In Vivo Cellular and Molecular Imaging Center

Summary of Research Components in the JHU ICMIC

Combining Anti-angiogenic therapy with siRNA targeting of choline kinase

(PI: Dr. Z.M. Bhujwalla)

Imaging the Role of HIF-1 in Breast Cancer Progression

(PI: Dr. G.L. Semenza)

Imaging and Targeting Hypoxia in Solid Tumors

(PI: Dr. V. Raman)

Molecular and Functional Imaging of the HER-2/neu Receptor

(PI: Dr. D. Artemov)

To determine the effects of choline kinase (CK) inhibition on breast cancer cell metabolism and invasion, under normoxic and hypoxic conditions. Breast cancer cell lines stably transfected with choline kinase targeting small interfering RNA (siRNA) under the control of a hypoxia response element (HRE) or under the control of a mifepristone-inducible (MFP) mammalian expression system will be used.

To inhibit choline kinase activity in solid tumors in vivo using anti-angiogenesis induced hypoxia or mifepristone as a molecular switch, and determine its effect on metabolism, vascularization and metastasis.

To develop preclinical approaches to target choline kinase activity in solid tumors. Adenoviral therapy using the constructs developed will be performed in combination with anti-angiogenic therapy of solid tumors.

To analyze the role of HIF-1 in promoting breast cancer growth and angiogenesis.

To determine the relationship between angiogenesis and oxygenation/metabolism in breast cancers as a function of HIF-1α expression levels.

To determine the effect of alterations in HIF-1α expression and tumor metabolism on breast cancer invasion.

To determine the effect of alterations in HIF-1α expression and tumor physiology on breast cancer metastasis.

To develop a novel, highly specific non-mammalian receptor/ligand imaging system (ER-1 mem) under control of a hypoxia response element and compatible with PET and MR imaging, to image hypoxic regions in preclinical breast cancer models, and monitor the efficacy of hypoxia targeted therapeutic reagents.

To stably express a therapeutic peptide, under the control of the hypoxia response element (HRE), and determine its effect in hypoxic environments in breast cancer cells and preclinical models.

To combine Aims 1 and 2 to noninvasively follow the course of hypoxia during treatment of tumors with the therapeutic peptide using gene therapy and conventional chemotherapy.

To develop and optimize MR methods for noninvasive detection of HER-2/neu receptors in preclinical breast cancer models.

To simulate microenvironment conditions of hypoxia and extracellular acidosis in culture, and determine the effect of the microenvironment on the expression and stability of HER-2/neu receptors. To determine the relationship between receptor contrast and vascular volume and permeability with MRI.

To evaluate tumor pharmacokinetics and the cytotoxic and antiangiogenic effects of Herceptin in solid tumors. To combine anti-HER-2/neu Herceptin therapy with gene therapy targeted against hypoxic regions to improve treatment outcome.