Life Sciences Commons^™

Exploiting Modulation Of The Blood-Brain And Blood-Tumor Barrier Permeability By Translational Focused Ultrasound For Therapeutic Delivery To Cns Metastases, Tasneem A. Arsiwala

Graduate Theses, Dissertations, and Problem Reports

Transcranial low-intensity focused ultrasound is a unique technology to modulate the integrity of tight endothelial junctions and transiently increase BBB/BTB permeability to enhance therapeutic delivery. Despite promising early studies, present literature lacks agreement on key experimental conditions, which restricts our knowledge and the technique's widespread translation. This dissertation first provides a critical review of the current gaps in knowledge regarding the universal use of LiFUS in preclinical and clinical use. We then identify key parameters for translational and predictable opening of the BBB using a 3T MRI coupled with a clinical device. Our investigation highlights that passive permeability of the …

Bypassing The Blood-Brain Barrier: A Physical And Pharmacological Approach For The Treatment Of Metastatic Brain Tumors, Samuel A. Sprowls

Graduate Theses, Dissertations, and Problem Reports

This dissertation (a) provided an in depth literature review of methods to disrupt the BBB/BTB and improve therapeutic distribution to brain tumors, (b) evaluated the use of azacitidine as a single agent therapy for the treatment of brain metastasis of breast cancer and a potential molecular mechanism by which brain tropic cells are sensitized to hypomethylating agents, (c) determined the impact cannabidiol has on P-glycoprotein mediated efflux at the blood-brain barrier and its potential for use as a single agent treatment for metastatic brain tumors, (d) developed a preclinical radiation therapy protocol for use in small animals and in vitro …

Development Of Multifunctional Overhauser-Enhanced Magnetic Rresonance Imaging For Concurrent In Vivo Mapping Of Tumor Interstitial Oxygenation, Acidosis And Inorganic Phosphate Concentration, Artem A. Gorodetskii, Timothy D. Eubank, Benoit Driesschaert, Martin Poncelet, Emily Ellis, Valery V. Khramtsov, Andrey A. Bobko

Faculty & Staff Scholarship

Tumor oxygenation (pO2), acidosis (pH) and interstitial inorganic phosphate concentration (Pi) are important parameters of the malignant behavior of cancer. A noninvasive procedure that enables visualization of these parameters may provide unique information about mechanisms of tumor pathophysiology and provide clues to new treatment targets. In this research, we present a multiparametric imaging method allowing for concurrent mapping of pH, spin probe concentration, pO2, and Pi using a single contrast agent and Overhauser-enhanced magnetic resonance imaging technique. The developed approach was applied to concurrent multifunctional imaging in phantom samples and in vivo in a mouse model of …

Uncovering The Signaling Landscape Controlling Breast Cancer Cell Migration Identifies Novel Metastasis Driver Genes, Esmee Koedoot, Michiel Fokkelman, Vasiliki-Maria Rogkoti, Marcel Smid, Iris Van De Sandt, Hans De Bont, Chantal Pont, Janna E. Klip, Steven Wink, Mieke A. Timmermans, Erik A. C. Wiemer, Peter Stoilov, John A. Foekens, Sylvia E. Le Dévédec, John W. M. Martens, Bob Van De Water

Faculty & Staff Scholarship

Ttriple-negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype. Enhanced TNBC cell motility is a prerequisite of TNBC cell dissemination. Here, we apply an imaging-based RNAi phenotypic cell migration screen using two highly motile TNBC cell lines (Hs578T and MDA-MB-231) to provide a repository of signaling determinants that functionally drive TNBC cell motility. We have screened ~4,200 target genes individually and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, which are linked to signaling networks predictive for breast cancer progression. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF are essential …

Shp2 Acts Both Upstream And Downstream Of Multiple Receptor Tyrosine Kinases To Promote Basal-Like And Triple-Negative Breast Cancer, Fatimah Matalkah, Elisha Martin, Hua Zhao, Yehenew M. Agazie

Faculty & Staff Scholarship

Introduction: Dysregulated receptor tyrosine kinase (RTK) signaling is a common occurrence in basal-like and triple-negative breast cancer (BTBC). As a result, RTK-targeting therapies have been initiated but proved difficult, mainly owing to the multiplicity of dysregulated RTKs. Hence, targeting master regulators of RTK signaling might alleviate this obstacle. Before that, however, defining the mechanism of such molecules is required. In this report, we show that the Src homology phosphotyrosyl phosphatase 2 (SHP2) is a master regulator of RTK expression and signaling in BTBC.

Methods: Xenograft tumor growth studies were used to determine the effect of SHP2 inhibition on tumorigenesis and/or …