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.
“Targeting Metabolic Vulnerabilities in Primary Effusion Lymphoma Using the Novel Nucleoside Analog (6-ETI)”
Jouliana Sadek, PhD
Weill Cornell Medicine
Abstract: A number of nucleoside analogues have been used for the treatment of several lymphomas, but these have distinct efficacies and toxicity profiles, and many patients do not respond to treatment and eventually develop resistance. Thus, identifying novel therapies with predictive biomarkers to personalize therapy is crucial. A high-throughput screen conducted in our lab identified the nucleoside analog 6-ethylthioinosine (6-ETI) as a potent and selective inhibitor of primary effusion lymphoma and other plasma cell malignancies, including plasmablastic lymphoma (PBL) and multiple myeloma (MM). Our studies indicate that 6-ETI is a pro-drug activated by adenosine kinase (ADK), an enzyme that is overexpressed in theses cancers. 6-ETI induced S phase arrest and inhibition of DNA synthesis. RNA sequencing of resistant clones and CRISPR knock out of ADK indicate that mutations or loss of expression in ADK as a mechanism of 6-ETI resistance. Metabolic and transcriptomic profiling revealed significant depletion of nucleotide pools and downregulation of nucleotide biosynthesis genes in WT treated cells, while an increase in phosphorylcholine metabolite was observed in the ADK KO resistant treated PEL cells. This proposal centers on delineating the mechanism of action of 6-ETI by: (1) determining the specific target of 6-ETI by investigating its effects on nucleotide biosynthesis, (2) characterizing the role of ADK as a biomarker for 6-ETI response and interrogating the mechanisms driving resistance to guide the design of effective combinatorial regiments. The studies proposed here will help us exploit the therapeutic potential of a novel lymphoma inhibitor and identify combinations that will combat resistance.
“Targeting protein glycation as a new strategy for lymphoma therapy”
Memorial Sloan Kettering Cancer Center
Abstract: While an epidemiological correlation between lymphoma and diabetes has been established, the molecular mechanism linking these two conditions remains murky. Understanding the contribution of underlying metabolic abrogation to lymphoma is critical for its prevention, detection and treatment. Glycation, which is the non-enzymatic reaction of sugars with proteins, is a hallmark of diabetes and correlates with the severity of various complications. We recently found that histone proteins accumulate glycation adducts in breast cancer cell lines, xenografts and patient samples. Moreover, we characterized these adducts on a biochemical and biophysical level and found that they promote changes in chromatin architecture by changing histone-DNA contacts and the distribution of histone post-translational modifications (PTMs), particularly PTMs associated with lymphoma. The goal of this proposed research is to target histone glycation for therapeutic purposes by inhibiting DJ-1, a key deglycase we identified with a role in preventing cell death. Combining the chemical biology and epigenetic strength of the David lab with the cancer biology and translational mentorship of Hans-Guido Wendel, we aim to both characterize the molecular mechanism linking glycation and lymphoma pathogenesis and develop a translational route to target it.
Protein glycation in epigenetics and cancer. Abrogated metabolism and mutational stress promote accumulation of non-enzymatic glycation on histones. These adducts disrupt histones modifications, altering the epigenetic landscape, thus leading to changes in the cellular transcriptome and inducing transformation. Cancerous cells generate reactive sugars and ROS that further drive the cycle.
“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).