Yves Pommier, M.D., Ph.D.
Yves Pommier, M.D., Ph.D., a molecular pharmacologist who has done pioneering work on the mechanisms of topoisomerase and PARP inhibition as well as on the discovery of novel biomarkers for anticancer drug responses, is announcing his retirement after 45 years at the NIH.
Pommier grew up in Caen, France, near the famed World War II beaches of Normandy. He did his medical school training there before moving to Paris for his residency in hematology/oncology. “It was very fortunate that the chair of my school in France was a good friend of Bruce Chabner, who was the Director of what was then called the Division of Cancer Treatment at NCI. My Parisian chair and Bruce started a little program where they selected two or three students a year to come to the U.S. who they thought would be the future of academia in France. So, my chair got me involved, got me connected to come, and Bruce was my first mentor,” said Pommier.
Early in his NCI career, with Kurt Kohn, M.D., Ph.D., and others, Pommier helped discover how topoisomerase inhibitors work and expanded the understanding of how bioregulatory networks operate. “It was such an exciting time, and I was so happy at NIH that I just couldn't go back to Europe. They wanted me to come back to Paris, but I had too much pleasure doing what I was doing here.”
For the past four decades, Pommier has been a leader in the field of DNA topoisomerase biology, biochemistry, molecular pharmacology and its cancer relevance. As chief of the Developmental Therapeutics Branch, he has overseen the branch’s clinical/translational research program, which emphasizes new approaches to cancer treatments targeting DNA and connected biomarkers.
Pommier is internationally recognized for the discovery and development of topoisomerase I (TOP1) inhibitors. He discovered indenoisoquinolines as novel TOP1 inhibitors and the mitochondrial topoisomerase gene, TOP1mt. Three of his TOP1 inhibitors are in phase 1/2 clinical development and all show potent activity in Comparative Oncology Trial Consortium clinical studies and in patient-derived xenograft models of triple-negative breast cancers.
To understand the determinants of response to topoisomerase inhibitors, he studied the repair pathway centered on tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2) and poly (ADP-ribose) polymerases (PARP).
To help advance finding the best treatments for each patient, he developed a tool called CellMiner to perform genomic analyses in patient-derived cancer cell lines. While developing these tools, Pommier discovered the broad relevance of an interferon-inducible gene, Schlafen 11 (SLFN11), which has become one of his latest contributions. He recently showed its inactivation in approximately 50% of patient-derived cell lines and tumors and how the gene irreversibly arrests the replication of cells with replicative DNA damage while stabilizing proteins.
Pommier received an NIH Merit Award in 1992 as well as three NIH Director’s Awards since 2011. Over the course of his career, he has authored over 800 publications and holds over 30 patents for inhibitors of DNA topoisomerases, tyrosyl-DNA phosphodiesterase, checkpoint inhibitors and HIV-1 integrase. He has mentored over 60 postdoctoral fellows, Howard Hughes Medical Institute trainees, graduate students, and students who went into medical and scientific academic positions as well as pharmaceutical and editorial careers.
In the Q&A that follows, Pommier discusses the work he has performed over the years and advice he has for others interested in working at NCI.
Throughout your career, what scientific achievements are you most proud of?
I helped conceptualize the "interfacial inhibitors" mechanism based on our finding that DNA topoisomerase inhibitors act by trapping topoisomerase-DNA complexes. This led, in part, to the elucidation of the repair pathways for topoisomerase-induced DNA damage. We made the landmark discovery that PARP inhibitors act as anticancer agents by trapping PARP-DNA complexes and established that clinical PARP inhibitors differ among each other in their ability to trap PARP.
I was given PARP inhibitors to study because I am a molecular pharmacologist — and that's how we discovered “PARP trapping.” It's a term I coined, which is now accepted and used worldwide. PARP trapping is essentially a mechanism by which PARP inhibitors induce DNA damage and prevent DNA repair, replication and transcription in cancer cells by "locking" PARP1 and PARP2 enzymes at sites of DNA damage, ultimately leading to cell death. The ability of PARP inhibitors to trap PARP is a key determinant of their efficacy as anticancer drugs.
This discovery has totally changed PARP inhibitor drug development, because initially they were given as just enzymatic inhibitors. But what we discovered is they were trapping the PARP enzyme on DNA and making DNA-protein crosslinks. When we first reported this finding, it was considered heretical. Nobody liked it as gentle PARP inhibitors were what was preferred. We said, “No, these things are not gentle; they are damaging replicating DNA.”
Another thing I'm known for now is Schlafen 11 (SLFN11); we discovered the activity of this gene because of CellMiner, and it was just a correlation initially. But then we discovered it was causal with response to a broad range of chemotherapeutic agents attacking DNA replication. It's taking off pretty strongly in the clinic as a biomarker and in basic research, and as a medical doctor, it is a goal to help achieve precision medicine. But topoisomerases and molecular pharmacology are really my home base.
Do you have any advice for those looking to a career at NIH? Or why you’ve stayed at NCI for over 4 decades?
I think NIH is a unique institution. Over the many years that I've been here, the extramural program (universities, medical centers and other institutes that are funded by NIH) has grown beautifully. Another valuable part of NIH for me is that the non-grant, intramural system allows us to switch from one project to the next. We can seamlessly translate our research from the bench to the bedside.
NCI has just a different atmosphere. We don't need to compete for grants, so we can spend time working together. Many innovative ideas were launched here and are still launched here. Our core facilities are outstanding. We need that for the patients, and for the science.
What are you looking forward to most in your retirement?
My wife's family had a family home in Burgundy, so we moved from Normandy to Burgundy where we built a house years ago, so I'd like to spend time there. I still have a lot of good friends from medical school in France, and I still have good connections with people I’ve been collaborating with. I love the USA, my adoptive country. My two sons were born here and are working near Washington, D.C., and I will also spend time in Bethesda.
My last name in French translates to “apple tree.” At my house in Burgundy, I’ve planted an orchard with special apple trees to make cider. I have purchased the barrel and the press, and I'd like to make cider again as I did when I was a kid. So, I'll spend some time making cider, drinking and inviting people and colleagues to visit and toast to a long, wonderful career at NCI.
Dr. Yves Pommier will retire from CCR on July 14, 2025, Bastille Day, but will remain as an NIH Scientist Emeritus.