Identifying molecular targets and evaluating the efficacy of novel therapeutic compounds

Research Team:  Brown, Eklund, Evens, Gordon, Guitart, Jardetzky, Kansas, Krett, Kuzel, Longnecker, Mehta, O'Halloran, Platanias, Rosen, Singhal, Tallman, Winter

Members of the Hematologic Malignancies Program have been organized into four disease focused groups To facilitate interactions which have increasingly lead to translating results from basic sciences laboratories into clinically related projects. These teams focus on: a.) acute myeloid leukemia and myelodysplasia, b.) multiple myeloma and chronic lymphocytic leukemia, c.) lymphoma, d.) cutaneous T cell lymphoma.

Drs. Platanias and Tallman have made significant progress in extending the observations from Dr. Platanias laboratory into clinical trials. For example, they have a collaborative project based on Dr. Platanias' work on the effect of mTOR inhibition on acute myeloid leukemia cells in vitro. Dr. Platanias has combined this effort with Dr. Tallman's longstanding interest in defining the role of arsenic trioxide for the treatment of AML. In pre-clinical trials, Dr. Platanias found that the mTOR inhibitor rapamycin potentiates the effects of arsenic trioxide on acute myeloid leukemia cells. Based on this promising preclinical data,one phase I/II trial combining arsenic trioxide and the novel mTOR inhibitor Temsirolimus (CCI-771) in relapsed and refractory AML has been designed and the second combining Temsirolimus with high-dose ara-C in patients with first relapsed AML is in development.

Dr. Eklund received a Leukemia and Lymphoma Society of America Translational Research Award to investigate the use of Sodium Stibogluconate in subjects with MDS and secondary AML. These studies are based on work on Dr. Eklund's laboratory regarding the impact of abnormal SHP2-protein tyrosine phosphatase activity in malignant myeloid disease. In collaboration with Dr. Tallman, Dr. Eklund is performing pre-clinical evaluation of the impact of PTP inhibition with Sodium Stibogluconate on myeloproliferation and cell survival using bone marrow samples from MDS and secondary AML subjects. These studies will be extended to a phase I trial of this agent in these diseases

Based on studies from his laboratory, Dr. Steve Rosen is investigating the use of the novel Protein Kinase C inhibitor Enzastaurin in the treatment of multiple myeloma and cutaneous T cell lymphoma. Pre-clinical studies in his laboratory demonstrated the utility of this agent for potentiation of the apoptotic effect of dexamethasone in myeloma cells. This is a key observation, because Drs. Krett and Rosen demonstrated that this effect was present even in cell lines with relative glucocorticoid resistance. In additional studies in collaboration with Drs. Kuzel and Guitart, Drs. Rosen and Krett also determined that this agent induces apoptosis in T cell lymphoma lines. Because of this very promising pre-clinical data, clinical trials with an oral form of Enzastaurin are planned for multiple myeloma and cutaneous T cell lymphoma. Dr. Rosen and Krett have also continued their translational studies of 8-chloro and amino adenosine and other novel nucleoside analogues which were praised at the time of the previous program review.

Dr. Richard Longnecker's laboratory has been defining the EBV proteins involved in lymphoma genesis. The basic science work from his laboratory is being applied by Dr. Leo Gordon to investigations of the impact of EBV reactivation on lymphoma in immune compromised patients. The goal of these studies is to develop translational approaches to inhibit the EBV proteins such as LMP2A which are involved in the pathogenesis of malignant transformation in lymphoma. These studies focus both on defining markers of EBV related lymphoma genesis in at risk patient populations and developing therapeutic targets.

Dr. Thomas O'Halloran's laboratory has been developing nanotechnologies to improve drug delivery for hematologic malignancies. In collaboration with Drs. Rosen and Winter, these technologies are being extended to develop novel delivery systems for delivery of toxic drugs, such as anthracyclines, to non-Hodgkin's lymphoma. For these studies, Dr. O'Halloran's laboratory is exploring the use of immuno-conjugate nanobins (liposomally encapsulated drugs) for targeted delivery of drug to NHL cells. The goal of these studies is to ultimately develop treatments that will be useful for heavily pre-treated lymphoma patients with extensive previous exposure to such active drugs.

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