Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer death in the world, accounting for about 1.4 million new cases and almost 700.000 deaths in 2012. Although the advent of targeted therapies has increased life expectancy of selected patient subsets, cancer cells become progressively resistant to conventional and targeted treatments, leaving essentially no therapeutic options for advanced stage/metastatic patients. Current knowledge on therapy-resistant cancer cells is scarce, thus hindering an effective targeting of this population. Cells endowed with increased properties of self-renewal, survival and migration called cancer stem cells (CSCs) have been demonstrated to fuel tumor progression, metastatization and relapse. A subset of CSCs is characterized by a non-cycling state which, together with a peculiar metabolic landscape, confers them resistance to chemotherapy and targeted therapies. Quiescent therapy-resistant CSCs (Q-CSCs) represent an armored reservoir of stem cells within the tumor that can be targeted through innovative approaches based on a deep knowledge of their molecular and biological features. By using a proliferation-sensitive dye, we isolated and characterized a rare subpopulation of quiescent cells from colorectal tumors which, upon gene expression, proteomic and functional studies, revealed combined features of stemness, drug resistance and epithelial-to-mesenchymal transition (EMT). Based on this solid framework constructed in previous years of work on Q-CSCs we aim to select drugs showing in vitro activity against Q-CSCs that will be translated to in vivo preclinical model including CSC-derived xenografts with fluorescent reporter for quiescent cells.
Due to the extreme difficulty in treating metastases, patients with disseminated cancer have essentially no therapeutic options. This hurdle is particularly relevant in CRC, being among the top three causes of cancer-related death. Metastatic CSCs are protected from cytotoxic insults by both intrinsic features and an efficient capacity to establish protective interactions with the tumor microenvironment. The integrated approach for Q-CSCs targeting described here represents a ground-breaking strategy to tackle therapy resistant cancer cells. The studies described in this project provide innovative approaches based on the specific drug targeting of pathway/processes distinctive of this cell population. The preclinical validation of candidate drugs acting on Q-CSCs on advanced models of CRC will pave the way for a subsequent use of such strategies in the clinical setting in order to reduce therapy resistance, metastasis formation and tumor relapse. Targeting strategies directed against Q-CSCs are expected to influence multiple phases of tumor progression, relapse and response to treatments, in particular by reducing the incidence of MRD and thus improving the clinical efficacy of current cancer therapies. In fact, it is assumed that strategies that take into account the targeting of Q-CSCs will result in a successful therapeutic action. The combined use of selected compounds able to target Q-CSCs and a construct that allows to visualize and monitor the quiescent cells, provides a fertile ground for the discovery of innovative strategies of Q-CSCs targeting.