This week we would like to introduce you to the work of Professor Vera Krymskaya, Associate Professor of Medicine at the University of Pennsylvania Perelman School of Medicine. Professor Krymskaya’s primary research interest is how signalling pathways cause disease when perturbed, with a focus on the pulmonary diseases Lymphangioleiomyomatosis (LAM) and Birt-Hogg-Dubé (BHD) Syndrome.
Like BHD, LAM is a cystic lung disease caused by an over-proliferation of smooth muscle tissue in the the lungs, mainly affecting women of child-bearing age and individuals with tuberous sclerosis complex (TSC). Professor Krymskaya’s group found that deletion of TSC2 led to the smooth muscle over-proliferation seen in LAM by dysregulation of mTOR signalling. This study also showed that in cell culture the mTOR inhibitor, rapamycin, reduced mTOR signalling and slowed down the growth of TSC2-null cells. This study was the first that suggested that rapamycin could be an effective treatment for LAM, and formed the scientific basis of the MILES trial, which showed rapamycin is an effective treatment for pulmonary LAM (Goncharova et al., 2002; McCormack et al., 2011). This study used cells taken directly from LAM patients’ lungs and grown in culture; Professor Krymskaya’s lab remains the only group in the world to successfully perform this procedure using cells from LAM patients.
While rapamycin halts the growth of lung cysts it does not reverse the lung damage seen in LAM, and has to be taken continuously to stop the disease progressing (McCormack et al., 2011). However, long-term use of rapamycin has been shown to have some severe side-effects, such as hypercholesterolemia and mucositis (McCormack et al., 2011). More recently, Professor Krymskaya’s team have shown that combined therapy of rapamycin and simvastatin in a mouse model of LAM not only stopped the progression of the disease, but that simvastatin seemed to partially reverse the lung damage seen in these animals (Goncharova et al., 2012). Simvastatin is widely used to reduce cholesterol and is not known to have any common adverse side-effects with long-term use. Therefore, if simvastatin proved effective in the treatment of LAM in clinical trials, it could be made available to all LAM patients very quickly.
Hoping to reproduce her success in LAM, Professor Krymskaya’s work on BHD aims to elucidate how FLCN mutations cause cyst formation in the lungs, with the expectation that finding this mechanistic link will suggest potential therapies. Indeed, Professor Krymskaya’s team co-authored a recent study reporting that FLCN interacts with PKP4 to regulate RhoA signalling (Medvetz et al., 2012; Nahorski et al., 2012), suggesting that progress in this area is already being made.
To find out more about Professor Krymskaya and her work at the University of Pennsylvania, please watch our video interview (with its accompanying transcript and audio-only files). Video interviews are also available with Professor Frank McCormack, who also works on LAM and was instrumental in the set up of the MILES trial; and Dr Doug Medvetz and Professor Elizabeth Henske who led the FLCN and RhoA signalling study.
Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM, Panettieri RA Jr, & Krymskaya VP (2002). Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). The Journal of biological chemistry, 277 (34), 30958-67 PMID: 12045200
Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM, & Krymskaya VP (2012). Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Science translational medicine, 4 (154) PMID: 23035046
McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium & MILES Trial Group (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364 (17), 1595-505 PMID: 21410393
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
Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, & Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics, 21 (24), 5268-79 PMID: 22965878