Due to the heterogeneity of hematological malignancies, it is very difficult to identify effective therapies once a cancer has become resistant to standard treatments. Pharmacoscopy (PC), named after its ability to â€œwatch drug action through a microscopeâ€¯, is a novel approach for the ex vivo high-content image-based analysis of drug response in liquid biopsies. Following a highly promising proof-of-concept phase, this proposal aims to systematically study the ability of PC to identify personalized resistance-breaking therapies in hematologic cancers. The goal is to profile ~200 patients with hematological cancers, relapsed and/or refractory to standard therapy at the DivHemato using PC. Patients will be treated taking PC results into account and clinical outcome rigorously tracked and compared to PC. Our first aim is evaluate the performance of PC in assisting clinical decision-making. The second goal is to understand the mechanism of action of newly identified resistance breaking therapies and resistance to standard ones. Finally, we expect to find recurrent patterns of novel off-label uses of drugs to justify a clinical trial. This cutting-edge proposal (patent filed, under revision at Cell) partners two successful institutions with different expertise (technology and clinical innovation), addresses an important medical need (treatment combating poor prognosis), and is literally precise, patient specific, pre-tested medicine, not indirectly inferred from molecular data.