1. Regulation and Function of the Myc Oncogene
Expression of the c-Myc proto-oncogene is often deregulated in a wide-variety of human tumor cells, including leukemias, breast, colon, prostate carcinomas, neuroblastoma, and lung cancers, yet the mechanism of action of the Myc oncoprotein remains unknown. Clearly Myc protein plays a universal role in controlling cell proliferation, as activation of this oncogene drives many types of cells derived from diverse tissues to grow in an uncontrolled manner. Interestingly, Myc can also induce non-transformed cells to undergo programmed cell death or apoptosis. It is thought that this apoptosis program is stimulated by Myc in normal cells to act as a 'safety' mechanism to rid the body of cells that have acquired deregulated, often overexpressed Myc protein. By this approach, the mutated cell constitutively expressing Myc, can be triggered to undergo apoptosis so that further tumour development is quickly curtailed and the organism as a whole remains tumour-free. Thus, in normal cells Myc is essential, ubiquitously expressed and plays a central role in controlling cell growth and cell death; however, when overexpressed Myc can contribute to tumour development in a wide-variety of cell types.
By understanding the mechanism of Myc action we aim to develop strategies to control Myc function and develop novel therapeutics to inhibit tumour growth. Myc is a nuclear, oncoprotein that is thought to function as a regulator of gene transcription. By identifying the subset of genes regulated by Myc we can better understand the biological effectors of the Myc-stimulated growth and death pathways. Moreover, with Myc-target genes in hand we can work from the 'gene up' to identify the molecular mechanism of Myc gene regulation. To this end we have recently helped to develop a new ChIP-on-chip technology which exploits the sensitivity and specificity of chromatin immunoprecipitation (ChIP) with the high throughput microarray technology (chip). With ChIP-on-chip we can profile the specific regions of the genome bound by Myc in living cells. This enables the direct target genes of Myc to be profiled and allows many long-standing questions in the field to be addressed. What are the target genes that Myc regulates to drive tumorigenesis? What is the molecular mechanism of Myc-induced apoptosis? We also aim to understand the mechanism of gene transcription regulated by Myc and have developed a research program to identify the co-factors Myc recruits to chromatin to regulate gene transcription. Our goal is to understand which of these protein:protein interactions is critical to tumorigenesis and then develop inhibitors to disrupt these complexes and block Myc function.
Finally, for a Myc-activated cell to develop into a tumour, Myc-triggered apoptosis must be controlled and we are delineating the mechanism of Myc-induced death. To identify genetic events that can inhibit Myc-induced apoptosis and thereby cooperate with Myc in the transformation process, we are using a retroviral cDNA expression system to functionally clone cDNAs whose product can abrogate apoptosis in a manner similar to bcl-2. By this approach we have been able to identify novel genes as well as known genes whose function in apoptosis regulation had not yet been realized. Thus we have a focused research program directed at understanding Myc regulation and function in tumour initiation and progression.
2. Triggering Tumour-specific Apoptosis
We have shown that statins can induce tumour, but not normal, cells to undergo apoptosis at clinically achievable concentrations. Statins are presently used clinically in the control of hypercholesteremia and thus are readily available for use as anti-cancer agents. We have shown that statins can trigger cell lines and primary cells derived from acute myelogenous leukemia to undergo apoptosis in a highly sensitive manner. Importantly, normal bone marrow and myeloid progenitor cells do not die in response to statins. This research suggests statins may be used clinically to control certain leukemias and, application of statins to patient care is in progress in collaboration with Drs. Mark Minden and Suzanne Trudel (Ontario Cancer Institute, Princess Margaret Hospital, University Health Network). In addition, we have shown statins can trigger additional cells from malignant transformations to undergo apoptosis. We are interested in further defining the molecular mechanism of statin-triggered apoptosis and have numerous projects underway to address this issue. Thus, we have identified that statins can trigger cells of certain tumour types to undergo apoptosis and are now delineating the mechanism of action and clinical efficacy of this potential novel therapeutic.