Drug discovery, HTS assay development, small molecules, structural biology, immunotherapy, myeloid cell phagocytosis, CD47, SIRPα
Quantitative High Throughput Screening for Small Molecules Targeting CD47 in Cancer Development of immune checkpoint inhibitors using DOTS – an innovative fragment-based drug design approach
Establishing a colon cancer patient-derived 3D tumoroid biobank for the development of personalized immunotherapy.
CD47 is an immune checkpoint overexpressed in solid and hematological tumors that correlates with treatment resistance and poor prognosis. It downregulates anti-tumor immune responses via the inhibitory receptor SIRPα on tumor associated myeloid cells. Though anti-CD47/SIRPα biologics are being tested in clinical trials, toxicological issues related to ubiquitous CD47 expression are barriers to their clinical advancement. The iSCB Team (Morelli/Collette) is pioneering small molecule-based strategies to create the next generation of more effective immune checkpoint inhibitors. Using this approach, we are developing the first small molecules targeting SIRPα to block the SIRPα-CD47 interaction for better TME selectivity, lower toxicity, enhanced solid tumor penetration (Miller, 2019; Burgess, 2020; Gondois-Rey, 2022). CD47 is an immune checkpoint overexpressed in solid and hematological tumors that correlates with treatment resistance and poor prognosis. It downregulates anti-tumor immune responses via the inhibitory receptor SIRPα on tumor associated myeloid cells. Though anti-CD47/SIRPα biologics are being tested in clinical trials, toxicological issues related to ubiquitous CD47 expression are barriers to their clinical advancement.
Animal and cellular models
primary cell and cell line-based 2D coculture phagocytosis assay (PMN, macrophage) using FACS or microplate reader
colorectal cancer patient-based organoids/3D coculture with macrophages for phenotypic and functional characterization.
Technics and methods:
structure-based drug design (NMR, x-ray, molecular modeling)