Dr. Johnson’s laboratory works on three major projects. The first project is aimed at elucidating molecular mechanisms that regulate myeloid differentiation, with a long-term goal of translating laboratory findings into clinical trials for leukemia patients. These studies have determined that activation of the MEK/ERK kinase signaling pathway is critically important for chemical- and cytokine-induced differentiation of normal myeloid progenitors. A transgenic model has been developed that allows inducible expression of a constitutively-active MEK enzyme exclusively in myeloid lineage cells. Ongoing characterization of this model is allowing assessment of the in vivo role of the MEK/ERK pathway in myelopoiesis and leukemia development. Additionally, Dr. Johnson’s lab has shown that Src Family Kinases (SFKs), which are frequently hyperactivated in leukemias, act to negatively regulate myeloid differentiation. Molecular targets of SFKs in myeloid cells are currently being identified via microarray and proteomic approaches. Moreover, these studies have led to the development of an ongoing clinical trial in acute myeloid leukemia patients that incorporates an SFK inhibitor (dasatinib) in combination with a differentiation agent (ATRA). Analysis of patient specimens from this trial is expected to provide further insight regarding the in vivo role of SFKs in leukemia.
The second project in Dr. Johnson’s lab involves determination of the mechanisms of chemotherapy resistance in head and neck cancer, and evaluation of small molecule inhibitors of Bcl-2 family members. These studies have revealed that anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-XL, Mcl-1) are overexpressed in head and neck cancers. Targeted inhibition of these anti-apoptotic proteins using a variety of cutting-edge small molecule inhibitors dramatically enhanced the sensitivities of head and neck cancer cells to conventional chemotherapy drugs. These preclinical studies are being used to design novel therapeutic strategies for clinical testing in head and neck cancer patients.
The third project in Dr. Johnson’s lab aims to investigate the mechanisms and impact of next-generation proteasome inhibitors on in vitro and in vivo growth of head and neck cancer cells. These studies have shown that proteasome inhibitors induce upregulation of pro-apoptotic Bcl-2 family members (Bik and Bim) that are required for cell killing by these compounds. Additionally, proteasome inhibitors induce the expression of anti-apoptotic Mcl-1, as well as STAT-3, which act to attenuate killing by the compounds. Pharmacologic inhibition of Mcl-1 or STAT-3 served to markedly enhance the abilities of proteasome inhibitors to kill head and neck cancer cells. The anti-tumor efficacies of these combinatorial approaches are currently being evaluated using in vivo models.
Miranda MB, RL Redner and DE Johnson. Inhibition of Src family kinases enhances retinoic acid-induced gene expression and myeloid differentiation. Molecular Cancer Therapeutics 6:3081-3089, 2007.
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