Grant: Foundation Grant

Cell Signalling Networks; Gastric Cancer; Gene Expression; Growth Factor; Intracellular Trafficking; Oncogenic Activation; Preclinical Models; Receptor Tyrosine Kinase; Resistance; Triple Negative Breast Cancer

<html> <body> <p> <b>Challenge</b> Current therapies are ineffective in many aggressive cancers, which are often refractory to therapeutic interventions and develop drug resistance. Combination therapies could effectively address this issue, however, to select the right combination will require a greater molecular understanding of response in heterogeneous tumors.<br> <br> <b>Overarching goal</b>: To improve success of targeted therapies in cancer patients, my research program will focus on a prominent clinical target, the Met RTK. We have focused on gastric cancers owing to their abysmal survival rates and the fact that Met inhibitors are lead agents in multiple clinical trials, and triple negative breast cancers (TNBCs), which lack targeted therapies, and where the Met RTK is an emerging target associated with enhanced metastasis, poor outcome and resistance to both chemo and radiotherapies.<br> <br> <b>Objectives</b> We propose to build on our extensive knowledge of Met signaling, tumor and molecular biology, using unique pre-clinical models and human derived tissue to:-<br> <br> 1. <i>Identify mechanisms of resistance to Met inhibitors currently in the clinic</i> using our established cohort of resistant gastric cancer patient derived xenografts and a combination of functional genomics approaches.<br> <br> 2. <i>Identify novel mechanisms to enhance degradation of oncogenic RTK as a therapeutic strategy,</i> using a combination of biochemical, fixed and live-imaging approaches to assay RTK subcellular localisation and stability in response to pathway intervention.<br> <br> 3. <i>Discover mechanisms through which Met promotes stemness and enhanced resistance to</i> <i>chemo- and radiotherapies</i> using tumorsphere and co-culture conditions to recapitulate the tumor microenvironment and employing signaling and genomic approaches.<br> <br> 4. <i>Identify actionable collaborating events for TNBCs.</i> We will perform integrative mouse-human tumor genomic analyses and genome editing technologies, using unique Met-dependent models and human TNBC patient-derived xenografts (PDX) to functionally identify critical tumor suppressor genes within the chromosome 5q32-35 region lost in ~60% of TNBCs .<br> <br> <b>Impact</b>: We will provide clinicians with new therapeutic options in aggressive cancers. Our program will (i) decipher mechanisms of resistance to Met inhibitors currently in clinical trials, (ii) identify combinatorial strategies to enhance response and mitigate resistance (iii) define mechanisms through which Met signaling maintains a stem-like program and promotes resistance to standard therapies and (iv) identify actionable strategies or targets to abrogate this response.<br> <br> <b>Core expertise</b>: I have assembled an interdisciplinary team of experts with expertise in: (i) cancer genomics; <i>(ii)</i> proteomics and phosphoproteomics; <i>(iii)</i> cancer energetics; <i>(iv)</i> cancer computational biology and bioinformatics; and <i>(v)</i> clinical research. The highly multidisciplinary fundamental and translational nature of our team provides the collective expertise to achieve our objectives.<br> <br> <b>Mentoring and training</b>: I will train the next generation of highly multidisciplinary biomedical scientists, with hands-on experience in a translational research setting. I will provide my trainees with expertise in cancer biology, signal transduction and functional cancer genomics, which are highly demanded skills in current academic research and pharmaceutical industry. I will teach my trainees to adhere to the highest standard of research ethics and excellence.</p> </body> </html>