Team Julie PANNEQUIN
Signalization, plasticity and cancer
Project Development of Innovative Strategies for Targeting the PXR Nuclear Receptor in the Treatment of Colorectal Cancer
PRINCIPAL INVESTIGATOR
IGF staff involved
Julie PANNEQUIN
DR, CNRS
Lucile BANSARD
PhD, CNRS
Colorectal cancer is the third most diagnosed cancer in the world today; however, treatments often fail in the majority of cases after the onset of metastases. Treatment resistance and tumor relapse are frequently associated with cancer stem cells (CSC). We have demonstrated that the nuclear receptor PXR (NR1I2) is preferentially activated in cancer stem cells, and genetic inhibition of its expression sensitizes this cell population to chemotherapy, significantly delaying tumor recurrence in a preclinical model relevant to the pathology.
To date, there is no clinically usable PXR inhibitor, but we have developed a Proteolysis Targeting Chimeras (PROTAC) approach inducing targeted degradation of PXR (WO O2016026933). The goal of this project is to optimize now the pharmacokinetic properties and formulation as nanoparticles of this molecule. The degradation of PXR is crucial as it has been identified as a factor in undesirable drug interactions and a marker of poor prognosis in numerous cancers, including colorectal cancer.
PROTAC strategy for targeted degradation of PXR. A) Structure of JMV7048 and its inactive JMV7159 analog. B) The use of an inactive CRBN analog (JMV7159) of JMV7048 or the pretreatment with the ubiquitin E3 CRBN inhibitor (MLN4924) confirmed the ubiquitin-proteasome-dependent machinery in JMV7048-mediated PXR degradation.
Main publications
• Bansard L,, et al. (2022) Stem Cell Reports,17(4):835-84
• Planque C, t al., (2016) Oncogene, 7(35):56558-56573
Funding
• 2022-2024 MITI-80 – PRIME (CNRS INSB)
• 2020-2022 Prematuring programs (CNRS – INSB & SATT AxLR)
• 2019-2021 ANR PXR-PROTAC
Collaborations
• Muriel Amblard (IBMM, Montpellier)
• William Bourguet (CBS, Montpellier)
• Sabine Gerbal Chaloin (IRBM, montpellier)
Alumni
• Margot AYEUL (M2)
Patents
• Pannequin J, Hollande F et Pascussi JM, WO O2016026933
• Pascussi JM, Pannequin J, Amblard M, Laconde G et Martinez J, WO O2016026933
