We announced an International Collaborative Study focusing on Synovial Sarcoma this morning in the May 2014 issue of ESUN. You can read the announcement at http://bit.ly/1n2qHir and the experimental plan at http://bit.ly/1ktzo4j. This research involves a very gifted team whose ultimate goal is to translate their research into targetable pathways into clinical trials to provide new options for patients with synovial sarcoma. The complete Table of Contents for the May 2104 issue of ESUN is at http://bit.ly/R2ZGAk.
This looks promising. However, it will take me a lot of time to actually understand all the gene mutation /translocation science that is taking place.
Nogin, indeed it is difficult to understand what they want to do if you don't have a degree in biochemistry :-(
After 10 years reading books on the subject to improve my understanding, here is how I picture the whole thing:
All of our cells carry instructions, the DNA that tells them what to do and when to do it. The DNA is made of chromosomes, which are like books of instructions. Each chromosome is made of genes, which are like sets of instructions on how to build a particular protein. One day book X and book 18 got both broken into 2 pieces. In a hurry, the cell mended the books but reassembled the beginning of book X with the end of book 18 and vice versa. This accident is what we call the translocation. The books were ripped in the middle of a set of instructions to built the protein SSX (in book X) and the protein SS18 (in book 18). So now, one of the mended book is giving instructions to built the beginning of SS18 with the end of SSX and the other book is giving instructions to build the beginning of SSX with the end of SS18. Apparently only one of these 2 new sets of instructions is significant and gives rise to a mutant protein also called SS18-SSX fusion protein.
Did you notice all our cells are not identical although they carry the same instructions (same DNA)? Why aren't we a big ball of uniform material then? Well, now, imagine the books of instructions were printed with magic ink. At any given time in a given cell, some sets of instructions become visible while others become invisible and the cell only follows the visible instructions. This has to do with how the DNA is folded (study of which is called epigenetics) and what molecules are attached to it (for example transcriptions factors). DNA is rolled around proteins called histones. These proteins can be modified by adding or removing tags (by processes called methylation, demethylation, acetylation or deacetylation). This in turn changes the DNA folding and dictates which set of instructions is visible and which is not.
What the researchers know so far is that book X and book 18 unfortunate accident, with the help of the mutant protein, changed which sets of instructions became visible and which became invisible. They also know that the combination of visible/invisible sets of instructions at the time of the accident affects the outcome of the accident. Indeed, they know that if the accident happens in a mature cell for example, the cell will die. What they don't know is which combination of visible/invisible sets of instructions lets the accident transform the cell into a monster.
In the project, the researchers intend to use shRNA to try to figure out which sets of instructions are required to be visible and which are required to be invisible for the monster to thrive. They call it the permissive state. What makes the whole thing complicated is that there are probably different combinations that are permissive... That's why they will use a lot of different cell lines and models of synovial sarcoma. The study sounds quite comprehensive that way. Hopefully, there are drugs out there that can eliminate all the permissive combinations...