Recent advances in our understanding of cancer cell biology provide new opportunities to identify drugs which target the molecular mechanisms involved in neoplastic transformation, cancer growth and metastasis. The proposed research analyzes two novel targets for anti-cancer therapeutics, the histamine H2-receptor (H2R) and the tetraspanins. The H2R mediates myeloid cell differentiation. Therefore, H2R agonists may be useful in treatment of acute myelogenous leukemia (AML). The feasibility of H2R agonists as differentiation therapy for AML will be addressed by 1) characterizing the differentiation of HL-60 pro-myelocytes and AML cells with histamine, all-trans retinoic acid (RA) and with histamine + RA, 2) analysis of the molecular basis for the signaling pathway- dependent pharmacological properties of the H2R. The H2R is a G- protein coupled preceptor that mediates activation of adenylyl cyclase via the G-protein Gs and activation of phospholipase C via G1/G16. This proposal will address the hypotheses that 1) pro-myelocytes express two H2R subtypes and that 2) specific G-proteins determine the pharmacological proteins of the H2R. The tetraspanins are a recently discovered, large, and broadly expressed family of integral membrane proteins. Tetraspanins are a recently discovered, large, and broadly expressed family of integral membrane proteins. Tetraspanins interact with, and regulate the activity of, specific integrins and regulate cell adhesion and migration. Tetraspanins suppress metastasis in several animal tumor models, and reduced tetraspanins expression correlates with increased metastatic potential and poor prognosis in six different cancers. We will 1) define the structural requirements for tetraspanin association with integrins and 2) define the mechanism of tetraspanin function in cell migration, activation and differentiation. Our hypothesis is that tetraspanins associate with integrins via the hypervariable loop in the second extracellular domain and that this association allows tetraspanins to modulate integrin avidity. The development of compounds that target the H2R or tetraspanins will involve 1) the optimized design of H2R agonists by evaluation alternative scaffolds, 2) the characterization of H2R agonists in biologic systems, 3) the development and screening of imadazole-based libraries for substituents possessing tetraspanin affinity and 4) the evaluation and refinement of H2R agonists tetraspanin ligands identified in high-throughput screening for combinatorial libraries. The proposed work will provide important information on the feasibility of cancer therapy strategies that are distinct from traditional cytostatic approaches.
Showing the most recent 10 out of 240 publications
