Pier Paolo Pandolfi

Pier Paolo Pandolfi de Rinaldis, M.D. (born May 14, 1963 in Rome, Italy) Pier Paolo Pandolfi received his M.D. in 1989 and his Ph.D. in 1995 from the University of Perugia, Italy, after having studied Philosophy at the University of Rome, Italy.  He received post-graduate training at the National Institute for Medical Research and the University of London in the UK.  He became an Assistant Member of the Molecular Biology Program and the Department of Human Genetics at Memorial-Sloan-Kettering Cancer Center in 1994.  Dr. Pandolfi grew through the ranks to become a Member in the Cancer Biology and Genetics Program at the Sloan Kettering Institute; Professor of Molecular Biology and Human Genetics at the Weill Graduate School of Medical Sciences at Cornell University; Professor, Molecular Biology in Pathology and Laboratory Medicine, Weill Medical College at Cornell University; and Head of the Molecular and Developmental Biology Laboratories at MSKCC. Dr. Pandolfi was also the incumbent of the Albert C. Foster Endowed Chair for Cancer Research at Memorial Sloan-Kettering Cancer Center.

Dr. Pandolfi presently holds the Reisman Endowed Chair of Medicine, and is Professor of Medicine and Pathology at Harvard Medical School (HMS). He joined the HMS faculty at Beth Israel Deaconess Medical Center (BIDMC) in 2007 to serve as Scientific Director of the Cancer Center, the Director of the Cancer Genetics Program, and the Chief of the Division of Genetics in the Department of Medicine; he is also a Member of the Department of Pathology at BIDMC. He was recently appointed to serve as the Cancer Center Director and the Director of the Cancer Research Institute at BIDMC and HMS.

Research

The research carried out in Dr. Pandolfi’s laboratory has been seminal to elucidating the molecular mechanisms and the genetics underlying the pathogenesis of leukemias, lymphomas and solid tumors as well as in modeling these cancers in the mouse. Dr. Pandolfi and colleagues have characterized the function of the fusion oncoproteins and the genes involved in the chromosomal translocations of acute promyelocytic leukemia (APL), as well as of major tumor suppressors such as PTEN and p53, and novel proto-oncogenes such as POKEMON.  The elucidation of the molecular basis underlying APL pathogenesis has led to the development of novel and effective therapeutic strategies. As a result of these efforts, APL is now considered a curable disease. Additional novel therapeutic concepts have emerged from this work and are currently being tested in clinical trials. More recently, Dr. Pandolfi and colleagues have presented a new theory describing how mRNA, both coding and non-coding, exerts their biological functions with profound implications for human genetics, cell biology and cancer biology. 

APL Module: Discovery of APL fusion genes, modeling APL in mice, developing cures through models

While a last year medical student, Pandolfi was fortunate enough to clone and characterize PML-RARa, the product of the long sought after t(15;17) chromosomal translocation of acute promyelocytic leukemia (APL), and its normal counterpart PML (at that time called myl and subsequently renamed PML). Since then, Pandolfi's lab deconstructed the genetics and molecular complexity underlying APL, in turn discovering that several molecular subtypes of APL exist, which respond differentially to treatment. The Lab went on to model these APL subtypes in the mouse and to optimize APL treatment using these faithful mouse models. As a result APL is considered cured and combinatorial treatments are available for each APL subtype. The Lab further discovered that the genes of APL are frequently implicated in the pathogenesis of human cancer at large, beyond their involvement in APL, by acting as tumor suppressor genes (TSGs). The TSGs of APL, their role in human cancer, and the development of therapies to target their pathways is a current main focus of Pandolfi's research.

PML Module: Developing new therapeutic opportunities for the treatment of leukemia and solid tumors

PML is involved in 98% of APL cases, where it is found translocated to the RARa gene. It is therefore undoubtedly the tumor suppressor gene of APL. However, PML is also frequently lost in other forms of human cancer and regulates a number of key tumor suppressive pathways. It epitomizes a macromolecular multi-protein sub-nuclear structure, which depends on PML to properly form the PML Nuclear Body, but it also exerts critical cytosolic functions. Of importance, the Pandolfi Lab recently and surprisingly discovered that targeting PML for therapy affects the maintenance of tumor and leukemia initiating cells in turn paving the way to novel therapeutic modalities with PML targeting drugs for the eradication of cancer/leukemia initiating cells.

