Center for Content Rich Evaluation of Therapeutic Efficacy
Katherine Ferrara, Distinguished Professor and Director, Department of Biomedical Engineering
Steven C. Currall, Dean and Professor of Management Graduate School of Management
Ralph deVere White, Director of the UC Davis Comprehensive Cancer Center and Distinguished Professor of Urology
Fredric Gorin, Professor and Chair, Neurology
Bruce Hammock, Distinguished Professor, Department of Entomology and UC Davis Cancer Center
Alexander Revzin, Associate Professor Department of Biomedical Engineering
Clifford Tepper, Associate Research Biochemist, Department of Biochemistry and Molecular Medicine
In the Center for Content Rich Evaluation of Therapeutic Efficacy (cCRETE, pronounced “secrete”) RISE program, we focus on assays of cell secreted factors in vitro and in vivo, including exosomes, peroxide, and matrix metalloproteinases (MMPs). Cell secreted factors are of interest in 1) gauging the response to therapy with new drugs and 2) the development of an understanding of cell-to-cell communication. The “rich” content to be assessed to understand the impact of cell secretions goes beyond the quantification of traditional markers such as proliferation and apoptosis to evaluate markers of invasive potential, inflammation, “stem-ness”, autophagy and metabolic pathways.
With respect to the response to therapy, the cost of bringing a new drug to market is now estimated to exceed $1 billion, with the timeline for developing a drug and getting it to market approaching 15 years. During the next 4 years, 9 of the top 10 and 18 of the top 20 best-selling drugs in the world will go off patent. A major challenge for the pharmaceutical industry is their lack of tools to identify promising candidates and to separate the winners from the losers early in the development process. Such tools have the potential to substantially reduce the cost to market for new drugs. To address the critical need for screening tools, a team of cancer biologists, social scientists, bioinformatics experts and bioengineers has formed a single disciplinary group to develop and validate biomarker assays for the effect of new therapeutics. In addition, members of the group (Hammock, Gorin, Ferrara) have developed novel therapeutics that effectively inhibit key pathways in cancer and atherosclerosis; the success of these new therapeutics will require biomarkers, which are one focus of our team. Therefore, one important problem to be solved is the creation of high throughput and content rich assays to summarize the impact of therapeutics on cellular functionality. We are developing in vitro cell microsystems where micropatterned co-cultures of cancer and non-cancer cells are juxtaposed with arrays of sensing elements for monitoring downstream readouts of cell-drug interactions. Further, we are developing and applying in vivo imaging approaches to assess specific targets and efficacy.
Exosomes, which are 50-120 nm lipid vesicles that are released by cells under normal conditions and during stress, have become a focus for our thrust in cell-cell communication. These small vesicles provide a pathway through which diseases, such as cancer and infections, are propagated. Stem cells, differentiated cardiac myocytes, and highly abnormal cancer cells all produce exosomes, but only cancer and stem cell exosomes are known to be abundant and efficiently internalized by other cells, resulting in phenotypic changes. Yet, the mechanisms behind this efficient cell-to-cell communication remain unknown. Investigations of exosomes have been primarily descriptive, with limited investigation of intercellular signaling and trafficking of exosome content. Also, cell-to-cell communication of miRNAs in exosomes is now emerging. Recent functional studies suggest that miRNAs can regulate angiogenesis, endothelial cell stress, senescence, proliferation and vascular inflammation and may provide the basis for therapy in cardiac ischemia and heart failure. As a part of our ongoing RISE program, we have added a focus on characterization of cell secretions of exosomes and miRNA.
1. Zhang G, Panigrahy D, Mahakian LM, Yang J, Liu JY, Stephen Lee KS, Wettersten HI, Ulu A, Hu X, Tam S, Hwang SH, Ingham ES, Kieran MW, Weiss RH, Ferrara KW, Hammock BD. Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth and metastasis. Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6530-5. doi: 10.1073/pnas.1304321110. Epub 2013 Apr 3, PMC3631682.
2. Malik ZA, Kott KS, Poe AJ, Kuo T, Chen L, Ferrara KW, Knowlton AA. Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am J Physiol Heart Circ Physiol. 2013 Apr; 304(7):H954-65. Epub 2013 Feb 1, PMC3625894.
3. Qin S, Fite BZ, Gagnon, KG, Curry F, Thorsen FA, Ferrara KW, The application of imaging to assess the in vivo delivery of therapeutics, Invited paper Annals of Biomedical Engineering, Ann Biomed Eng. 2013 Sep 10. [Epub ahead of print], NIHMS 523072.
4. Leon LJ, P.N., Gorin F, Carraway KL (2013) A cell-permeant amiloride derivative induces caspase-independent, AIF-mediated programmed necrotic death of breast cancer cells. PLoS One. , 8, e63038. PMC3639988.
5. Pasupuleti N, L.L., Carraway KL 3rd, Gorin F. (2013) 5-Benzylglycinyl-amiloride kills proliferating and nonproliferating malignant glioma cells through caspase-independent necroptosis mediated by apoptosis-inducing factor. J Pharmacol Exp Ther., 34, 600-615. PMC3583503.
News releases on 2013 PNAS paper with Hammock Lab here and here