin D2 and Cyclin E2 which also induces tumor-specific apoptosis. All this sounds pretty impressive to me but as the authors stated it is still the beginning. More than likely several powerful tumor repressing microRNAs will be discovered in close future and once clinical studies investigate toxic consequences of therapeutic microRNA treatment we will be close to making a great leap in curing cancer.

Down's syndrome involved in tumor suppression

It has already been observed that individuals affected by Down's syndrome show reduced tumor growth and speculations arised that the additional copy of Chromosome 21 could feature the genes leading to this effect. Now a study published in Nature (http://www.nature.com/nature/journal/v459/n7250/abs/nature08062.html) proofed one of these genes to be coding for a protein inhibiting the VEGF-Calcineurin pathway, the so called Down’s syndrome candidate region 1 (DSCR1). In mouse models for lung carcinoma and melanoma the a tird copy of the DSCR1 encoding gene was sufficient to reduce angiogenesis and thus significantly slowing down tumor growth. As already mentioned in the part concerning Immunotherapy, the VEGF is a rather prominent target for anti-tumor drugs. A naturally occuring negative regulator of the VEGF pathway opens the way for a completely different set of therapeutic tools to control tumors.

Immunotherapy - applying antibodies against critical molecular targets in tumor cells

Among them you can find some of the most profit-making drugs on earth, like Avastin or Rituxan, selling for around 700 Mio $ each in 2008 (http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11767). So why are we not done yet? If you look at the websites for Avastin (http://www.avastin.de/) and Rituxan (http://www.rituxan.com/) you encounter the main problem. Avastin for example targets a variety of cancers in breast, lung and kidneys, and in all applicable forms of tumor the target is VEGF, the vascular endothelial growth factor (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=micad&part=Bevacizumab111In). The target for Rituxan is the membrane protein CD20. This explains why Avastin or Rituxan can be applied for different types of tumor and why we are still lacking pharmaceutical agents that target all types of breast cancer or all types of lung cancer. There is no common marker expressed in all types of breast cancer that can be targeted without afflicting serious damage to healthy tissue as well. Antbodies against specific surface molecules on tumor cells is still something to open a business.

Getting started

Whew, that was more work than anticipated. But I still don't know where to begin. How about a gene responsible for alcohol resistance? (well, everybody talks about that anyway...) Or how targeted breast cancer therapies work on molecular level? Choices ...