Our lab has previously shown that SCD1 is implicated in the maintenance and expansion of the cancer stem cell (CSCs) compartment and that the connection between SCD1 and CSCs is rooted into its regulation of signaling pathways. Nevertheless the therapeutic potential of SCD1 inhibition and the clinical significance of its aberrant activity remains unclear
We hypothesize a scenario where SCD1 promotes the resistance of CSCs to various anticancer agents, including both chemotherapeutics and targeted agents. On this ground we will carry out extensive mechanistic and molecular studies to elucidate whether pharmacological inhibition of SCD1 reverts both intrinsic and acquired resistance. To this end, we will exploit patient-derived CSC-based in vivo models obtained from patients with advanced melanoma (MEL)and non-small cell lung cancer(NSCLG). Thus, preclinical studies will be paralleled by a clinically focused task in the attempt of developing SCD1 associated molecular signatures predicting survival outcomes.This project has been designed to elucidate the connection between SCD1 and CSCs through
-analyzing the link between SCD1 and therapeutic resistance, focusing on the ability of SCD1 inhibition to revert intrinsic/acquired resistance
-elucidating the mechanisms underlying the anti-CSC properties of SCD1 inhibition to a greater extent through integrative gene- and transcript-level analysis coupled with lipidomic profiling
-evaluating the relationship between the SCD1 regulatory network and survival outcomes in patients with MEL and NSCLC
Genomic, transcriptomic and lipidomic analyses will be performed to assess the potential impact of specific molecular contexts in determining sensitivity/resistance to MF-438. Results from the preclinical part of the project will be tested in the clinical setting to identify lipid metabolism-associated signatures predicting clinical outcomes.
The present study has been designed to generate evidence on the ability of SCD1 inhibition to efficiently kill CSCs and revert their intrinsic therapeutic resistance. This holds the potential to expedite a wave of interventional trials with agents targeting SCD1 in association with chemotherapy or targeted agents in selected patient populations. Moreover, the experimental approach we propose also envisions a rapid translation of laboratory findings into the clinical setting, entirely dedicated to the study of SCD1-related processes in cancer patients. Overall, the experimental approach we propose is expected to culminate in the design of biomarker-driven clinical trials with new agents, as well as in prospective studies with biomarker validation purposes.Our project aims to use the biological lessons acquired from the functional characterization of CSCs to identify efficient anticancer therapies to be introduced into routine clinical practice. Moreover, the search of biomarkers predicting the anti- CSCs activity of SCD1 inhibition will be instrumental for defining the patient population that more likely will benefit from the delivered intervention. This will also lead to a consistent reduction in costs correlated with delivering ineffective treatments, thus mobilizing resources to improve the outcome of other patients who are currently not receiving appropriate treatment. Overall, the experimental approach we propose is expected to culminate in the development of novel anticancer therapeutics and companion diagnostics.
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