Spencer Gibson

Biography

In maintaining integrity and homeostasis of multicellular organisms, the balance between cell death and survival is fundamentally important. When this balance is altered, diseases occur such as cancer. One protein important in the regulation of cell death is the Bcl-2 BH-3 only member BNIP3. BNIP3 expression is induced under low oxygen (hypoxia) conditions and is over expressed in solid tumours in hypoxic regions. When BNIP3 is over expressed in cancer cells it induces cell death mediated by mitochondrial dysfunction. This cell death instead of being apoptotic is autophagic (a new form of programmed cell death). This paradox of BNIP3 killing cancer cells and being over expressed in live cells within tumours is a focus of our research. To date three explanations could account of these differences. The first difference is growth factors block BNIP3 cell death function and tumours have deregulated growth factor signaling leading to cell survival (see below). Secondly, BNIP3 is also localized in the nucleus of tumour cells prevent its interaction with the mitochondria blocking its cell death function. Finally, the BNIP3 gene is mutated to an inactive protein. This protein acts in a dominant negative fashion blocking hypoxia induced cell death. The importance of these mechanisms for cancer progression and treatment is under active investigation. Cell survival is as important as cell death. The epidermal growth factor receptor (EGFR) is expressed at high levels in several cancers such as breast cancer. We discovered that pretreatment of breast cancer cell lines with epidermal growth factor (EGF) effectively blocked drug and death receptor induced apoptosis. This protection from apoptosis is mediated by a serine threonine kinase called AKT through up-regulation of the Bcl-2 anti-apoptotic family member Mcl-1. Besides breast cancer, we have found that a lipid, lysophosphatic acid (LPA) blocks apoptosis in chronic lymphocytic leukemia (CLL) cells using a similar mechanism. We are currently investigating the regulatory elements controlling Mcl-1 expression. Molecular-based therapies could alter the balance between cell death and survival towards killing cancer cells. Tumour necrosis factor related apoptosis-inducing ligand (TRAIL) selectively kills cancer cells while normal cells are resistant to TRIAL-induced apoptosis. In collaboration with Dr. James Johnston, we are investigating the potential of TRAIL as a therapy for chronic lymphocytic leukemia (CLL) alone or in combination with chemotherapy. In addition, we previously discovered that chemotherapeutic drugs increase TRAIL death receptor (DR4/5) expression and this contributes to drug-induced apoptosis. We are defining the regulatory elements controlling DR4/5 expression in CLL cells to enhance the clinical effectiveness of TRAIL.

Research Interest

To define the signal transduction pathways leading to cell death or survival. This will elucidate pharmaceutical targets that could alter the cellular balance in favour of cell death. This research will be the foundation to establish clinical trials using molecular targeted therapies to increase effectiveness of chemotherapy in cancer.