AP’ONCALYPSE

Current cancer management aims at integrating molecular signatures in the design of personalized therapies. Recent advances in “omics” have led to the identification of predictive factors pinpointing “drugable” signaling pathways, which can be interrupted by targeted therapies. Those molecular signatures (such as Oncotype DX or Mammaprint° in breast cancers (BC)) only rely on tumor cell profiling, overlooking the host reactivity to the tumor and practically allow to identify those patients that may not need adjuvant high dose chemotherapy, failing to propose a more personalized therapy for bad prognosis patients. However, accumulating evidence underscores a bidirectional tumor-host interaction during therapeutic intervention, indicating that molecular signatures should integrate host-intrinsic parameters. We showed that some cytotoxic compounds (i.e anthracyclines) are capable of triggering an “immunogenic” cell death, thereby eliciting an anticancer immune response that “vaccinate” the host against his cancer contributing to his definitive cure. Our data indicate that failure to activate an antitumor immune response compromises the success of conventional anticancer chemotherapies and can be predicted by specific molecular signatures. We have generated and patented an immunity-based predictor (“Immunpredictor”) in BC that allows us to estimate the probability of the patient to relapse despite anthracyclines (+/-taxanes). This predictive high performance signature consists in a small series of loss of function single nucleotide polymorphisms and candidate gene products involved in ER stress response and autophagy, derived from tumor DNA or RNA at diagnosis respectively. This immune signature is independent from and adds accuracy to the three known clinical factors (grade, HER2 and hormone receptor status) for breast cancer treated by adjuvant or neoadjuvant anthracycline-based chemotherapy. The project will be led by three complementary teams (cell death biology in INSERM U848, immunology in CICBT507 and bioinformatics in Ecole des Mines/Curie) as well as IGR&D technology transfer Department of IGR. The coordinated programm has two aims: 1/ validate these signatures in a two large retrospective cohorts of 680 patients in neoadjuvant and 800 patients in adjuvant, 2/ set up a multiplex chip array containing the validated set of nucleic acid probes for future exploitation and large scale prospective validation in anthracyclines-based therapies in BC. This urgent need for predictive tests that detect functional defects in anticancer immune responses in BC is prompted by the hindsight of designing appropriate compensatory therapies targeting these immune defects.