Preventing therapy-induced cancer stemness

The inability to eradicate metastasis, the major source of cancer-related deaths, is one of the most important challenges faced by modern oncologists. Cancer therapeutics used to treat advanced metastatic diseases are incapable of killing all cancer cells, leaving behind a reservoir of surviving cells, known as the minimal residual disease (MRD), from which relapse -almost invariably- emerges. Incompleteness of any tumoricidal treatment is commonly explained by the (pre)-existence of cells harboring drug resistant-conferring mutation(s), owing to high genetic intra-tumor heterogeneity. There is, however, increasing evidence that the surviving cells are not just static bystanders. Dynamic nongenetic reprogramming allows active adaptation to the treatment (stress). Our recent work has shown that (i) residual cancer cells can induce robust protective responses and acquire diverse drug-resilient features, including cancer stem cell properties, and highlighted (ii) the major contribution of therapy-induced stemness in tumor recurrence. We propose to develop therapeutic strategies that contend with and capitalize on nongenetic tumor evolution with the ultimate goal to prevent resistance to anticancer drugs. We will (i) dissect the molecular principles that govern drug-induced reprogramming into the stem-like state; (ii) devise strategies that target (common) drivers (i.e. chromatin remodelers, lncRNAs/eRNAs) of therapy-induced stemness and (iii) test their efficacy in preventing relapse in the context of rationally designed MRD-directed combination therapies. This proposal may lead to a paradigm shift in the treatment of advanced cancers and long-lasting clinical benefits for a considerable number of patients.

Keywords:Therapy resistance, cancer cell plasticity, cancer stem cells, lncRNAs, Minimal residual disease, melanoma

Disciplines:Oncology not elsewhere classified