This is part of an ongoing series featuring interviews with physicians on topics related to hereditary cancer. This is a summary of a discussion with Roger Greenberg, MD, PhD, the Basser Center’s Director of Basic Science and the Director of the new Penn Center for Genome Integrity.
The mission of the newly opened Penn Center for Genome Integrity (PCGI) is to understand the molecular basis of diseases that arise from structural aberrations to the human genome. Many different human syndromes result as a consequence of inherited mutations in DNA repair genes that affect the integrity of our genome. Hereditary breast and ovarian cancer are prominent examples of this intimate relationship, but many other cancer syndromes also stem from loss of genome stability due to DNA repair mutations. Beyond that, DNA repair gene mutations underlie many other disease processes that are not quite as obvious. For example, there are autoimmune diseases, such as Aicardi-Goutières syndrome, which can come from DNA repair mutations. Hereditary bone marrow failure and neurodegeneration can also occur from deficiencies in DNA repair. So really, the integrity of our genome ties in to almost every kind of biological process and human disease indication.
What we want to do in the Center is to try to understand those processes. Classically, entities described as “genome integrity centers” focus on DNA repair and DNA replication. But we wanted to have a more comprehensive scope that includes scientifically diverse investigators; for example, people studying the cell cycle and mitosis, innate immunity, stem cell biology, neurobiology, and so on. We want to bring together all these investigators who might not normally interact, but yet could have compelling reasons to do so, and provide them with shared resources that will promote interdisciplinary collaboration.
This is a unique model for a center. My experiences in the Basser Center have helped shape the ideas for this kind of comprehensive, collaborative approach. While leading team science grants for the Basser Center, something that we found works particularly well is to raise a series of provocative questions–important issues that would require the efforts of more than one lab to explore. The creation of teams around these questions brought people together and allowed them to share their expertise, while also helping certain scientists enter new fields that they had never worked in directly before and providing them with resources and direction. The idea of collaborative teams is a fundamental part of the Center for Genome Integrity. The provocative questions we’re trying to solve were thought up collectively by scientific members of the PCGI. We asked everyone what they’re interested in and what were some particularly important problems they would work on if they could–topics that required interdisciplinary expertise and collaboration.
Basic Science: From the Lab to the Doctor’s Office
Centers like the Basser Center and the Center for Genome Integrity are vital to advancements in cancer treatment. Basic science can be complicated to summarize, so let me give some specific examples of how we get from ideas in a lab to actual treatment options in the clinic. Biology, for the most part, is not a theoretical science. It requires doing experiments that address specific questions or hypotheses. That’s really what we do in the lab. I think patients and clinicians would be gratified to know that nearly every therapeutic advance has been achieved as a result of basic science.
For example, in 2005, papers in Nature showed that inhibiting PARP was lethal in BRCA mutant cancer cells that had lost both alleles, whereas it was not toxic in cells that were heterozygous (that had one normal allele and one mutated). Patients are heterozygous: every cell in their body has one normal copy. Tumors that arise in these patients generally lose the normal copy and then they have two mutant copies. So that mimicked the clinical setting. It mimicked the idea that you could selectively kill the tumor that had lost all BRCA function, while creating acceptable toxicity in every other cell in the patient that had one normal copy of BRCA. Four years later, the first clinical trial came out in 2009, showing that PARP inhibitors worked in patients with BRCA mutant cancers. Subsequently these PARP inhibitors were approved by the FDA for use in BRCA-related ovarian and breast cancer, and they are being investigated for use in pancreatic and prostate cancers that harbor BRCA pathway mutations.
The Center is still at an early stage, but we’re trying to set off with an ambitious way of looking at how to solve these problems and answer these questions. I view the PCGI as really an expansion of the basic science aspect of the Basser Center that will contribute to our understanding of genome integrity and human disease across systems. Part of it will be different, but one of the things that we’re trying to communicate is the idea that this is really a center that’s dedicated to fundamental science and we don’t know exactly where it will lead. We’re just trying to answer basic questions and have the confidence that if we get good data, we can figure out how and where to apply it.
Some of the Center’s work will tie back to the Basser Center and hereditary cancer. One key example relates to questions we’re asking about how to overcome resistance in BRCA mutant cancers. A breakthrough that we’ve had came from a collaboration with Junwei Shi, PhD, a pioneer in developing CRISPR Cas9 screens. That led to the discovery of a new drug target for BRCA mutant cancers. We’re really excited about the work. It changes the way we think about the problem and what is available in terms of how to approach it.
Something like this recent CRISPR advancement gives us a concrete new target in terms of understanding resistance in BRCA-related cancer. For example, if we locate an inhibitor to this molecule, to this protein, we’re confident that it’s going to work in BRCA mutant cancers based on a lot of data. And at the PCGI, we’re making this kind of technology a shared resource. Scientists will have the equipment, the libraries, and the technical support to use these technologies and others in a manner that is much less daunting than if they had to figure out everything on their own.
There are many other fascinating projects too, like one from Ben Black, PhD, who has developed artificial human chromosomes. This is a new technology that we can use to study DNA damage response. Michael Lampson, PhD, and Dennis Discher, PhD, are exploring tissue mechanics and how this affects genome integrity, while Sunny Shin, PhD, and Igor Brodsky, PhD, are investigating the molecular basis of inflammatory signals that activate immune responses following loss of genome integrity. We also have Wei Tong, PhD, and Matt Weitzman, PhD, looking at endogenous, physiologic damage that might be the initiating cause of bone marrow failure syndromes and the etiology underlying tissue specificity of certain cancers. We’re also working with the Center of Excellence in Environmental Toxicology, who have technology that allows identification of endogenous DNA lesions. We’re interested in using this to understand tissue specificity in BRCA-related cancers. Are there different types of DNA damage that are common to breast and ovarian cancer but less prevalent elsewhere? There are many possibilities, but these are some of the questions we’re asking.
In general, the PCGI won’t just focus on cancer. We’re going to ask some fundamental questions and see where that takes us. We’re really trying to take advantage of the breadth of scientific expertise within the Penn community. That has worked really well for us at the Basser Center and I’m confident that it will allow us to develop a world class program at the PCGI.