This week we would like to introduce you to the work of Dr Douglas Medvetz, a Post-Doctoral Research Fellow in Professor Elizabeth Henske’s team at Brigham and Women’s Hospital. Dr Medvetz moved to Professor Elizabeth Henske’s group in 2008, after completing his PhD in medicinal chemistry at the University of Akron, in Ohio.
Dr Medvetz is currently working to determine to role of the BHD protein, FLCN, in cell adhesion and desmosome formation in BHD lung and skin tumorigenesis, and is funded by the BHD Foundation. Part of this work was published in 2012, and showed that FLCN interacts with PKP4 to regulate RhoA signalling, cell-cell adhesion, desmosome formation and cell migration (Medvetz et al., 2012). This publication also reported the first skin-specific mouse model of BHD. Dr Medvetz and his colleagues found that mice lacking epidermal FLCN were smaller than their wild type littermates and displayed course wavy fur, bald patches and delayed eye-opening – a phenotype which is seen in other cell-cell adhesion gene knockouts (Perez-Moreno et al., 2006). Given that lungs need to expand and contract properly in order to function and that correct cell adhesion is likely to be important for this process, Dr Medvetz suspects that aberrant cell adhesion may cause the lung pathogenesis in BHD.
In addition to his work on BHD, Dr Metvetz is also trying to identify novel therapies for tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM). It has been observed that while Rapamycin treatment halts the deterioration of lung function in LAM, and the growth of angiomyolipomas in TSC, both diseases recommence progression when Rapamycin treatment is stopped (McCormack et al., 2011). Recently, a team of researchers from Professor Elizabeth Henske’s group, including Dr Medvetz, found that the expression of a pro-survival microRNA, miR‑21, is induced by Rapamycin (Trindade et al., 2013). The expression of this miRNA may allow TSC and LAM cells to survive Rapamycin treatment, suggesting that dual mTOR and miR-21 inhibition may not only halt, but instead reverse, disease progression in TSC and LAM.
During the course of his PhD research at the University of Akron, Dr Medvetz published two first author papers demonstrating that cyclic amine and thiaether metal complexes have anti-cancer properties in ovarian cancer cells, and that Silver-based complexes have anti-cancer properties towards both ovarian and breast cancer cells (Medvetz et al., 2007; Medvetz et al., 2008). Finding a drug or therapy for BHD Syndrome remains a motivation and aspiration for Dr Medvetz.
- Medvetz DA, Stakleff KD, Schreiber T, Custer PD, Hindi K, Panzner MJ, Blanco DD, Taschner MJ, Tessier CA, & Youngs WJ (2007). Ovarian cancer activity of cyclic amine and thiaether metal complexes. Journal of medicinal chemistry, 50 (7), 1703-6 PMID: 17343369
- Medvetz DA, Hindi KM, Panzner MJ, Ditto AJ, Yun YH, & Youngs WJ (2008). Anticancer Activity of Ag(I) N-Heterocyclic Carbene Complexes Derived from 4,5-Dichloro-1H-Imidazole. Metal-based drugs, 2008 PMID: 18615197
- Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, & Henske EP (2012). Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PloS one, 7 (11) PMID: 23139756
- Trindade AJ, Medvetz DA, Neuman NA, Myachina F, Yu J, Priolo C, & Henske EP (2013). MicroRNA-21 is induced by rapamycin in a model of tuberous sclerosis (TSC) and lymphangioleiomyomatosis (LAM). PloS one, 8 (3) PMID: 23555865
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.