Paola Arimondo

Epigenetics defines when and where genes are expressed. Epigenetic marks are reversible and inheritable, integrate the impact of the environment and provide cellular plasticity. Aberrant epigenetic patterns are involved in tumor formation, maintenance and resistance. Notably, epigenetic modifications can be modified by chemical agents. In this context, we developed an original approach at the interface of Chemistry and Biology to identify new inhibitors of DNA methylation. We have successfully used several chemical strategies (rational drug design, pharmacomodulation, chemical library screening) and set up biological assays to characterize the cellular consequences induced by these inhibitors in cancer cells. Our findings encouraged us about the role of DNA methylation in tumor aggressiveness and the ability of epigenetic drugs to reprogram cancer cells.

The Research Unit dedicated to Epigenetic Chemical Biology (EpiChBio) focus on

• the design of chemical molecules targeting DNA and histone methylation,
• their use as probes to scan the molecular process that deregulate these modifications in cancer and
• their use as potential therapeutic agents to reprogram gene regulation in cancer cells.

A precise elucidation of why the methylation processes is aberrant in cancer is the key to a better understanding of the disease and to fight it. The understanding of these processes will open the way to the discovery of novel anti-cancer targets, eventually also biomarkers, and innovative therapeutic strategies.

The project objective is the design, the preparation and the use of chemical inhibitors of the methylation modifications as probes of the whole process. The attention will focus in particular on cancer aggressiveness and resistance. This strategy will be validated in metastatic melanoma, very aggressive tumors showing highly invasive and chemoresistant features that could be reversed by epigenetic reprogramming.

This interdisciplinary approach combines Medicinal Chemistry, Pharmacology, Molecular Biology, Biophysics, Chemical Biology and Cellular Biology.

Dr. Paola B. Arimondo works at the interface of Chemistry and Biology and develop original chemical tools able (i) to elucidate, at the molecular level, the biological mechanisms that are aberrant in human diseases and (ii) to target these mechanisms aiming at novel therapeutic strategies. She studied Chemistry at the University of Pisa (Scuola Normale Superiore, Italy) and received her Ph.D in Biophysics at the MNHN in Paris. In October 2001, Paola Arimondo was recruited by the CNRS in Paris. Her research focused on the interactions between nucleic acids and proteins and their modulation by small chemical molecules. Initially she developed a strategy to target at a specific DNA site a class of antitumor agents directed against human DNA topoisomerases I and II, resulting in site-specific “DNA scissors”. The strategy was patented and developed in collaboration with a pharmaceutical company, Sigma Tau, Italy. After a six-month sabbatical in 2005 at the University of California in Berkeley, she initiated a new project developing an innovative antitumor strategy aiming at the epigenetic control of gene expression in cancers. In 2011, Paola Arimondo was recruited to lead the Laboratory of Epigenetic Targeting of Cancer (ETaC) USR3388, a joint public-private Laboratory between the CNRS and Pierre Fabre Laboratories, in Toulouse, France. ETaC research projects spanned from the chemistry of the natural products to the discovery of chemical modulators of DNA methylation in cancer. Under her leadership the ETaC laboratory in Toulouse has discovered novel potential drugs and biomarkers. In 2016-2017 she was Oversea Fellow of the Churchill College, Cambridge, UK. In January 2018 she start a new Research Unit Epigenetic Chemical Biology (EpiChBio) at the Institut Pasteur dedicated to the design and use of novel chemical tools to study the molecular mechanisms underlying the aberrant methylation in cancer cells towards a better understanding of the disease and how to target it.   The Institut Pasteur offers a unique integrated research frame from microbiology to cancer, from chemistry, structural biology to cellular biology and in vivo experiments. The chemical tools I develop will bring an alternative approach to address the biological questions and, in return, their knowledge and expertise in biology will be a certain asset for our research.