Cancer Cell Death

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Cancer Cell Death - Research at Peter Mac

The Cancer Cell Death laboratory aims to understand the mechanisms through which the immune system detects and kills cancerous and virus-infected cells. We apply what we learn to (1) understanding how cancer drugs work and optimising their use, alone and in combination; (2) developing new drugs to block the immune system in graft-versus-host disease, a common and serious complication of bone marrow transplantation; (3) optimising immune-based therapies of cancer and other diseases and (4) understanding the basis of immune deficiency related to perforin dysfunction.

Overview

Good evidence is now emerging that the immune system can play a key role in preventing or controlling cancer by detecting and destroying pre-malignant or even malignant (e.g. metastasising) cells. The Cancer Cell Death laboratory focuses on the molecular pathways used by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to induce cell death. These cells synthesise and store toxins such as the pore-forming protein perforin and a family of pro-apoptotic proteases (granzymes) within their secretory granules, and release them when they make stable contact with a target cell. The immune system prevents cancer by detecting and destroying pre-malignant or malignant cells, whether at the initiation of the process of cellular transformation or during the process of metastasis formation. A major focus of our laboratory is to determine how perforin forms pores in the target cell membrane, allowing the passage of granzymes into the target cell cytosol, where apoptotic pathways are triggered. We have developed a variety of assays to determine how perforin mutations are identified in children with the rare congenital immune-deficiency hemophagocytic lymphohistiocytosis (HLH) results in disordered perforin function. Over the past decade or more, the Cancer Cell Death laboratory has also led the world in working out the biochemical pathways activated by granzymes — showing that the principle pro-apoptotic human granzyme (granzyme B) powerfully activates a mitochondrial death pathway regulated by Bcl-2. As many human cancers over-express Bcl-2, we are now determining how granzyme B and new drugs that inhibit Bcl-2, can cooperate. In certain pathologies, perforin is responsible for life-threatening tissue damage — for example, in kidneys undergoing graft rejection, pancreatic beta cells killed in the course of type I diabetes, and cells in the gut and skin attacked by the immune system during graft-versus-host disease, a frequently fatal complication of bone marrow transplantation. We are therefore developing novel small molecular perforin inhibitors to prevent and/or treat these diseases. We have also found that many of the molecules involved in cytotoxic granule-mediated cell death are encoded by polymorphic genes, and the significance of this finding is under investigation.