Our objective is to understand the regulatory mechanisms that control the proliferation, differentiation and apoptosis of cells and how oncoproteins subvert these mechanisms to cause cancer. Cancer involves the loss of regulatory mechanisms that control the balance between cell growth, apoptosis and differentiation. We are studying key signaling pathways that are involved in oncogenesis to both understand the underlying molecular pathways and also design drugs to target these pathways. We have two main projects. One project involves a mouse model of pancreatic cancer and another using a novel approach to design prodrugs to target enzymes commonly up-regulated in cancer cells.
Pancreatic cancer metastasis:. Pancreatic cancer is one of the deadliest human malignancies. A striking feature of pancreatic cancer is that oncogenic activating Kras mutations are found in ~90% of cases. However, apart from a restricted population of Pdx1-expressing cells, most pancreatic cells are refractory to Kras transformation. In this study, we are determining which subsets of Pdx1+ cells may be responsible for tumor growth. We identified, isolated and characterized a population of KrasG12D-expressing Pdx1+ cells with an inherent capacity to metastasize. This population of Pdx1+ cells bears the surface phenotype of EpCAM+CD24+CD44+CD133-Sca1- and is closer in its properties to stem-like cells than to more mature cell types. Our findings are consistent with the hypothesis that the adult pancreas harbors a dormant progenitor population that is mobilized under conditions of oncogenic stimulation and is able to initiate tumor growth. Our recent data imply that deregulation of Ras/Erk/Myc pathway is an important determinant of metastatic predisposition.
Pro-Drug development against cancer : Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. We are developing a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents. We are presently optimizing the prodrug modifications to improve selectivity for cancer cells.
For additional information, please see a technology overview of our approach to novel cancer Pro-Drug development (pdf file).