Detall

El proper 16 de juny a les 12h, l'Aula Magna del Campus Clínic acollirà el cinquè dels seminari del Cicle Continuat de Conferències de la Facultat de Medicina i Ciències de la Salut. 

El seminari porta per títol "Reduced mitochondrial priming drives global resistance to leukemia therapy" i estarà a càrrec de la Dra. Shruti Bhatt, Assistant Professor at National University of Singapore in the Department of Pharmacy.

Aquest seminari, esta adreçat a tot el PDI de la Facultat de Medicina i Ciències de la Salut i els diferents centres de recerca de Barcelona i no requereixen inscripció prèvia per poder assistir-hi.

A continuació trobareu una breu sinopsi dels temes que abordarà la Dra. Bhatt durant el seminari:

Although major focus of drug development in acute myeloid leukemia (AML) is shifting to targeted therapy, acquired resistance remains important clinical challenge. To overcome this challenge, we investigated the age-old clinical conundrum of why tumors exposed to single agents often relapse with insensitivity to many agents. We modelled in-vivo acquired resistance to drugs with widely varying mechanism of action, including FLT-3 inhibitors, BCL-2 inhibitor, MCL inhibitor, SMAC mimetic and BRD-4 inhibitor in AML patient-derived xenograft (PDX) models. We derived landscape of pharmacologic sensitivity for 18 PDX models together with genomic and transcriptomic profiles. We identified common mechanism of resistance for all – a reduction in mitochondrial apoptotic priming measured by BH3 profiling of paired PDX myeloblasts. Despite of global reduction in mitochondrial priming, drug-induced mitochondrial priming by dynamic BH3 profiling (DBP) identified drugs with persistent in vivo activity in a drug-specific manner — BH3 mimetics and HDAC inhibitors showing overlapping activity across different drug-resistant models. We next showed that human AML patients at relapse also broadly lose sensitivity to agents in a similar pan-resistant manner as PDX models by comparing ex vivo sensitivity responses to >500 drugs across relapse and diagnosis patients. Using RNAseq, we found that resistance to distinct single agents share a common transcriptomic signature carrying enrichment in Ras, MPAK, JAK-STAT, drug efflux pathways, and downregulation in DNA repair pathways in PDXs and primary tumors. Overall, we demonstrate that reduction in mitochondrial priming is conserved mechanism of acquired resistance that causes selective persistent vulnerabilities across different classes of agents in-vivo.

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