Development and Cancer Module: NPM, PLZF and POK transcription factors

The Pandolfi Lab has a long-standing interest in testing the hypothesis that fundamental developmental processes are deregulated in cancer. The analysis of the genes of APL and their associated proteins proved to be a terrific ground to test this hypothesis, as exemplified by PLZF and BCL6, members of the POZ and Kruppel (POK) family of transcriptional repressors. PLZF is the second most frequent RARa partner in APL associated chromosomal translocations, while BCL6 was identified by virtue of its involvement in chromosomal translocations in Non-Hodgkin's lymphoma. Pandolfi has shown that both PLZF and BCL6 play critical roles in development and cancer. Their interest in PLZF and BCL6 has more recently allowed for the identification of POKEMON (for POK, Erythroid, Myeloid ONtogenic factor), also a member of the POK family, as a key player in tumorigenesis and developmental control. Another relevant example is represented by NPM1, also a partner of RARa in APL-associated translocations, which also proved to act as an essential developmental gene. The role of developmental pathways and genes in tumorigenesis represents a major focus of the Pandolfi lab.

Pten Module: Characterizing and modeling the in vivo role of tumor suppressor phosphatases

The PTEN phosphatase is the most frequently mutated, deleted, silenced and down-regulated tumor suppressor in the post-p53 era. A key and rate-limiting enzyme that exerts essential tumor suppressive functions in tumors of various histological nature. PTEN is of great interest to the Pandolfi Lab because it antagonizes the PI3-kinase pathway, which, in turn, impacts on control of mRNA translation initiation. Regulation of this axis as well as ribosome biogenesis control, as driving forces underlying the neoplastic process represent a main focus of our research. The analysis of the role of PTEN in tumor suppression led to novel fundamental concepts in tumor biology and genetics and to novel synthetic lethality approaches for cancer treatment (e.g. pro-senescence therapy for cancer).

Competing endogenous RNAs (ceRNAs) Module: a new function and language for ncRNAs

Non coding RNAs (ncRNA) have emerged as a new exciting component of the mammalian transcriptome. miRNAs, linc-RNAs, pseudogenes and circRNAs vastly outnumber the protein coding mRNA dimension. Linear and circular ncRNAs have already been proven to be of critical functional relevance by many groups, both in in vitro as well as in vivo in mouse models. More recently the Pandolfi Lab has proposed and are currently testing, a new working hypothesis whereby linear and circular RNAs cross-talk through competition for shared miRNAs hence regulating each other in trans, by acting as “competing endogenous RNAs” (ceRNAs). This in turn attributes a putative and uncharacterized RNA dependent function to protein coding and non-coding linear RNAs as well as to circRNAs. Importantly, this allows us to bioinformatically predict and experimentally validate which ceRNA might cross-talk with other ceRNAs in a given cell type, on the basis of a new “language” or code, made of shared miRNAs response elements (MREs).

Awards

Dr. Pandolfi also has been awarded the NIH MERIT Award for superior competence and outstanding productivity in research in 2005. In 2006, Dr. Pandolfi was elected as a member of the American Society for Clinical Investigation (ASCI) and the American Association of Physicians (AAP), and in 2007 as Member of the European Molecular Biology Organization (EMBO).

In 2011, Dr. Pandolfi received the Pezcoller Foundation–AACR International Award for Cancer Research. He was also awarded the Scanno International Award for Medicine in 2012, the Pomilio Ethic International Award in Biomedicine, the European Foundation Guido Venosta Award for Cancer Research in 2013, and the America International Award in 2014.

On June 2, 2015, Dr. Pandolfi was Knighted by the President of the Italian Republic and received the Medal of Honor as “Officer of the Order of the Star of Italy” (Ufficiale dell'Ordine della Stella d'Italia). In 2015 Dr. Pandolfi has also received the prestigious Outstanding Investigator Award from the NIH/NCI

External links

Publications

A complete list of work can be found on Dr. Pandolfi's PubMed page: http://www.ncbi.nlm.nih.gov/pubmed/?term=pandolfi+pp

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