John Zuber from the Institute of Molecular Pathology in Vienna tried to find genetic vulnerabilities in leukemia cells
Now he's on a hot trail passes. Initial results were just published in "Nature".
Standard: cure cancer is a goal for decades of research. What is your strategy?
Zuber: I have been working many years with leukemia. The treatment of blood cancer has always played a pioneering role within the cancer research. One reason is that we can observe the hematopoietic system and understand well. Today we know that there are over 100 genetic mutations in various combinations, leading to leukemia. The more we know, the greater the complexity. However, it was passed in the treatment of leukemia and first major breakthrough with new therapeutic methods, the new hope and inspiration.
Default: How?
Zuber: Two medicine. Gleevec, which the hitherto almost untreatable chronic myeloid leukemia (CML) was manageable, and Atra, a vitamin A supplement that with an aggressive leukemia known as M3 is achieving good results. Both fall under "targeted therapies", targeted therapies.
Standard: Targeted therapies are often referred to but only for marketing purposes, so ...
Zuber: Treatment with Gleevec results in up to ten years more life. I think it gives hope and courage, weiterzuforschen. Because there are forms of leukemia, which are much more complex than those we can now treat all right. This is intentional, because it is directed against genes that contribute to cancer development or survival of cancer cells.
Standard: What is your approach?
Zuber: Our research goes beyond the search for cancer-causing mutations. We look for genetic weaknesses in cancer. Modern sequencing show that for the cancers that were previously summarized in a different diagnosis, and almost every metastasis is different. The exploration of mutations and signaling pathways is therefore a dizzying work, and the idea to find for so many different types of disease a single, universally effective treatment is even more unrealistic. Mutation analysis is important, we try to figure out which genes are needed for survival from cancer. That is the crucial question we are trying to resolve the so-called hairpin-technology (see know) systematically.
Standard: Is it different in cancer cells because the same vulnerability?
Zuber: leukemia cells, but other cancer cells differ from normal cells. They share more quickly, have a different metabolism. We also know that the DNA-packaging - the so-called chromatin - is altered in cancer cells. Specifically, the Chromatinanteile that regulates how DNA is transcribed, modified extensively in leukemia. Therefore we decided to test the group of chromatin-modifying genes as potential therapeutic approaches systematically.
Standard: Why exactly are these chromatin-modifying genes that interesting?
Zuber: First, because we know for sure that the Chromatinlandschaft is altered in cancer cells. Especially with the leukemia that is exactly occupied, and there are already drugs which specifically target precisely these Chromatinregulatoren. What is even more important: Chromatinveränderungen are different reversible than mutations in DNA can be reversed. In addition, most Chromatinregulatoren enzymes. We can therefore affect molecules as well, specifically inhibit, that is off. They are small, have - considered molecularly - pockets into which you can inject structures. In order to develop drugs can, which is a crucial characteristic. Currently there are about 250 known Chromatinregulatoren, this is a manageable number in order to systematically "auszuknipsen" with the hair-pin technology and see what happens. The most sensitive leukemia cells responded when we called a gene-switch off of Brd4.
Standard: What exactly does that mean?
Zuber: The acute myeloid leukemia cells are driven to a suicide program. They are transformed into mature white blood cells. For hematologists exactly this kind of differentiation is a sign of the success of a therapeutic procedure. In the search for drugs that now that we found gene can inhibit Brd4, we were lucky, because James Bradner in Boston just had a Brd4-inhibitor developed.
Standard: A coincidence?
Zuber: Yes, a stroke of luck so to speak. Bradner because the drug from a completely different approach has been developed. He was fundamentally interested in the binding of Brd4 and DNA. Through our systematic investigation of the hairpin-technology, it became clear that this gene Ausknipsen kills leukemia cells and may be Brd4 inhibitor in leukemia, perhaps also in other cancer types can be used. In the mouse model that has worked very well. The conditions are so good, but it is still before a number of very important issues to address. On the way to a drug, there are many hurdles to overcome.
Standard: What is with all other forms of leukemia?
Zuber: Since we're on. We look at the effect of chromatin-regulating genes, especially in cell culture and intensive work here together with Peter Valent of the Department of Hematology / Internal Medicine I at the General Hospital. We can draw on their cell material and test the effect of the hairpin-technology to the various forms of leukemia. We are planning to jointly establish a study center for drug development.
Standard: How exactly do you imagine that?
Zuber: If we want to use the technology in the future hairpin wider, we must look for more cancer-specific genetic vulnerabilities such as Brd4. The research at Cold Spring Harbor here has already done valuable preliminary work. Now we want to take a systematic approach and examine other tumors. The result of last week's paper published in Nature, which concerns the treatment of leukemia, very promising. The publication (RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukemia) in which I was involved, is a great motivating weiterzuforschen.
Standard: What conditions provide a research site in Vienna?
Zuber: After five years in the U.S. I can compare and say that the conditions are ideal here at the IMP. My goal is to strengthen cooperation with the Vienna General Hospital and together with Boehringer Ingelheim (Note: the pharmaceutical company is the main sponsor of the IMP) to work intensively on a drug development. Interaction potentials, it is enough. (Karin Pollack / DER STANDARD, print edition, 10 8th, 2011)
-> Knowledge: Molecular hairpin Technology
John Zuber from the Institute of Molecular Pathology in Vienna tried to find genetic vulnerabilities in leukemia cells
Molecular hairpin Technology
In the 1990s, scientists discovered the U.S. Andrew Fire and Craig Mello, a new biological regulatory mechanism, RNA interference, or RNAi for short RNA silencing. In turn this natural process small, double-stranded RNA molecules from genes, that induce a gene knockdown. The small RNA molecules in their structure look like hairpins, which is why they are also called the hairpin.
At the hairpin or small hairpin RNA molecules are technology used to destroy larger molecules of messenger RNA (mRNA). The mRNA is responsible for the transfer of information from genome (DNA) to the ribosome ("protein factory"). So it is a chemical structure that serves the transcription of genetic material into proteins (proteins). If they destroyed the gene can not be translated into a protein and is therefore "disabled".
This finding was startling because it can be revealed by a whole new picture of how genes are regulated in nature. Still many fundamental mechanisms of gene regulation by small RNA molecules are poorly understood - their education is more about a focus at the Institute for Molecular Biotechnology (IMBA) in Vienna.
For the medically applied research brought the discovery of the hairpin is a very efficient tool with which researchers can easily switch off any gene. For the work of research groups, such as those at the Institute of Molecular Pathology (IMP) in Vienna, this is a big help. The hairpin technology enables a systematic search for target genes for the treatment of diseases and to study the effects of inhibitors in advance. Correspondingly, there is the importance of this line of research in the search for new drug compounds.