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Raymond R. Mattingly, PhD
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RESEARCH INTERESTS:
Cellular and Molecular Pharmacology:
Signal Transduction through Small GTPases of the Ras Superfamily
Our studies focus on the physiological roles and pharmacological significance of small GTPases of the Ras superfamily. In particular, we are interested in how to target disorders where the Ras pathway is activated without direct oncogenic mutation of the Ras protein itself. While such activating changes in Ras are the most common oncogenic mutations in human cancer, the majority of cancers and many other hyperproliferative disorders have increased Ras signal transduction that is driven through other mechanisms. In recent years, our efforts have concentrated in the areas of Type 1 Neurofibromatosis (NF1) and breast cancer.
NF1 is the most frequent genetic cause of both tumors and neurological problems, with a birth incidence of about 1 in 3,000. Nearly all patients have benign neurofibromas, and there is increased risk of malignant peripheral nerve sheath tumors and other cancers. There is no effective current pharmacological treatment for these tumors. We have developed collaborative projects with the goal of the identification of non-toxic and mechanistically specific drugs for NF1 treatment. Our hypothesis is that increased activation of Ras signaling underlies the pathological development of NF1 and provides therapeutic targets.
Some potential pharmacological targets in the maturation and function of Ras
Our work in breast cancer research is focused on the identification of new therapeutic approaches through the development and use of novel 3D in vitro models. We believe that this approach will provide more relevant results than are obtained from testing new drugs in conventional cell culture in 2D on plastic dishes, while being significantly more rapid and high-throughput than testing in animals. We are addressing two main problems: discovery of the factors that cause the progress from ductal carcinoma in situ (DCIS) to find how to block malignant progression; and identification of a viable targeted approach to triple-negative disease/basal-type breast cancer. We expect that the models and approaches that we are developing will address both of those challenges, and also be useful to other investigators who are tackling other important issues in breast cancer.
3D culture models of normal breast structure and pre-malignant progression to the dysplastic DCIS stage. Images are composites of differential interference contrast visualization and detection of the actin cytoskeleton (red), nuclei (blue), and activated caspases in cells undergoing apoptosis (green).
Lab Personnel
Quanwen Li, Senior Research Scientist
Komal Sane, Pharmacology Graduate Student
Hitchintan Kaur, Graduate Student
Courtney Baracy, Master’s Student
Ray Menard, PhD 2003, now an Instructor at St Petersburg College
Huibin Yang, Postdoctoral Research Associate (2002 – 5), now Research Investigator at the University of Michigan
Josh Dilworth, PhD 2006, now medical resident at Beaumont Hospital
Dan LaLonde, summer undergraduate student (2004 – 7), now in Wayne State University medical school
Jonathan Wojtkowiak, PhD 2008, now a Post-Doctoral Fellow at the Moffitt Cancer Center
Selected Recent Publications
* Q. Li, S. Roshy-Mullins, B.F. Sloane & R.R. Mattingly. p21-activated Kinase 1 Coordinates Aberrant Cell Survival and Pericellular Proteolysis in a Three-dimensional Culture Model for Pre-malignant Progression of Human Breast Cancer. Neoplasia 10: 314-328 (2008)
[http://www.ncbi.nlm.nih.gov/pubmed/18392133]
* J.W. Wojtkowiak, F. Fouad, D.T. LaLonde, R.A. Gibbs, J.J. Reiners Jr, R.F. Borch & R.R. Mattingly. Induction of apoptosis in Neurofibromatosis Type 1 malignant peripheral nerve sheath tumor cell lines by a combination of novel farnesyl transferase inhibitors and lovastatin. J. Pharmacol. Exp. Ther. 326: 1-11 (2008)
[http://www.ncbi.nlm.nih.gov/pubmed/18367665]
* Q. Li & R.R. Mattingly. Restoration of E-cadherin cell-cell junctions requires both expression of E-cadherin and suppression of ERK MAP kinase activation in Ras-transformed breast epithelial cells. Neoplasia 10: 1444-1458 (2008)
[http://www.ncbi.nlm.nih.gov/pubmed/19048123]
* Q. Li, A.B. Chow & R.R. Mattingly. Three-dimensional (3D) overlay culture models of human breast cancer reveal a critical sensitivity to MEK inhibitors. J. Pharmacol. Exp. Ther. 332: 821-8 (2010)
[http://www.ncbi.nlm.nih.gov/pubmed/19952304]
* K.M. Sane, M. Maynor, D.T. LaLonde, I.S. Dean, J.W. Wojtkowiak, F. Fouad, R.F. Borch, J.J. Reiners Jr., R.A. Gibbs & R.R. Mattingly. A novel geranylgeranyl transferase inhibitor in combination with lovastatin inhibits proliferation and induces autophagy in STS-26T MPNST cells. J. Pharmacol. Exp. Ther. In press DOI:10.1124/jpet.109.160192 (2010)
[http://www.ncbi.nlm.nih.gov/pubmed/20086055]
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