The Centers of Biomedical Research Excellence (COBRE), together with support from Rhode Island Hospital and the Rhode Island community will enable us to develop the faculty and facilities needed to build a strong, interactive cancer research center focusing on the development of junior faculty pursuing research relevant to the cellular and molecular pathogenesis of cancer.
Project 1 - Rachel Altura, MD - Post-translational modification of survivin: a novel therapeutic approach for cancer
Survivin is a cancer-associated protein with dual functions as a cell death inhibitor and as a cell division regulator. It is highly expressed in chemo-resistant tumors, making it a prognostic marker for high-risk disease. Tumor cells that express Survivin cannot compensate for a dysfunctional Survivin protein and undergo rapid and spontaneous cell death in its absence. The biochemical mechanism by which Survivin binds to itself and to its partner proteins is unclear. Our preliminary data suggests that Survivin is modified by acetylation, implicating this biochemical process as a mechanism of its function and stability. The short-term goals of this proposal are to identify the proteins that acetylate Survin, identify the specific residues at which the acetylation occurs and determine how these biochemical modifications alter the pro-survival function of Survivin in human tumor cells. The long-term goals of this project are to provide insight into unexplored biochemical mechanisms that will ultimately lead to novel therapies directed to pivotal steps in tumor cell death pathways.
Project 2 - David Mills, PhD – Involvement of stem-like cells in models of spontaneous transformation
Research in the laboratory of David Mills, PhD seeks to identify and characterize candidate cancer stem-like cells using various rat and human cell lines. More recently, we have applied our tumor models to the collaborative development of a novel metalloprotein nanoconjugate MRI contrast agent with strong therapeutic potential. We have briefly conjugated genetically modified ferritin to a monoclonal antibody against Necl-5, a cell surface glycoprotein expressed by many epithelial cancers. In recently published work, in vitro studies showed strong reactivity of the nanoconjugate to transformed Necl-5 positive rat prostate epithelial cells and demonstrated that the agent exhibited strong MRI contrast characteristics. Significantly, recent in vivo studies successfully targeted Necl-5 positive tumor xenografts grown in an immunodeficient mouse model, demonstrated highly specific targeting of the tumor by the nanoconjugate and confirmed the utility of this agent as a highly sensitive MRI contrast agent. We anticipate that the successful completion of our studies has the potential to advance early cancer detection methods and improve patient therapeutic options.
Project 3 - Jennifer Sanders, PhD - Growth Regulation of Liver Progenitor Cells
Based on previous work on liver development in the rat, Jennifer Sanders, PhD hypothesizes that oval cells and the subpopulation of fetal cells capable of liver repopulation will exhibit a selective growth advantage, the hallmarks of which will be mitogen-independence, sustained c-Myc activity, and rapamycin resistance. Sanders will address this hypothesis by studying the regulation of key mitogenic pathways involving ERK, phosphatidylinositol 3-kinase (PI3K), Akt and mTOR, JNK and Wnt/beta-catenin in these cell types. Sanders will also study the regulation of the c-Myc/Max/Mad network. Western immunoblotting, immunofluoresence, RT-PCR, and chromatin immunoprecipitation will be used to delineate the role of these signaling networks in oval cell and fetal liver progenitor proliferation and growth. The proposed studies may lead to the identification of factors that promote or inhibit liver progenitor cell engraftment and expansion. Furthermore, given the role of oval and liver progenitor cells in hepatic cancer, these studies may provide insight into mechanisms of hepatic carcinogenesis.
Project 4 - Kimberly Perez, MD- Heterogeneity of Colorectal Cancer
This project explores the role of phenotypic heterogeneity of colorectal tissue in clinical prognosis and therapeutic outcomes. The advent of imaging mass spectrometry (IMS) and WAVE technology offer a novel means to assess the extent of phenotypic heterogeneity by determining the geographic signature of an individual’s tumor tissue, thereby avoiding the need for specific antibodies and the potential artifacts inherent in quantitative immune-histochemical (IHC) analysis.