2013 - 2021
Identification of new drug targets in CML and other MPN.
The project part leader, Giulio Superti-Furga, is Director of CeMM (Vienna, Austria) and well-known and well-embedded in the scientific community. His group has made pioneering research in the structural analysis of BCR/ABL and in the characterization of major BCR/ABL-drug interactions. During the past few years, the group of the PI has established kinase interaction profiles for various TKI in CML. The lab of the PI is working on three converging tracks, with the aims to perform structure-function analyses of BCR/ABL to identify new critical target-sites, to characterize the molecular machinery and wider protein interaction networks that integrate BCR/ABL within the CML cell signaling pathways and biological processes, and to use chemical proteomics to elucidate the mechanism-of-action and target spectra of various TKI.
In the current SFB, project #11 expands interaction proteomic mappings to various MPN and various cell types including LSC, in order to identify and characterize novel candidate target genes in CML and other MPN. The specific long-term aim in project #11 is to identify novel drug targets and target-networks in neoplastic cells and LSC in CML, JAK2 V617F+ MPN, KIT D816V+ MCL, and FIP1L1/PDGFRA+ CEL.
Project #11 contributes substantially to the common goal of this SFB for several reasons: One of the attractive features of the pharmacoscopy platform is its versatility. We have been able to use it for approximately 10 different diseases (including MPN in different forms, B-ALL, T-ALL, NHL, CMML, myeloma), employing peripheral blood, lymph node biopsies, pleural effusions, and BM. Access to phenotypically and clinically well-characterized samples of various MPN cohorts will be organized in F47 through #01 (biobank) and #04. This F47-internal collaborative platform is absolutely essential for our current project. In these collaborations we will be able to work on primary LSC as well as other, defined, cell types in BM and PB samples. The teams of #04 and #11 have a long-lasting collaboration on CML and other MPN. Pharmacoscopy has already been tested with MPN patients in collaboration with #02, #04, and Heinz Gisslinger. Part of the future collaborative plan is to systematically test the effects of various experimental anti-MPN drugs with focus on those agents that have been or will be developed and/or tested in the F47 consortium. For example, interferon-alpha (IFN-A), ruxolitinib, and CALR-targeting agents provided by #02 will be tested by pharmacoscopy. Synergies with #02 will also provide the opportunity to correlate pharmacoscopy data with particular genetic make-ups of the patient samples examined. The LSC-targeting drug combinations identified in #04 will be confirmed by pharmacoscopy and will be validated using lager patient cohorts. Other drugs and drug combinations, including CDK6 inhibitors (cooperation with #06), STAT5-targerting drugs (cooperation #07), or BRD4 blockers (cooperation #10), will be tested alone and in combination on LSC viability and function, using our pharmacoscopy platform. All drugs mentioned will be included in the standard panel applied and thus tested in combination with drugs used to treat MPN in daily practice which will also support the cross-validation strategy of F47. Synergies between #01, #04 and #10 provide the opportunity to correlate BCR-ABL1 mutations and epigenetic states with outcome in the pharmacoscopy screens. Without the F47 network, pharmacoscopy would have trouble investigating its potential, not only by having access to patient cells from different neoplastic diseases, but also cells with molecularly characterized genetic and epigenetic make ups. Moreover, F47 will grant access to innovative therapeutic initiatives (epigenetic drugs, CDK6, STAT5 inhibitors). Importantly, the F47 partners will be absolutely instrumental in validating intriguing combinations that will emerge from the #11 subproject in their validation assays, including pre-clinical testing in mice. The group of #11 has several joint publications with #01, #02, #04, #06, #10 (see list of publications). Many more papers are in the pipeline where consortium partners and the team of #11 are involved.