In Her Own Words...
A research team led by Titia de Lange, PhD (The Rockefeller University) established for the first time that the Rif1 gene is an important contributor of DNA repair. The results were printed in the February 8, 2013 issue of Science, where BCRF was acknowledged as the sole funder of the published research. Dr. de Lange's findings are particularly important in breast cancers associated with BRCA1 mutations and offer insights into how potentially to avoid the development of resistance to therapies, such as radiotherapy and PARP inhibitors, that involve DNA breakage.
Dr. de Lange, whose work has been supported by BCRF for ten years, speaks about her findings and future applications of this research.
Let me explain what we've found and what we've published. Other scientists have made the discovery that a specific kind of drug, called a PARP inhibitor, can be used to treat breast cancers caused by BRCA1 or BRCA2 mutations. The clinical development of these drugs is underway now, and as always there are many aspects that need to be studied in detail, especially the underlying biology of the drug and the drug-to-tumor interactions. The reason why you want to know the underlying biology is because with any treatment you will eventually get "therapy resistance," or reduced effectiveness. And therapy resistance often comes about through changes in the pathways that make the cells sensitive to a drug. You need to know how a drug works in order to understand why a cell becomes resistant.
Now, our recently published work provides new insights into how these PARP inhibitors work and how BRCA1 associated cells can become resistant to these drugs. It is already known that cells can become resistant to PARP inhibitors when they lose the activity of a gene called 53BP1. And we discovered that there is another gene that can make cells resistant to PARP inhibitors, and the name of that gene is Rif1.
One may ask how does a lab like mine, which primarily works on telomeres (the ends of chromosomes) and how they affect breast cancer development, come to publish on BRCA1 tumors and their ability to be killed by PARP inhibitors? This work is quite far off the beaten path for my lab. Yet, this work is a fabulous illustration of what BCRF has done for me.
About ten years ago, we started working on the gene, Rif1, a gene that has been studied in yeast. Since in yeast Rif1 is very important for the function of telomeres and regulates their length, we thought that if we could get the human version of Rif1, then probably it will also do something at human telomeres. We struggled very, very hard to get the human version of this gene. When we finally did, it turned out that Rif1 had nothing to do with telomeres in human cells. It was a very disappointing finding. But what we found is that when you harm cells with radiation, which makes breaks in the DNA, Rif1 functions as a DNA-damage-response factor required for cell survival after radiation damage. In other words, there is a close relationship between Rif1 and the DNA-damage response but not telomere function. We published these findings in 2004, and that is where we would have left the story because my lab receives National Institutes of Health (NIH) funding only to work on telomeres, not on DNA damage.
At that time, I talked to Larry Norton, MD, BCRF Scientific Director, about our work on Rif1. He encouraged me to continue the research, but I reminded him that I could not pursue this with federal funding because our NIH support applied only to telomeres. He suggested that I apply for a BCRF grant, and I was fortunate to be awarded one.
Rif1 is a very complex gene, and the research has taken a long time. Now, our work is starting to pay off because it is giving us very interesting insights into the treatment of BRCA1 breast cancer, which is characterized by DNA damage. Also, the work we published was very competitive--many other labs, at least four others, came to the same conclusions at about the same time. I think without our initial work on Rif1, this would not have happened. All of this would not have been possible without BCRF funding.
My lab is best at doing fundamental research, mechanistic research, on how cells do things. To follow up this publication, what we are doing now is figuring out how Rif1 really works and the mechanism by which it functions. My hope is that, the people who are doing clinical work and have collections of clinical samples, will pick up on our findings and run with them. For example, they can look at whether the Rif1 gene has been changed in BRCA1 tumors that have been treated with PARP inhibitors and have become resistant. It is also my hope that my basic research work leads to the next step in the clinic. Also, I am right across the street from Memorial Sloan-Kettering (Cancer Center) and NewYork-Presbyterian, where the clinical researchers are very much aware of what I have found, and they are going to make use of these discoveries.
So, the BCRF funding paid off not only in terms of my lab's discoveries but for the whole scientific community. When you support one lab doing good work, then other people pick up from where that lab is and follow up on the findings and take the next step. BCRF has funded something that the NIH would not have at the point I needed funding. And to me, it's a good example of how a funding entity like BCRF can do something very important. I hope everyone understands how much we investigators appreciate what BCRF does, together with an amazing base of donors who allow us to do work that may be a little outside the box and sometimes risky but with potentially great rewards. And I thank all of you for that.