The Radiation Research Society has bestowed its highest honor — the Failla Memorial Lecture Award — on Michael B. Kastan, MD, PhD, executive director of Duke Cancer Institute and William and Jane Shingleton Professor, Pharmacology and Cancer Biology.
Kastan is the 59th recipient of the Failla Award, which is given annually in the form of an engraved plaque, gold medal and cash award, to “an outstanding member of the radiation research community in recognition of a history of significant contributions to radiation research.” The award was established in 1962-1963 to honor the late Gioacchino Failla, ScD, one of the founding fathers of the Radiation Research Society and its second president.
A pediatric hematologist-oncologist and renowned cancer biologist, Kastan delivered his award lecture “DNA Damage Responses: Bedside to Bench to Bedside” during the first evening of the 68th Annual International Meeting of the Radiation Research Society, held October 16 to 18 in Hawaii. His lecture was followed by a reception and dinner in his honor.
Kastan reported a number of seminal discoveries in a series of papers published in 1991-1992 demonstrating that the protein p53, the most commonly mutated gene in human cancers, is a critical mediator of how cells respond to DNA damage. The protein regulates the growth and death of cells after DNA damage and is a critical determinant of whether cells turn into cancer. The papers reporting these discoveries, which included the linkage of the cancer susceptibility gene, ATM, to the activation of p53, were among the most highly cited papers in the scientific literature in the decade of the 1990’s. These discoveries established the initial biochemical steps in what’s now known as the “DNA Damage Response pathway” and have had a major impact on our knowledge of how cancers develop and how they respond to chemotherapy and radiation therapy.
“An unbiased review of his credentials and nominating letters found Dr. Kastan to be deserving of our highest award — serving testament to his accomplishments among his scientific peers. The award was richly deserved based on his career accomplishments in the field of radiation- and cancer biology,” wrote University of California Irvine radiation biologist Charles Limoli, PhD, in an email. Limoli is past president of the Radiation Research Society and served as chair of the committee that awarded the Failla to Kastan. (Committee members nominate candidates for the award and these nominees are combined with candidates nominated by the membership to form a final roster from which the recipient is selected.)
Kastan discussed, in his Failla Memorial Lecture, the history of the elucidation of the DNA Damage Response pathway and how studying the hereditary cancer predisposition syndromes Ataxia-Telangiectasia (which impacts the nervous system and immune system) and Li Fraumeni Syndrome informed his discoveries.
“This pathway is a critical mediator of both tumor development and tumor responses to chemotherapy and radiation therapy,” he explained. “Much of what we have learned about these signaling pathways has come from the study of human diseases, particularly cancer predisposition syndromes, representing classic examples of ‘bedside to bench’ research. ATM, the gene mutated in the cancer-prone, radiosensitive disorder, Ataxia-telangiectasia, is a protein kinase that is a central mediator of responses to DNA double-strand breaks in cells. Once activated, ATM phosphorylates numerous substrates in the cell that modulate the cell’s response to DNA damage. Many of these substrates, including p53, NBS1, BRCA1, CHK2, FANCD2, HDM2, and others, are also known inherited cancer susceptibility genes. Mutations in any of these genes contribute to cancer development via a variety of mechanisms.”
The focus of the Kastan Laboratory continues to be elucidation of the molecular and biochemical mechanisms of cellular stress responses. Kastan’s insights into radiation-induced DNA damage signaling have led to the development of novel cancer therapies and improved treatment approaches, including those homegrown at DCI.
Kastan has co-founded two start-up companies aimed at developing novel radiation therapeutics. One was started in collaboration with former mentee DCI radiation oncologist David Kirsch, MD, PhD (the Barbara Levine University Distinguished Professor, professor of Radiation Oncology and professor of Pharmacology and Cancer Biology) and the other was started in collaboration with Bruce Sullenger, PhD (Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery, professor of Surgery, professor of Pharmacology and Cancer Biology, and professor of Neurosurgery), whose translational research lab focuses on RNA based therapeutic agents.
Mark Dewhirst, DVM, PhD, Gustavo S. Montana Distinguished Professor Emeritus of Radiation Oncology at Duke and former vice director for Basic Science at Duke Cancer Institute, received the Failla Memorial Lecture Award in 2008. (His talk: “Exploring Oxidative Stress and HIF-1 in Early Angiogenesis and Response to Radiotherapy and Chemotherapy.”)
“Of all of the contemporaneous scientists who are engaged in the study of radiation biology, I cannot think of another that meets his level of accomplishments. His discovery of the role of ATM/P53 in DNA damage repair set the stage for the whole field of the DNA damage response pathway. Many of our members are engaged in research that directly benefitted from his pioneering work,” Dewhirst wrote in his letter nominating Kastan for the award. “Dr. Michael Kastan is among the elite radiation scientists of all time.”
Dewhirst wrote that Kastan’s “advocacy of the broadest ranges of cancer research and confidence in those involved drives creativity and success” at Duke Cancer Institute, and he also drew attention to Kastan’s “active role in mentoring the next generation of radiation researchers,” noting that the majority of his 70+ mentees remain active in academic medicine or the pharmaceutical industry.
Dewhirst and Kastan are the only two from Duke to have received the Failla Award in its nearly 60-year history.
Lecture attendee Omar Mian, MD, PhD, radiation oncologist with the Cleveland Clinic Lerner Research Institute specializing in genitourinary malignancies, posted photos of Kastan's Failla Award lecture on Twitter, and commented, "An amazing body of work spanning 30+ years and going strong."
Kastan earned his MD/PhD from Washington University School of Medicine in St. Louis in 1984 and did his clinical training in Pediatrics and Pediatric Hematology-Oncology at Johns Hopkins University. He was a professor of Oncology, Pediatrics, and Molecular Biology at Johns Hopkins prior to becoming chair of the Hematology-Oncology department and later Cancer Center Director at St. Jude Children's Research Hospital. He was recruited to Duke in 2011 to lead DCI.
Kastan is an elected member of the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences, and was recipient of the AACR-G.H.A. Clowes Memorial Award. He has served as chair of the Board of Scientific Counselors of the National Cancer Institute (NCI), and on the Boards of Directors of the American Association for Cancer Research (AACR) and the American Association of Cancer Institutes (AACI), and serves on the advisory boards of numerous cancer centers and foundations. He was the founding editor-in-chief of the AACR journal Molecular Cancer Research and editor of the textbook Clinical Oncology.