Proteomic Profiling of Blood Cancers

 

To develop more effective treatment schedules for hairy cell leukemia (HCL), HCL variant (HCLv) and other B-non Hodgkin lymphomas (B-NHLs), it is critical (i) to understand the signaling pathways providing essential survival signals in malignant B cells, (ii) to explore why malignant B cells persist under current treatment schedules, (iii) to identify additional survival pathways, and (iv) to develop rational strategies to target these survival pathways with drugs. The key to these queries likely lies in the proteome, since it is protein expression, which determines cell functionality. We developed a new, highly sensitive data-independent acquisition-mass spectrometry (DIA-MS) proteomics workflow for the analysis of few thousand fluorescence-activated cell sorting (FACS)-isolated cells (Amon S., Meier-Abt F. et al. Mol Cell Proteomics 2019). This technology was applied in pilot proteomic studies, a bioinformatic pipeline was set up to analyze the proteomic measurements and to integrate the proteomic results with genomic, epigenomic and functional data from the same patient samples. We are now extending the analyses to a large cohort of HCL/HCLv and other B-NHL samples as well as healthy control B cell populations (in cooperation with M. Seifert, Essen). The resulting information is expected to deepen the understanding of drug response profiles in individual patients and to pave the way for more targeted and personalized treatment approaches in HCL, HCLv and other B-NHLs.

Chromosomal plot with RNA and protein expression in del11q CLL.

chromosome 11.png
Protein complex in tri12 CLL.
Protein complex.png

Collaboration:

Dr. Wolfgang Huber and Dr. Junyan Lu, EMBL Heidelberg, Germany

Prof. Dr. Ruedi Aebersold and Prof. Dr. Bernd Wollscheid, ETH Zurich, CH

PD Dr. Marc Seifert and Artur Kibler, Essen, Germany

Prof. Dr. Elias Campo and Dr. Ferran Nadeu, Barcelona, Spain

Prof. Dr. Clive Zent, Rochester, USA

Next generation precision medicine for patients with Leukemia and Lymphoma/Myeloma

 

To develop rational and biology-based ways for patient benefit from advances in molecular understanding and targeted drug treatment, we pursue an innovative strategy based on the comprehensive mapping and understanding of individual cancers' vulnerability to compounds, pathway inhibitors and drugs as well as genome-wide silencing triggers (RNAi, CRISPR).

We systematically map pathway sensitivity (and resistance) of primary tumor cells ex vivo using diverse and relevant compound library across leukemia and lymphoma. By analyzing response patterns of sensitivity and resistance, we group tumors functionally, by response phenotype. In parallel, we directly associate and understand drug actions and their variability by investigating the underlying (causative) genetic or epigenetic changes, critical pathway activation, metabolic changes, the biology of the cell of origin and the microenvironment. Following the identification of clinically actionable vulnerabilities on primary tumors, we will mechanistically validate these with in vitro (incl. RNAi) and in vivo models and develop rational starting points for clinical development. We classify disease based on pathway sensitivity and the systematic understanding of underlying molecular networks.

Collaboration:

Jean-Pierre Bourquin, Kinderspital, Zürich, CH
Wolfgang Huber, EMBL, Heidelberg, Germany

Sascha Dietrich, Universitätsklinik Heidelberg, Germany
Thomas Oellerich, Universitätsklinik Frankfurt, Germany
Berend Snijder, ETH, Zürich, CH

Exploring the Therapy of T-cell Lymphoma

T-cell leukemias and lymphomas are disease entities with typically limited response to standard-chemotherapy and correspondingly poor overall survival. To tackle this challenge, we screened these diseases for drug sensitivity using a diverse set of drugs, using ex vivo platforms.
We interrogate candidate drugs with omics profiling and quantitative protein expression data, to identify new potential treatments, and uncover pathway dependencies. In a second step we aim to identify biological features associated with drug sensitivity and resistance. The single-patient resolution of this approach will further our understanding of T-cell malignancies and develop personalized medicine.

MP.png

Collaboration:

Wolfgang Huber, EMBL, Heidelberg, Germany.

Sascha Dietrich, Universitätsklinik Heidelberg, Germany.

Berend Snijder, ETH, Zürich, CH

Drug resistance & p53

 

Over the last years, we have contributed to the understanding how mutations contribute to lymphomagenesis. One particular focus of the group has been to define the role of the p53 pathway and particular mutant p53 in lymphoma. In addition to the assessment of molecular and clinical consequences of these genetic lesions, we focus on the identification of alternative drivers of disease traits such as the regulation of drug target expression (CD20), p53 degradation and gain-of-function.

Collaboration:

Moshe Oren, Weizmann Institute, Rehovot, Israel

Genomics of drug sensitivity / Precision medicine

 

We use omics profiling of primary cancer cells to understand the individual make-up of different diseases and individual tumors. We use this information to identify new therapeutic targets and stratification tools to develop precision medicine for patients with all types of hematologic malignancies, particularly lymphoid neoplasms (e.g. CLL, HCL). We develop clinical protocols and guidelines to position biomarkers into clinical routine. It is our vision that a detailed map of individual tumors will ultimately lead to better treatments for cancer patients – one patient at a time.

Collaboration:

Omar Abdel-Wahab, MSKCC, NY, USA
Wolfgang Huber, EMBL, Heidelberg, Germany
Frederic Damm, Charite, Berlin, Germany
Olivier Bernard, INSERM, Paris, France
Christopher Oakes, OSU, Columbus, USA