Scott Lowe, PhD
Sloan-Kettering Institute for Cancer Research
Research Project: Targeting p53 Mutations in Pancreatic Ductal Adenocarcinoma
Award: 2018 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2018 – June 30, 2020
Dr. Lowe is professor and chair of the cancer biology and genetics program at Sloan Kettering Institute in the Memorial Sloan Kettering Cancer Center. He earned his BS from the University of Wisconsin, and then conducted his doctoral and postdoctoral studies at Massachusetts Institute of Technology. The Lowe laboratory is interested in understanding how the genetic alterations in cancer cells contribute to tumorigenesis (tumor formation), alter treatment response and create vulnerabilities that may be targeted therapeutically. For his work, Dr Lowe has received several awards, including the American Association for Cancer Research (AACR) Outstanding Investigator Award, the AACR Clowes Award and the Paul Marks Prize, and has been elected into the American Academy of Arts and Sciences and the National Academy of Sciences.
The second most commonly altered gene in pancreatic cancer is p53, with more than 70 percent of patients having mutations that disrupt its function as “guardian of the genome.” As guardian of the genome, p53 functions as a tumor suppression gene that prevents DNA damage and blocks the growth and division of cells with mutations. Decades of research have shown that p53 is one of the strongest barriers to tumorigenesis. This is due to the vast number of functions that p53 coordinates, ultimately orchestrating a powerful anti-tumor response. Despite its importance, there are no therapies that capitalize on our knowledge of p53, partly because p53 mutations are currently undruggable, diverse in nature and capable of permanently stopping normal p53 function.
Dr. Lowe’s proposal is built on the idea that effective therapeutic strategies for pancreatic cancer must target its genetic drivers (genes responsible for cancer formation). His research group is in an ideal position to advance this goal as they have recently found that inhibiting specific proteins’ activity can prevent cancer cell division and mimic restoration of normal p53 function or inactivation of mutant p53. They have developed models that reproduce the human disease and have established genetic tools that allow for systematic inactivation of candidate molecules to facilitate their search for potential drug targets. They have also optimized new technologies to indicate vulnerabilities of pancreatic cancer tumors, such that the specific molecules responsible for cancer maintenance can be identified.
Dr. Lowe and his colleagues now advance these concepts and tools to study how mutations in p53 cause disease and contribute to the survival of pancreatic cancer cells, with the goal of testing therapeutic strategies to mimic the tumor-suppressive effects of normal p53 function and block the tumor-promoting function of mutant p53. They will use this information to define strategies to develop more effective treatment options.
Beyond leveraging their long-standing expertise on p53, this project takes advantage of the resources of Memorial Sloan Kettering Cancer Center to expedite the project and establish relevance to the human disease. Dr. Lowe expects their studies will produce information of broad relevance to the pancreatic cancer research and clinical communities, and define new drug targets and response biomarkers relevant to the large fraction of pancreatic cancer patients with p53 mutations.