The Future of Discovery in DNA Repair
Developing Therapies for Cancers Caused by DNA Repair Defects
We live in a world that is trying to kill us—UV light from the sun, aryl hydrocarbons from car exhaust, nitrates in our food, even the oxygen we breath all damage DNA. Unrepaired DNA damage leads to aging organs and cancer. Thus, life can be seen as a race between exposure to myriad environmental toxins and the ability of our cells to repair the DNA damage those toxins cause. Lose this race, and crucial organs such as the liver, lung and bone marrow fail to function, or worse, transform to malignancy.
Nearly 1 percent of the general population inherits defects in DNA repair, some of which are quite serious and lead to a much shorter lifespan and some of which are not even noticed because we have back-up repair pathways. Defects in the homologous recombination (HR) repair pathway are especially deleterious because they can lead to breast, ovarian, pancreatic and prostate cancers. For example, women with an inherited mutation in the HR components BRCA1 or BRCA2 have six-fold higher chance of developing breast cancer. Inherited and acquired mutations in over 15 other HR components can also promote transformation to cancer. Tragically, cancers that derive from defects in HR are often resistant to conventional chemotherapy.
HR is the major pathway to repair and restart stalled DNA replication. Thus, these HR-deficient cancer cells must use a back-up DNA replication repair pathway just to divide. Uncontrolled cell division is the main characteristic of cancer. Blocking these back-up pathways kills the cancers that lack HR by a process called synthetic lethality and has led to a new class of cancer drugs termed the PARP1 inhibitors. PARP1 inhibitors gave new hope for cancer patients who failed to respond to conventional chemotherapy. Unfortunately, the very defect in DNA repair that causes these cancers in the first place leads to a high incidence of mutations that ultimately make the cancer resistant to these drugs. Thus, all patients on these drugs will relapse over time, and new therapies for these cancers are desperately needed.
Patrick Sung, D.Phil., associate dean for research at the Joe R. and Teresa Lozano Long School of Medicine, is world-renowned for discovering the mechanism of a fundamental step in HR repair. At that time, he was searching for a method to reverse DNA damage when repair goes awry. While the hope of reversing DNA damage remains, through the new CRISPR/Cas9 technology, he is currently applying his expertise in HR to understanding how HR-deficient cancers use back-up DNA repair pathways to survive.
HR enables DNA repair in which genetic information is not altered and the DNA is restored to its previous state. Thus, losing HR means that the cell loses the major repair pathway that is completely accurate, and must rely on less accurate pathways, leading to an increase in mutations. “HR is incredibly complex,” Dr. Sung said. “There are probably a hundred different genes involved in the processing of the break and subsequent steps of repairing it, but most of the genes have been identified; I would say at least 90 percent, so we know what the targets are. What we are lagging behind in is our understanding of what exactly these genes are doing.”
He has discovered how using these back-up pathways can lead to malignancy. “The type of tumors we work on are defective in HR, and they mutate very quickly because they use other DNA repair pathways that are more prone to errors,” Dr. Sung says. These errors lead to the mutations that can cause a normal cell to become cancerous in the first place. “Cancer cells use these normally minor pathways to do their repair, so it creates an opportunity to develop compounds that shut down these minor pathways and achieve massive killing of tumor cells. We are employing our knowledge of the biology of these minor pathways to find a solution.”
The basic science of understanding the functions and structures involved in DNA repair in HR-deficient cancer cells will lead to major advances in identifying new targets for synthetic lethal therapies of these cancers, predicts Dr. Sung. These new therapies can be added to the PARP1 inhibitors to extend the life of HR-deficient cancer patients and prevent the development of therapy resistance. For example, Dr. Sung is developing drugs that target RAD51 paralogues and RAD54, important components of back-up DNA repair pathways.
“We know the chromosome can be in a relaxed state that is amenable for repair, or it can be in a condensed state and not amenable for repair. We know some of the DNA repair genes are, in fact, genes that code for enzymes that open up the chromosome structure so that repair can occur.” Understanding DNA repair function, he says, is sometimes like looking for a diamond: “You have to remove a lot of rocks and debris first before you can find it. Then we must understand what they do, how they do it, and how the genes work together to form a complex machine.”
A recent discovery elucidated the role of enzymes that process DNA ends before repair occurs through HR. Rather than studying clean DNA breaks, Dr. Sung and Sandeep Burma, Ph.D., vice chair for research in the Department of Neurosurgery, have found that “dirty” breaks more closely resemble the DNA breaks that occur in nature. “We found that humans cells have several of these break processing enzymes,” Dr. Sung said. “We have learned that each enzyme is capable of processing a certain type of lesion. They are not redundant entities. Each is there to do a specific job.” Cancers use this “dirty break” repair machinery commonly. This creates the opportunity to develop chemical compounds that selectively inhibit each of the break processing mechanisms as novel cancer therapeutics.
Dr. Sung described two ways of shutting down the back-up repair pathway to kill the HR-deficient cancer cells: “You need to understand the function and structure of the key proteins involved, and we’re doing that. Once you know that, you can use the information to define a screen for chemicals that target a specific attribute of that protein. For example, finding a drug that can inhibit a target enzyme activity.” The other way is to find compounds that bind anywhere on the surface of these proteins, not just to the active site, and then create a PROTAC (proteolysis targeting chimera) to degrade that target protein. Dr. Sung’s work in uncovering these targets, along with the PROTAC development work of Robert Hromas, M.D., FACP, medical school dean, combine for a kind of one-two punch in development of translational therapeutics to selectively eliminate cancer cells.
As associate dean for research, Dr. Sung influences decisions like which researchers to hire, how to leverage their skills, and how best to build out a synergistic research infrastructure. “I think impact on our research enterprise will be tremendous if we do it right,” he says. “Once the basic research is in place, the translation will be very, very robust down the line. I’m in the enviable position of helping shape how science is done on this campus. That’s why I came.”
As his basic science uncovers just how the gene repair engine works, it will also identify biomarkers to help clinicians better treat their patients. “Physicians will now know why the same drug may work in some of their patients, but not in others, even when the patients are from the same family.”
Dr. Sung believes that first understanding the function of complex gene repair pathways is essential to develop novel cancer therapeutics and biomarkers of response to known cancer drugs. “If I achieve that, I will consider myself as having a really successful career, and we are getting there, no doubt. You talk to 100 basic scientists, and 99 of them would tell you their motivation is to figure out how things work. There is an innate passion and curiosity. We want to know how nature works. That’s the driving force.”
