SCIPER · Studying Cancer Individuality by Personal and Predictive Drug Screening and Differential OMICs

The cellular and molecular systems that determine drug responses in cancer are complex, highly individual, and incompletely understood. As a result, many cancer patients receive ineffective or even harmful therapies, which endangers lives, burdens healthcare systems, and prevents new therapies from reaching clinical approval.To address this problem, we are developing a platform that measures hundreds of ex vivo drug responses from small patient biopsies by immunofluorescence, automated confocal microscopy, single-cell image analysis, and machine learning. We preserve cellular memory and maximize physiological relevance by not culturing or sorting cells prior to drug exposure. Sub-cellular, single-cell, and cell population-wide image analysis reveals on-target drug responses and disentangles multicellular ones. In a first interventional clinical trial, this phenotypic information alone led to strongly improved treatment of patients with aggressive hematologic malignancies.Enabled by this high-throughput, predictive, and phenotypic information, I here propose to identify the molecular and cellular systems that govern treatment response individuality in cancer. (Aim 1) We will combine drug response profiling with RNA sequencing and proteomic measurements of malignant and healthy cells from the same biopsies. Critically, the patient-internal comparisons in both screening and OMICs allow neutralizing complex confounding factors. (Aim 2) New multiplexed immunofluorescence and convolutional neural network-based analyses will identify multiclass cell-types and -states, and quantify non-cell-autonomous responses. (Aim 3) Computational integration and causal inference will identify the molecular determinants and governing principles of drug response individuality in cancer, amenable to further validation. This proposal will thus improve our mechanistic understanding of cancer individuality and develop powerful new tools for OMICs-based precision medicine.