Title: Fighting resistance in CLL
Eric ELDERING (Netherlands) Academic Medical Center Department of Experimental Immunology, Amsterdam
Dimitar EFREMOV (Italy) International Centre for Genetic Engineering and Biotechnolog, Monterotondo (Rome)
Alexander EGLE (Austria) Federal Hospital of Salzburg and Paracelsus Medical Private University, Salzburg
Idit SHACHAR (Israel) Weizmann Institute of Science, Rehovot
Stephan STILGENBAUER (Germany) Department of Internal Medicine III, Ulm University, Ulm
Martina SEIFFERT (Germany) German Cancer Research Center (DKFZ) Heidelberg
Florence CYMBALISTA (France) UMR InsermU978/Université Paris 13/ AP-HP GHPSSD Service d’hématologie biologique, Bobigny
Background and rationale. Chronic Lymphocytic Leukemia is a common cancer of mostly elderly people, and its incidence and burden will increase in our aging Western society. The disease is clinically heterogeneous, ranging from death within 2-3 years to indolent. CLL is a prime example where outcome is influenced by both genetic variation and microenvironmental factors acting on the cancer cells. Current standard treatment options, but also (combinations with) novel targeted drugs and immunotherapies about to enter the clinic, offer no curative perspective. These insights are based on recent molecular insight which demonstrated 1) new CLL cancer genes of unknown function, linked with treatment resistance, 2) early occurrence of minor subclones known to predispose to resistance, 3) emergence of novel mutations under treatment with new targeted drugs, 4) microenvironmental and signaling hetereogeneity which is linked with immune suppression and tumor escape.
Hypothesis: despite promising new therapeutics, resistance development due to tumor and microenvironmental heterogeneity will remain an obstacle for long-term clinical success in CLL
Aim: Lasting cure of CLL by combination treatment, based on molecular understanding of patient-specific genetic and microenvironmental heterogeneity.
Methods: an integrated approach with various modules that feed into and reinforce each other:
1. NGS characterization of leukemic heterogeneity and subclonality
a. From untreated and treatment resistant patient samples, various timepoints
b. From clinical trial samples in relation to outcome after different treatments
c. From different compartments, PB, LN, BM and Richters tranformation
d. From different locations within the same compartment
2. State of the art in vitro and in vivo models to develop and assess tailored combination strategies
a. Human models incorporating relevant accessory cell types and distinct CLL genotypes
b. Murine models incorporating relevant accessory cell types and distinct treatments
3. Functional analysis of (novel) CLL mutations in relation to microenvironment and treatment resistance
a. Genome wide impact (RNA, proteomics) of relevant mutations in patient samples in response to treatment(s)
b. Development and implementation of biomarkers for resistance
c. Mechanistic analyses of individual mutations in genetically modified human and murine cells
Expected results and potential impact. The results from this international, concerted effort will bring lasting cures for CLL within reach of clinical reality. The integration of expert groups across the EU with complementary expertise to address current clinical as well as fundamental questions provides a platform for scientific and clinical training of the next generation of clinicians and researchers. The impact of the results obtained will extend beyond the participating research groups and beyond CLL.
Chronic Lymphocytic Leukemia (CLL) is a common cancer and its incidence and burden is increasing in our aging Western society. CLL is clinically very diverse, ranging from death within 2-3 years to indolent disease. The clinical course is influenced by both genetic variation and the variable interaction of the cancer cells with the surrounding normal tissue cells - the so-called micro-environment.
Our consortium aims to reach a thorough molecular understanding of patient-specific genetic and microenvironmental heterogeneity to bring a curative perspective for CLL by combination treatment. Our methods consist of integrated modules that feed into and reinforce each other:
- Genetic characterization of individual and spatial clonal heterogeneity
- Measuring impact of microenvironment and immune surveillance in relation to clonal heterogeneity
- Breaking treatment resistance by tailored combination strategies
The impact from our concerted effort will help to bring lasting cures for CLL within reach of clinical reality. The integration of expert groups across the EU with complementary expertise to address current clinical as well as basic scientific questions provides a platform for training of the next generation of clinicians and researchers. The overall significance will extend beyond CLL.
(Project funded under JTC 2014)