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Currently, combined DNMT and HDAC inhibition is being investigated in myeloid neoplasms in the context of an ongoingPhase I trial, given the synergy that has been observed in vitro between these 2 pathways of epigenetic silencing. Future workwill focus on investigating combinations, involving agents that target aberrant transcription (such as chromatin remodelingagents) with those that inhibit dysregulated signaling pathways, in an effort to optimize the clinical and biologic effects ofthese agents in myeloid neoplasia.Sonali Smith, MDAssociate Professor of MedicineA major challenge in developing a research agenda for Hodgkin and non-Hodgkin lymphomas is the current recognitionof nearly 60 unique clinicopathologic subtypes. Many of the subtypes are in fact rare diseases with fewer than 5000 newcases per year throughout the country. The Lymphoma Program at The University of Chicago is a highly visible clinical andtranslational research program that has been in a period of substantial growth since 2001 and currently consists of fourfaculty members, including Drs. Koen van Besien, Sonali Smith, Kenneth Cohen, and Justin Kline. Dr. Smith, the associatedirector of the program, is institutional Principal Investigator on 10 clinical trials and hosts the annual International ChicagoLymphoma Symposium, the only lymphoma-dedicated symposium in the Midwest.Molecular Genetics& HematopoiesisThe Lymphoma Program at The University of Chicago has adopted a two-pronged approach in an effort to serve thevariety of patients seen in the clinic. The first is to provide opportunities for patients to participate in a range of clinicaltrials that are either subtype specific or that target a common oncogenic pathway believed to promote lymphomagenesis.Large scale front-line studies, intended for patients that are treatment-naïve, are primarily via collaborations forged withCALGB. Through the CALGB, Dr. Smith has published several reports, including a relatively widely quoted negative studyof thalidomide in patients with relapsed indolent lymphomas, which contrasts with the significant activity of secondgeneration immunomodulatory agents derived from thalidomide. The second programmatic approach is to focus onnew drug development for relapsed lymphomas through The University of Chicago Phase II Consortium. In this venue,investigator-initiated trials free of pharmaceutical bias are offered to patients with relapsed disease without other standardtreatment options. The University of Chicago, through this phase II mechanism, was the first to show activity of a classof agents called mTOR inhibitors against two of the most common types of lymphomas (diffuse large B-cell lymphomaand follicular lymphoma). mTOR, or mammalian target of rapamycin, is a ser/thr kinase that controls the start of mRNAtranslation. Several known oncogenic pathways converge upon mTOR, making it an attractive target to modulate upstreamsignals simultaneously. Furthermore, mTOR controls translation of several mRNA transcripts that are critical componentsof lymphomagenesis, including CCND1, VEGF, and MYC. Two subsequent proposals are being explored to examine mTORinhibition, in combination with other biologic agents, as well as with standard cytotoxic chemotherapy. In addition, theProgram seeks to identify predictive markers for response to mTOR inhibitors.The other major focus of the Lymphoma Program is to explore the role of both autologous and allogeneic hematopoietic stemcell transplantation for patients with relapsed lymphomas. High dose chemotherapy followed by autologous stem cell rescue(ASCT) can successfully salvage many patients with chemosensitive relapsed aggressive lymphomas, but relapse remains acommon and usually fatal event. The Program recently completed a trial evaluating the safety and efficacy of post-transplantimmunomodulation using GM-CSF and IL-2 to augment rituximab, with the goal of eradicating minimal/undetectableresidual disease following high dose chemotherapy to reduce relapse. Two ongoing studies are extending interest in posttransplantimmunomodulation, one trial using Ontak (toxin-linked monoclonal antibody against IL-2 receptor) followingtransplant for T-cell lymphomas and a second trial evaluating a novel monoclonal antibody targeting PD-1 as part of the B7-family of surface receptors for patients with diffuse large B-cell lymphomas.In summary, the Lymphoma program currently has 15 active therapeutic and database protocols addressing both commonand uncommon lymphoma patient populations. Dr. Smith’s future research objective is to expand on mTOR inhibition as aplatform for anti-lymphoma treatments.UCCRC SCIENTIFIC REPORT 200935