The Career Enhancement Program identifies and trains talented individuals committed to becoming translational investigators in the field of lymphoma. This program supports one or two promising scientists per year for up to two years. Recipients of the award become active members of all relevant activities of the lymphoma SPORE at Memorial Sloan Kettering.
“Repositioning therapeutic principles for Diffuse Large B-cell Lymphomas”
Columbia University Institute for Cancer Genetics
Abstract: Novel therapies are needed for 45% DLBCL patients who do not achieve long-term benefit with standard chemotherapy. Poor response is difficult to address because of the diseases’ genetic heterogeneity, which encompass ~100 low frequency alterations whose impact on therapeutic response is largely unknown. The Cell of Origin (COO) based classifier assigns DLBCLs to the ABC (Activated B-Cell like) or the GCB (Germinal Center B Cell) type but is only partially informative, as many genetic lesions are found in both subtypes. The premise of this project is that among FDA-approved drugs and compounds in advanced clinical development, many already target pathways essential for DLBCL. As these drugs are already approved for use in the clinics, they may be repositioned and rapidly impact DLBCL therapy. At the same time, unexpected sensitivities may reveal novel roles for targeted genes or pathways in DLBCL. As shown in preliminary data, we have validated this approach by repositioning the Src/Abl inhibitor Dasatinib for DLBCL, exploring its activity in vitro and in vivo for Ibrutinib-resistant disease and defining PTEN disruption as its main determinant of resistance. Here we plan to extend these efforts to the whole FDA-approved (n=1,443) set and an additional set of promising compounds (n=319) for the ability to suppress a panel of DLBCL lines (n=37). We aim at mapping drug activity to synthetic lethal interactions with known or novel pathways by integrating drug response with genetic and transcriptional profiles and validating in vivo our findings in cell lines and Patient Derived Xenotransplants (PDXs).