The Program Project includes an accomplished group of investigators who are leaders in their specific fields. The Principle Investigator responsible for the overall Program is Carol Prives. She is responsible for the coordination of the research and interactions between the program members, monitoring the progress, finances and interactions with the National Cancer Institute. In this third renewal of our grant, our Program is led by 6 PIs. Carol Prives (Project 1 and Core A), Brent Stockwell (Project 2), John Petrini (Project 3), Scott Lowe (Project 4), Arnold Levine (Core B), and Carlos Cordon-Cardo ( Core C). Core A is required to maintain the organizational structure of the program, while Cores B and C reflect the expertise of their respective leaders and supply needed computational support (Core B) and molecular histopathology (Core C) to all members of this program. Prives together with Stockwell, Petrini, Lowe, Levine, and Cordon-Cardo form the Executive Committee and Internal Advisory Board. In addition, this program has an outstanding External Advisory Board, whose members will serve as consultants and provide feedback on the different projects. Additional collaborators and advisors on individual projects are also part of this program.
Carol Prives, Ph.D. (PI, Project 1, Core A) is the DaCosta Professor of Biology at Columbia University and an American Cancer society Professor. She has combined biochemical and cell biological approaches that have illuminated many aspects of p53 structure and function. She was the first to purify biochemically tractable quantities of p53 and her work revealed that p53 could serve as a sequence specific transcriptional activator. This finding set the stage for the discovery by many groups of p53 target genes. Dr Prives’ work also led to the findings that DNA damage signals result in phosphorylation of p53 that weakens its interactions with Mdm2, a finding that provided the basis for understanding how p53 is stabilized after DNA damage. Her work has also provided insight into the properties of tumor-derived mutant forms of p53 including the roles that they play in regulation of oncogenic pathways. Dr. Prives, a member of the National Academy of Sciences, serves on several editorial boards including Cell, Genes & Development, PNAS and Oncogene. She has been a member and chair of the Experimental Virology and the Cell and Molecular Pathology Study Sections and has also served on the Internal Advisory Board of the NCI.
Brent R. Stockwell, Ph.D. (PI, Project 2) is a Professor at Columbia University in the Departments of Biological Sciences, Chemistry, and Systems Biology; he is also a member of Columbia’s Herbert Irving Comprehensive Cancer Center, Motor Neuron Center, Stem Cell Initiative, Translational Neuroscience Initiative, and Institute for Data Sciences and Engineering. He serves as Director of the Columbia NYSTEM Chemical Probe Synthesis Facility, and co-Director of the Columbia High-Throughput Screening Center. His research involves the discovery of precision medicines that can be used to understand and treat cancer, with a focus on mechanisms governing cell death. These interdisciplinary investigations have led to new methods of small molecule drug discovery, and the discovery of drug candidates that act through a new form of cell death he discovered, termed ferroptosis. Professor Stockwell has received numerous awards, including a Burroughs Wellcome Fund Career Award at the Scientific Interface, a Beckman Young Investigator Award, the BioAccelerate NYC Prize, the Lenfest Distinguished Columbia Faculty Award and the Great Teacher of Columbia College Award from the Society of Columbia Graduates. He co-founded the biotechnology company CombinatoRx Incorporated in 2000, and is the author of The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines. Dr. Stockwell has over 20 years of experience studying cell death mechanisms related to cancer using small molecules. His research has led to multiple clinical trials of drug candidates (8 drug candidates at CombinatoRx/Zalicus, PRLX93936 at Prolexys Pharmaceuticals).
John Petrini Ph.D. (PI, Project 3) is a Member of the Molecular Biology Program and Director of The Functional Genomics Initiative at Memorial Sloan Kettering Cancer Center. Dr. Petrini has made major contributions toward understanding the response to chromosome breaks in eukaryotic cells, and has been a leader of this field for nearly two decades. This response is mediated by a functional network comprising pathways that govern DNA repair, DNA damage dependent cell cycle regulation, and programmed cell death (hereafter, the DNA damage response—DDR). His work has illuminated the fundamental mechanisms of each of the major DDR pathways, as well as their links to tumor suppression and organismal development. Many of Petrini’s contributions are founded on his identification of the human Mre11 complex, consisting of Mre11, Rad50, and Nbs1. The Mre11 complex, as well as other mediators and mechanisms that make up the DDR are evolutionarily conserved, and a distinguishing feature of his research program is the fact that Petrini’s lab integrates data from yeast, mice, and human cells, taking advantage of strengths attendant to each system to obtain biological insight. He was responsible for the isolation of each subunit of the human complex, and based largely on his genetic characterization of this complex in mammals and yeast, we now understand that it influences all aspects of the DDR network. In his work, Petrini has analyzed DDR functions in physiological contexts, founding his interpretations on the basis for the evolution of the DDR network and its roles in vivo.
