Identifying and targeting the “Achilles’ heel” in proteasome inhibitor-resistant multiple myeloma
Automatisch geschlossen · 2018 bis 2021
Driessen Christoph, Besse Andrej, Kraus Marianne, Besse Lenka, Mendez-Lopez Max
The proposal aims at understanding the biology of proteasome inhibitor (PI)-refractory multiple myeloma (MM), in particular the specific vulnerabilities of PI-refractory MM, or so called “Achilles’ heel”, towards development of novel treatment options for this important unmet clinical need. The biology of PI-refractory MM is poorly understood in vivo, and we lack treatment approaches that target the biology of PI-resistant MM.
Over the past years, our group has established the most advanced in vitro model of PI-refractory MM, reflecting the critical features known from MM-refractory patients. It consistently demonstrates that PI-refractory MM cells adopt a reproducible and highly specialized complex metabolic signature that fundamentally differs from normal, PI-sensitive MM cells. These major adaptive changes are mostly found in the production, folding and/or transport of newly synthesized protein, the redox and energy state, and they together render PI-resistant MM largely independent from proteasome function. We hypothesize that PI-resistant MM rely on different essential pathways for cell survival, compared to PI-sensitive MM. These specific essential genes and pathways in PI-resistant MM we hypothesize to represent novel “vulnerable spots” specifically in PI-resistant MM, which consequently provide potential therapeutic targets. To identify this specific “Achilles’ heel” in PI-resistant MM, we have advanced our model of PI-resistant MM towards a truly single cell-derived, clonal platform with different individual MM cell lines, so that we are now in the unique position in the field
to use genome-wide, unbiased CRISPR-Cas9 loss-of-function screening in PI-resistant MM to identify essential drug targets and pathways.
Drug repurposing, the application of existing therapeutics to a new disease indication, holds promise of rapid clinical impact at a lower cost than de novo drug development. It can be performed in an academic setting in a globally competitive fashion, as we have previously demonstrated. The very recent availability of a comprehensive public online Drug Repurposing Hub (http://www.broadinstitute.org/repurposing) as a searchable database now allows the systematic identification of drug repurposing candidates for the manipulation of novel molecular drug targets in a streamlined preclinical development path. In the current proposal, we shall for the first time systematically exploit the potential of searchable drug repurposing platforms towards the identification of drug candidates that modify the essential survival pathways we aim to identify in PI-resistant MM. The candidate genes and lead compounds against PI-refractory MM will be validated in vitro and in vivo using our PI-resistance models and 2 in vivo MM models. The project builds on our internationally leading track record in the fields of proteasome inhibitor resistance and drug repurposing to treat PI-resistant MM. It uses the most advanced technologies for genome-wide drug target screening, identification of drug repurposing candidates and their preclinical testing in vivo. Successful candidates shall be directly moved to clinical phase I/II testing within the SAKK network, as we have successfully demonstrated before. We expect this to ultimately provide a cell biology-targeted therapy option for patients with PI-refractory MM.