The vast heterogeneity of genetic and epigenetic features both among samples from any cancer type and within individual tumors has been documented with increasing resolution. Of note, intratumoral heterogeneity, which fuels clonal evolution and generates treatment resistance, has been identified as the foremost obstacle to lasting cure. This is true of chronic lymphocytic leukemia (CLL), an initially indolent malignancy of mature B cells which inevitably becomes more aggressive over time, and whose clinical course is highly variable across individuals. Despite the recent approval of highly potent drugs (i.e. ibrutinib, idelalisib) that target key CLL pathways, drug resistance?sometimes associated with highly aggressive relapse while on treatment?has been reported. The challenges presented by this disease heterogeneity mandate large-scale interdisciplinary approaches to link genomic features with cellular behavior so that effective personalized treatments can be devised. Our hypothesis is that CLL has heterogeneous yet coherent genomic alterations leading to distinct phenotypic behaviors, subject to evolutionary selective pressures, which impact individual disease trajectories. The members of the proposed Program have a successful track record of collaborating together to make landmark contributions to our understanding of CLL. Despite our growing knowledge about CLL and the expanding armamentarium of effective therapeutics targeting it, the next quantum leap in our understanding of this disease will require network-level integration across data layers in well-powered series to comprehensively map the circuitry of CLL (Projects 1, 2), and systematic approaches to evaluate the impact of genomic alterations on prognosis and response to therapy (Projects 2, 3). Certainly, conventional approaches to functionally study genetic lesions of CLL have been limited by the lack of faithful cell lines and mouse models and by the widely acknowledged difficulties in genetically manipulating primary CLL cells. Through major innovations in approaches to dissect CLL, spearheaded by each Project Leader and ranging from computational to functional genetic and non-genetic based readouts in primary human B cells, we are well- poised to synergize together to address clinically relevant questions in CLL. These initiatives are strongly supported by the joint expertise of the Core Leaders and are expected to inform us on the rational design of the next generation of personalized and curative therapies for CLL.
The goals of precision medicine have been articulated as delivering the right drug, for the right patient, at the right time. In CLL, we have an opportunity to actualize this vision, and this Program has been specifically constructed to integrate the needed facets and hence to constructively advance this vision. Recent advances on both the therapeutic side (with the new availability of a host of new clinically active agents), and on the scientific side (with the development of novel sequencing tools and high throughput approaches for functional inquiry) have arrived at a critical stage such that it is possible to now bring all these data layers together, as we propose in this application, such that individual patients can be matched with specific tailored therapies.
|Ten Hacken, Elisa; Valentin, Rebecca; Regis, Fara Faye D et al. (2018) Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies. JCI Insight 3:|
|Lampson, Benjamin L; Brown, Jennifer R (2018) Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia? Expert Rev Hematol 11:185-194|
|Wang, Lili; Livak, Kenneth J; Wu, Catherine J (2018) High-dimension single-cell analysis applied to cancer. Mol Aspects Med 59:70-84|
|Landau, Dan A; Sun, Clare; Rosebrock, Daniel et al. (2017) The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat Commun 8:2185|
|Compagno, Mara; Wang, Qi; Pighi, Chiara et al. (2017) Phosphatidylinositol 3-kinase ? blockade increases genomic instability in B cells. Nature 542:489-493|
|Ten Hacken, Elisa; Guièze, Romain; Wu, Catherine J (2017) SnapShot: Chronic Lymphocytic Leukemia. Cancer Cell 32:716-716.e1|
|Murphy, E J; Neuberg, D S; Rassenti, L Z et al. (2017) Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia. Leukemia 31:1348-1354|
|Deng, J; Isik, E; Fernandes, S M et al. (2017) Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 31:2075-2084|
|Tiao, G; Improgo, M R; Kasar, S et al. (2017) Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia 31:2244-2247|
|Wang, Lili; Fan, Jean; Francis, Joshua M et al. (2017) Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia. Genome Res 27:1300-1311|
Showing the most recent 10 out of 11 publications