Scott W. Lowe, Ph.D. (PI, Project 4) is a Member and Chair of the Cancer Biology and Genetics Program in the Sloan Kettering Institute at the Memorial Sloan Kettering Cancer Center and serves as an Associate Director for Basic Cancer Research. He is also an Investigator in the Howard Hughes Medical Institute. Dr. Lowe’s previous work resulted in important contributions to our understanding of the p53 tumor suppressor pathway and the process of multi-step carcinogenesis. He was the first to show p53 could induce apoptosis in reponse to oncogenes and DNA damaging agents, and established the phenomenon of “oncogene-induced senescence” as a tumor suppressive mechanism. He made fundamental contributions to our understanding of programmed cell death as an innate anti-tumor mechanism and as a response to chemotherapy. He has pioneered the use of mouse models to evaluate the relationship between genotype and therapy response. Most recently, he has developed powerful genetic, genomic and animal modeling tools to characterize novel cancer drivers and dependencies, producing new insights into tumor suppressor networks and validating novel cancer targets that have stimulated clinical trials. Over the last funding cycle, his work on this project has documented non-cell autonomous mechanisms whereby p53 can suppress tumor growth, identified a druggable mechanism of mutant p53 action in promoting metastasis in ductal pancreatic adenocarcinoma, and established an important role for p53 in limiting plasticity during tumorigenesis. Dr. Lowe serves on several Cancer Center advisory boards as well as the Editorial Board of Cell and Cancer Cell. He also has won several awards for his innovative research. Dr. Lowe has been a member of this program since he was an Associate Professor at Cold Spring Harbor Laboratory; the work performed under the auspices of this P01 has been central to his research program.
Arnold Levine, PhD, (PI, Core B) is Professor of Natural Sciences at the Institute for Advanced Study, (IAS) Princeton NJ and Professor of Pediatrics and Biochemistry at the Cancer Institute of New Jersey, at the Robert Wood Johnson Medical School, Brunswick, NJ. He discovered the p53 protein, and demonstrated its association with the oncogenic products of 3 major DNA tumor viruses (SV40, Adenovirus and Human Papillomaviruses). Levine showed that p53 binds to the Mdm2 oncoprotein, and forms an autoregulatory loop with Mdm2. His mutational analysis of the p53 protein provided insight into its transcriptional activation functions. He was the first to provide experimental evidence in a xenograft mouse model that tumor derived mutant forms of p53 have pro-oncogenic activities. More recently, he has investigated the role of Single Nucleotide Polymorphisms (SNPs) in the p53 pathway and discovered a SNP in the human Mdm2 promoter that results in high expression of Mdm2 and dampened p53 response and showed that some cohorts of individuals with the high Mdm2 expression allele have earlier onset of cancers. His recent work also revealed that p53 regulates fertility in mice and humans. Dr Levine, a member of the National Academy of Sciences, has received, major awards for his contributions (eg. Bristol Myers Squibb, General Motors Mott Prize, the ACS Medal of Honor and others), and has served on many editorial and advisory boards.
Carlos Cordon-Cardo, M.D., Ph.D. (PI, Core C), is Chair of Pathology at Mt Sinai School of Medicine. Dr. Cordon-Cardo is internationally recognized for his studies on experimental pathology and molecular oncology, particularly his investigations of mouse models of cancer. His work revealed roles of p53 and PTEN in tumor suppression in bladder and other cancers and their relevance to patient survival. He has developed new approaches to systems pathology, and his studies on expression profiling using high throughput microarrays led to providing new insights into the molecular classification of certain solid tumors, including bladder cancer. His unique expertise in mouse onco-pathlogy has also been invaluable for collaborative efforts with leading cancer researchers including, most relevantly, Scott Lowe. In addition, he developed a mouse model for bladder carcinoma and demonstrated its relevance to human cancer particularly genitourinary malignancies. Dr Cordon-Cardo is a member of the WHO Collaborating Centers for Urologic Tumors (Sweden), member of the State Legislative Committee of the AACR, Chair of Translational Research of the Genitourinary Section of Southwest Oncology Group (SWOG), was President for the Solid Tumor Chapter of the Association for Molecular Pathology (2000), and member of the Review Committee for Cancer Centers and Research Programs of the National Cancer Institute (1995-2001).
