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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.<\/p>\n
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. \u201cHR is incredibly complex,\u201d Dr. Sung said. \u201cThere 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.\u201d<\/p>\n
He has discovered how using these back-up pathways can lead to malignancy. \u201cThe 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,\u201d Dr. Sung says. These errors lead to the mutations that can cause a normal cell to become cancerous in the first place. \u201cCancer 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.\u201d<\/p>\n
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.<\/p>\n
\u201cWe 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.\u201d Understanding DNA repair function, he says, is sometimes like looking for a diamond: \u201cYou 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.\u201d<\/p>\n
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 \u201cdirty\u201d breaks more closely resemble the DNA breaks that occur in nature. \u201cWe found that humans cells have several of these break processing enzymes,\u201d Dr. Sung said. \u201cWe 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.\u201d Cancers use this \u201cdirty break\u201d repair machinery commonly. This creates the opportunity to develop chemical compounds that selectively inhibit each of the break processing mechanisms as novel cancer therapeutics.<\/p>\n
Dr. Sung described two ways of shutting down the back-up repair pathway to kill the HR-deficient cancer cells: \u201cYou need to understand the function and structure of the key proteins involved, and we\u2019re 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.\u201d 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\u2019s 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.<\/p>\n
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. \u201cI think impact on our research enterprise will be tremendous if we do it right,\u201d he says. \u201cOnce the basic research is in place, the translation will be very, very robust down the line. I\u2019m in the enviable position of helping shape how science is done on this campus. That\u2019s why I came.\u201d<\/p>\n
As his basic science uncovers just how the gene repair engine works, it will also identify biomarkers to help clinicians better treat their patients. \u201cPhysicians 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.\u201d<\/p>\n
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. \u201cIf 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\u2019s the driving force.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"
The laboratory of Patrick Sung, D.Phil., a world-renowned biochemist, is battling cancer by unraveling defects in repair pathways that fuel the disease. <\/p>\n","protected":false},"author":43,"featured_media":1937,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[12],"magazine":[22],"issue-year":[45],"featured-story":[37],"class_list":["post-1910","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-research","magazine-future","issue-year-45","featured-story-landing-page"],"yoast_head":"\n