Grant: Foundation Grant

Cancer Progression And Metastasis; Cancer Therapeutics; Carbonic Anhydrase Ix/Xii; Epithelial-Mesenchymal Transition (Emt); Invasion And Invadopodia; Metabolism And Angiogenesis; Synthetic Lethal Screen; Therapeutic Antibodies; Tumor Hypoxia; Tumor Microenvironment; Tumor Recurrence And Drug Resistance

<html> <body> <p>The vision and overall objective of our research program is to uncover the molecular basis of how the Tumor Microenvironment (TME) influences tumor cell behavior, to build on our expertise in extracellular matrix (ECM) biology and tumor hypoxia, and to translate our findings into improving cancer therapy. A major focus of our program is tumor hypoxia, which results in severe environmental stress on the tumor cells, forcing adaptation mechanisms for survival and metastasis due to altered metabolism, pH regulation, epithelial-mesenchymal transition (EMT), migration/invasion and diminished immune response.<br> <br> My established CIHR funded programs in tumor hypoxia, EMT, and invasion have led to the identification of the Carbonic Anhydrase IX/XII ( CAIX/XII) as essential hypoxia-mediated regulators of tumor growth, invasion, cancer stem cell function and metastasis, indicating that these cell surface enzymes are promising therapeutic targets. In order to translate these findings to clinical relevance, we have developed a specific small molecule inhibitor of CAIX/XII, <strong>SLC-0111</strong>, which has recently entered multi-centre <strong>Phase 1 clinical trials for the treatment of solid cancers.</strong> In addition, we are developing novel anti-CAIX therapeutic and imaging antibodies as alternative &ldquo;theranostic&rdquo; strategies.<br> <br> While we have made substantial progress in establishing CAIX as a vital regulator of hypoxia mediated tumor progression and metastasis, significant challenges remain in our understanding of the mechanisms and molecular basis of system wide interactions between the metabolic effectors of hypoxia. The <strong>major goal</strong> of this Foundation Scheme program is to discover the network of proteins and interacting pathways involved in the adaptive response of tumor cells to hypoxia and acidosis.<br> <br> The specific objectives of this 7 year program will be:<br> <br> 1) a) Evaluate novel CAIX small molecule inhibitors and anti-CAIX therapeutic antibodies, and co-target CAIX with b) other pH/acidosis regulators ( CAXII, MCT-4 and NHE-1), c) anti-angiogenesis agents; and d) immune cell modifiers<br> <br> 2) Identify novel CAIX interactors and signalling networks through innovative genomic and proteomic approaches involving the CRISPR/Cas gene-deletion and novel BioID proximal ligation proteomics strategies, respectively.<br> <br> 3) Develop CAIX and MCT-4 single and compound knock-out mice in transgenic models of tumor progression.<br> <br> The results from this comprehensive program will provide new mechanistic insights in tumor cell adaptation to hypoxic stress, and the networks and pathways involved in the regulation of pH and acidosis in hypoxia. Significantly, this knowledge will be translated into improved cancer treatment through the identification of new therapeutic targets and the development of new pharmaceutical and biotherapeutic agents and co-targeting strategies.<br> <br> This research program will have exceptional core and institutional support at BCCRC and UBC and will be supported by a comprehensive group of Program Experts and Partners who will provide expertise in areas that require specialty techniques, bioinformatics analysis, and clinical data and samples.<br> <br> The program will result in the training and mentoring of new undergraduate and postgraduate students, post-doctoral fellows and senior staff scientists. These trainees will acquire expertise and skills in oncology and diverse biomedical research areas, and will have the opportunity to enter career paths in academia, industry and teaching.<br> </p> </body> </html>