We have assembled an outstanding group of advisors of our program. They will provide support, advice, reagents and collaborations as needed. The previous advisory Board consisted of Dr Tyler Jacks, Gerry Melino, Moshe Oren, Ute Moll, Matt Myerson and Uri Alon. We restructured the external SAB, reflecting the current directions of our program, to comprise the following 8 members:
Charles Sherr, MD, Ph.D. is Chair Dept. of Tumor Cell Biology, Howard Hughes Medical Institute, St. Jude Children's Research Hospital. Dr Sherr will serve as Chair of our Scientific Advisory Board. He is well known for his seminal work on G1 cell cycle regulators, and the INK4-ARF locus and their relationship to p53 and Mdm2. Dr Sherr divides his time between St Jude and MSKCC where he is a visiting investigator. He has attended several of our multi-lab meetings over the past few years and has been a truly invaluable source of advice, comments and suggestions.
Shelley Berger, Ph.D. is the Daniel S. Och University Professor, Departments of Cell & Developmental Biology; Biology; Genetics, and Director, Epigenetics Program University of Pennsylvania: Dr. Berger is an internationally known expert on gene regulation in general and the field of chromatin and epigenetics in particular. She is also an outstanding contributor to the p53 field, and recently published an exciting paper in Nature that was the subject of a News & Views Review by Prives and Lowe.
Dr. Tom Kelly M.D., Ph.D. is Director, Sloan Kettering Division of the Weill Cornell Graduate School of Medical Sciences; and Provost, Gerstner Sloan Kettering Graduate School. Dr Kelly is a world-renowned expert in DNA replication and repair who was the first to establish eukaryotic DNA replication in vitro. He will provide advice and comments for Dr Petrini and other members such as Dr Prives as relevant collaborative projects develop.
Dr. Ute Moll, M.D. is Professor of Pathology and Vice Chair for Research, Stony Brook, NY. Dr Moll, has made significant contributions to our understanding of the p53 family in cancer; mitochondrial apoptosis, p53 localization, and most recently functions of mutant p53. Her work has also illuminated means to treat cancer cells with mutant p53. As such she will provide valuable complementary expertise to Drs Prives, Stockwell and Lowe. She also provides expertise in human breast cancer.
Moshe Oren, Ph.D. is Professor of Molecular Cell Biology and Director of the Leo and Julia Forchheimer Center for Molecular Genetics, at the Weizmann Institute, Israel. Dr Oren has been a long-standing contributor to our understanding of the p53 tumor suppressor protein and the oncogenic roles of mutant forms of p53. He discovered that wild-type o53 is a suppressor of cell growth, and inducer of apoptosis, that Mdm2 targets p53 for degradation, and has made more important contributions to transcriptional regulation mediated by wild-type and mutant forms of p53. He has been an active supporter of this program since its inception.
Tim Osborne, Ph.D. is Professor and Director, Metabolic Disease Program, Sanford- Burnham Medical Research Institute. Dr Osborne provides expertise in cholesterol and fatty acid metabolism and the SREBP transcription factors that regulate the genes involved in these metabolic pathways.
His deep knowledge of this area will contribute to Dr Prives’ research program and will also be helpful to Drs Stockwell and Lowe.
Raul Rabadan, Ph.D. is Associate Professor of Systems Biology and Director of the Center for Topology of Cancer Evolution and Heterogeneity. Dr Rabadan’s work in systems biology will complement Dr Levine’s Core B. Raul has already collaborated with Drs Levine and Prives and his expertise in computational and systems biology is greatly valued for this program.
James Wells, Ph.D. is the Harry Wm. and Diana V. Hind Distinguished Professor of Pharmaceutical Sciences, and Chair of the Department of Pharmaceutical Sciences and Director of the Antibiome Center at UCSF. He is a chemical biologist with deep expertise in protein-protein interactions, post-translational modifications and small molecule discovery screening technologies. He will be an excellent colleague and advisor to Dr Stockwell’s Project 2.
This research is funded by the following projects administered by the National Cancer Institute: 5R01CA058316, 5R01CA077742, 5P01CA087497.
