Research Statements

2008 July – Present

OVERALL RESEARCH GOALS

GOAL
The overall goal of our research is to gain a better understanding of the molecular regulators of tumor microenvironment, specifically with interest in tumor angiogenesis and tumor metabolism, and how these factors regulate response to radiation therapy. Radiation therapy is the mainstay of treatment for malignant brain tumors, but in no way is curative and continues to have negative consequences. Accordingly, our focus is on identifying barriers to effective tumor cell kill and improved therapeutic index for radiation.

We have three inter-related research programs that integrate the different areas of research activity in Zadeh Lab to build a unifying program.

ESTABLISHING NOVEL IN-VIVO REAL TIME IMAGING STRATEGIES AND PRECLINICAL ANIMAL MODELS OF MALIGNANT BRAIN TUMORS
OVERVIEW

We have developed an experimental strategy that combines intracranial window models with two-photon imaging in chimeric mice that have fluorescent progenitor cells. This allows real-time in-vivo imaging of normal brain and brain tumour associated vasculature in small animal models and offers a novel method for studying in-vivo blood vessel formation in the brain and in response to therapy. We also have worked closely with the our small animal imaging and radiation therapy team to build an in-house stereotactic frame and radiation delivery system to facilitate stereotactic radiation delivery intracranially. Combining the intracranial window with stereotactic radiation offers a unique strategy for studying intracranial single-cell response to ionizing radiation, and puts me in an advantageous position relative to comparable researchers in the field.

INTEGRATED MOLECULAR ANALYSIS

A strong area of focus in our group, the MacFeeters-Hamilton Neuro-oncology Program, is to explore the genomic and molecular profile of brain tumors using integrated multiplatform analysis of human tumors, ranging from malignant gliomas to benign schwannomas and neurofibromas. Through this research we gain better understanding of molecular subtypes of brain tumors, their molecular signatures in response to therapy and mutational profiles that determine resistance to treatment. We are also interested in identifying targets of therapy, primarily focusing on fusion proteins that drive tumor progression. In collaboration with our bioinformatics and molecular genomic colleagues, OICR and international colleagues we are able to do these large scale collaborative multi-institutional studies.

TUMOUR METABOLISM

OVERVIEW
Altered cancer cell metabolism is recognized as a critical mechanism by which cancer cells survive unfavorable microenvironmental conditions. A classic biochemical adaptation is the metabolic shift to aerobic glycolysis rather than mitochondrial oxidative phosphorylation, regardless of oxygen availability, a phenomenon traditionally referred to as the “Warburg Effect”. Aerobic glycolysis, characterized by high glucose uptake, low oxygen consumption and elevated production of lactate is a feature of cancer cells. One of the key regulators of the Warburg Effect is hexokinase-2 (HK2). Our group has previously established that HK2 is aberrantly expressed in and is an important mediator of aerobic glycolysis in malignant brain tumours, providing a proliferative and cell survival advantage to cancer cells. Furthermore we have shown that HK2 is responsible for the highly invasive nature of malignant brain tumours, which is one of the key factors responsible for malignant brain tumours being resistant to therapy and exhibiting an extremely rapid recurrence rate. Therefore, our central hypothesis is that HK2 plays a pivotal role in regulating tumour metabolism, neo-vascularization and modulating response to therapeutics. To test this hypothesis we have been deciphering the molecular mechanisms by which HK2 alters brain tumour metabolism and in turn tumour neo-vascularization. In specific we have identified HK2-regulated genes that modify tumour metabolism, invasion, neo-vascularization and ultimately growth. We are in the process of determining whether HK2 is an efficient therapeutic target for GBMs and discover new compounds that can block HK2 activity. We have examined these compounds in combination with standard therapy or concurrently with anti-angiogenic therapies at different stages of tumour growth in preclinical models to validate their therapeutic benefit prior to translating results to clinical practice. Results from this proposal will be directly translated through clinical trials into clinical practice for improving outcomes for patients with malignant brain tumours.

To investigate our hypothesis we are testing four inter-related aims:
Aim 1: Establish the role of HK2 in regulating tumour neo-vascularization
Aim 2: Determine how HK2 modulates response to therapy
Aim 3: Identify HK2 regulated gene expression
Aim 4: Develop and test inhibitors of HK2 using a small molecule inhibitor library screen

TUMOUR ANGIOGENESIS

OVERVIEW
The overall goal of this research project is to determine the contribution of bone marrow derived progenitor cells (BMDC) to tumour neo-vascularization in order to identify novel therapeutic strategies that can target tumour vascular dependent growth. The specific objectives for this proposal are to determine the mechanisms of BMDC recruitment, migration, differentiation and integration into the tumour vasculature and microenvironment, and in response to radiation therapy (RT). Results from this proposal will provide insights into as yet unidentified mechanisms of tumour neo-vascularization and provide the basis for translational studies that will examine the benefits of targeting BMDC to restrict tumour growth. Central Hypothesis: Key subpopulations of BMDC play distinct roles in tumour neo-vascularization in a spatio-temporal manner. Objectives: Our objectives are based on three inter-related hypotheses: 1) Individual subpopulation of BMDC play distinct roles in tumour neo-vascularization at different stages of tumour growth, 2) BMDC contribute to tumour neo-vascularization in a tumour regional dependent manner, 3) Specific subpopulations of BMDC allow for tumour revascularization and recurrence following radiation therapy (RT). Brain tumours continue to have a poor prognosis and identifying novel approaches that can improve the clinical efficacy of anti-angiogenic agents provides a promising treatment strategy. Results from this project will directly lead to new targeted therapies that will restrict the vascular growth of brain tumours. We believe that specific subpopulation(s) of BMDC promote tumour vascularity at certain stages of tumour growth, while other subpopulations provide an inhibitory effect on tumour vascularity and cancer cell survival. Understanding the exact steps and stages involved in the contribution of BMDC to neo-vascularization will allow us to design precisely targeted therapies, delivered at critical stages of tumour growth, to gain the most effective inhibition of tumour neo-vascularization and prevent recurrence post-RT.

To investigate our hypotheses we are testing three inter-related aims:
Aim#1: Determine the spatio-temporal contribution of key subpopulations of BMDC
Aim#2: Define putative factors that regulate BMDC
Aim#3: Determine the contribution of BMDC to tumour neo-vascularity following RT.