SP2 - SeneSys
Experimental verification and exploitation of „Profile/State-Fate“ cluster models for innovative pro-senescent and senolytic co- or sequential therapies in lymphoma models
The main goal of SP2 within the consortium is to provide data-dense entry information from molecular senescence analyses as the basis for the systems-medicine-driven generation of static/dynamic senescence-related “profile state/fate (P/SF)” models, and, in turn, to identify cluster-specific vulnerabilities by functional perturbations and to experimentally validate those as novel therapeutic principles.
More specifically, SP2 will obtain and deliver comprehensive transcriptome-based senescence signatures in various model systems (Eμ-myc transgenic mouse lymphoma model, fibroblasts a.o.) over time for complex systems-medicine-driven analyses with respect to previously defined DLBCL clusters. Moreover, candidate driver signaling cascades, which were bioinformatically identified, will be further characterized in vitro and in vivo in primary Eµ-myc transgenic lymphomas exposed to genetic or pharmacological interventions. Those datasets will be pivotal for the mathematical modeling of P/SF cluster models and their subsequent dynamic fine-tuning in accordance with state changes detected in response to standard chemotherapy.
In turn, in silico identified cluster-specific signaling vulnerabilities will be interrogated by distinct pharmacological intervention strategies, which might reflect senescence-inducing as well as senolytic (i.e. senescent cells eliminating) compounds, in order to create co- or sequential targeting strategies. Following in vitro-surveys in murine and human model systems in the first place, particularly promising treatment options will be further evaluated in P/SF-assigned Eµ-myc lymphoma-bearing mouse cohorts regarding their in vivo-efficacy and to optimize dose-scheduling for later early-phase trials offered to DLBCL patients.