Recherche
Plasticité phénotypique et génétique du cancer : C. Sardet

Theme 1:  Identify and Target “Drug Tolerant Persister cells” to pave the way for new strategies to prevent the recurrence of Triple Negative Breast Cancer (TNBC) and High-Grade Ovarian Cancer (HGOC).

Homologous Recombination Deficient (HRD)- and P53-deficient TNBC and HGOC share molecular similarities and are invariably treated by chemotherapy. Their prognosis remains very poor due to residual tumor cells that are not eradicated by these chemotherapies and are responsible for frequent recurrences.
These cells, termed “Drug Tolerant Persister cells” (DTP), survive   chemotherapies, due to a transient and reversible phenotypic plasticity. The signals and mechanisms leading to this transient state of resistance are far from being fully characterized; their identification and targeting remains a priority challenge to design future therapeutic strategies aiming at reducing tumor relapse.  Based on longitudinal and complementary surveys of in vitro and in vivo (PDX, residual tumors) models of TNBC and HGOC at both bulk and single cell level, we aim at identifying the changes underlying the entry, maintenance and exit phases of the DTP mode under different chemotherapies. In addition to such comprehensive study, we also explore in parallel an hypothesis-driven scenario whereby DTPs may exploit a survival signaling cascade (designated PGAX) triggered by apoptotic cells and made of Phosphatidyl-Serine (PS) - carboxylated GAS6 – and the tyrosine receptor kinase AXL.

Theme 2:  Identify and target Achille’s heels of HR-defective (HRD) TNBC and HGOC.

 HRD tumors TNBC and HGOC share an elevated prevalence of BRCA1 loss of function, either through a coding mutation or inactivation by DNA hypermethylation of the promoter.  BRCA1 is a major player in homologous recombination (HR)-mediated DNA repair (HRR) and resolution of replication stress. As a consequence, HR-defective (HRD) cancer cells show elevated sensitivity to several chemotherapy drugs and to PARP inhibitors, the latter having opened new therapeutic perspectives for HRD cancers, but resistance is frequent. Based on our in vivo (PDX) and in vitro models of TNBC, bearing WT BRCA1 or various forms of BRCA1 inactivation (hypermethylation, mutations/deletions, CRISPR/Cas9) we develop several projects exploring the behavior and Achille’s heel of these HRD tumors, which address: i/ The response and resistance to PARP inhibitors, focusing on BRCA1 hypermethylation, the impact of tumor heterogeneity and the monitoring  of circulating tumor cells (CTCs), a project supported by the Ruban Rose association. ii/ The mechanisms underlying the exquisite sensitivity of HRD tumors to various combinations of chemotherapies, nucleotide synthesis inhibitors and checkpoint inhibitors. iii/ Explore the therapeutic potential of inducing pharmacological BRCA-deficiency in BRCA proficient tumors thru Cyclin-Dependent Kinases CDK1/2 inhibition, leading these cancers to become responsive to PARP inhibitors.

Theme3:  Identify and target Achille’s heels of HR-defective (HRD) TNBC and HGOC.

Cancer cells reprogram their metabolism to fuel unleashed proliferation and growth. Mitochondria are central energy factories that also participate to the production and degradation of fundamental cellular components, including fatty acids, amino acids, and nucleotides. Pharmacological inhibition of mitochondrial metabolism has emerged as a potential therapeutic strategy in cancer. Based on our previous work on E4F1 transcriptional control of metabolism we have identified cancer cell metabolic weaknesses and adaptations that may be interesting leads for future therapeutic strategies in TNBC. This prompted our interest for the proline cycle (proline to glutamate inter-conversion) and the mitochondrial step of the pyrimidine synthesis (DHODH-dependent), focusing on the impact of their targeting in TNBC breast tumors.