My research deals with apoptosis (programmed cell death) in tumors with the ultimate goal to overcome apoptotic resistance and to identify novel treatment regimens for one of the most difficult to treat tumors that is Glioblastoma WHO IV. Current treatments for this disease consist of surgery, radiation and chemotherapy (Temozolomide). Despite treatment almost all patients succumb to the disease within 12-18 months after diagnosis. Because gliomas are highly heterogeneous, establishing rational drug combination therapies is a central part of my research.
One of our current projects aims at the identification of targets that cause synthetic lethality in the presence of mitochondrial matrix chaperone inhibitors, which are called Gamitrinibs and are in clinical development. Targeting a specialized chaperone network found in tumor cells, Gamitrinibs elicit a tumor cell specific cell death, thus limiting side effects. Our earlier work has demonstrated that these compounds cause a mitochondrial unfolded protein response with a global change in transcription and a subsequent significant suppression of NF-kB signaling. This treatment sensitizes a broad range of recalcitrant cancer cells to extrinsic apoptosis induction in vitro and in vivo. In addition, we identified a novel lethal interaction between Gamitrinibs and the inhibition of a certain class of molecules that reside at the outer membrane of tumor mitochondria. This combined treatment approach is highly efficacious against a variety of tumor models in vitro and in vivo, including glioblastoma and BRAF-inhibitor resistant melanoma.
We are assessing our treatments in sophisticated in vivo models of glioblastoma in collaboration with Dr. Peter Canoll and Dr. Jeffrey Bruce (Department of Neurosurgery).
Karpel-Massler G, Ramani D, Shu C, Halatsch ME, Westhoff MA, Bruce JN, Canoll P, Siegelin MD
. Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo. Oncotarget
. 2016 Jun 7;7(23):33512-28. doi: 10.18632/oncotarget.9257.
Karpel-Massler G, Horst BA, Shu C, Chau L, Tsujiuchi T, Bruce JN, Canoll P, Greene LA, Angelastro JM, Karpel-Massler G, Horst BA, Shu C, Chau L, Tsujiuchi T, Bruce JN, Canoll P, Greene LA, Angelastro JM, Siegelin MD
. A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers. Clin Cancer Res
. 2016 Sep 15;22(18):4698-711. doi: 10.1158/1078-0432.CCR-15-2827.
Karpel-Massler G, Banu MA, Shu C, Halatsch ME, Westhoff MA, Bruce JN, Canoll P, Siegelin MD
. Inhibition of deubiquitinases primes glioblastoma cells to apoptosis in vitro and in vivo. Oncotarget
. 2016 Mar 15;7(11):12791-805. doi: 10.18632/oncotarget.7302.
Karpel-Massler G, Bâ M, Shu C, Halatsch ME, Westhoff MA, Bruce JN, Canoll P, Siegelin MD
. TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo. Oncotarget
. 2015 Nov 3;6(34):36456-71. doi: 10.18632/oncotarget.5505.
Ghosh JC, Siegelin MD
, Vaira V, Faversani A, Tavecchio M, Chae YC, Lisanti S, Rampini P, Giroda M, Caino MC, Seo JH, Kossenkov AV, Michalek RD, Schultz DC, Bosari S, Languino LR, Altieri DC. Adaptive mitochondrial reprogramming and resistance to PI3K therapy. J Natl Cancer Inst
. 2015 Feb 3;107(3). pii: dju502. doi: 10.1093/jnci/dju502.
Pareja F, Macleod D, Shu C, Crary JF, Canoll PD, Ross AH, Siegelin MD
. PI3K and Bcl-2 inhibition primes glioblastoma cells to apoptosis through downregulation of Mcl-1 and Phospho-BAD. Mol Cancer Res
. 2014 Jul;12(7):987-1001. doi: 10.1158/1541-7786.MCR-13-0650.Siegelin MD
. Inhibition of the mitochondrial Hsp90 chaperone network: A novel, efficient treatment strategy for cancer? Cancer letters
. (2013). Jun 10;333(2):133-46.Siegelin, M.D
. Utilization of the cellular stress response to sensitize cancer cells to TRAIL - mediated apoptosis. Expert Opin Ther Targets.
(2012). 16(8): 801-17. Siegelin, M. D
., T. Dohi, C. M. Raskett, G. M. Orlowski, C. M. Powers, C. A. Gilbert, A. H. Ross, J. Plescia and D. C. Altieri. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J Clin Invest
. (2011). 121(4): 1349-60.
Ghosh, J. C., M. D. Siegelin
, T. Dohi and D. C. Altieri. Heat shock protein 60 regulation of the mitochondrial permeability transition pore in tumor cells. Cancer Res
. (2010). 70(22): 8988-93.
Kang, B. H., M. D. Siegelin
, J. Plescia, C. M. Raskett, D. S. Garlick, T. Dohi, J. B. Lian, G. S. Stein, L. R. Languino and D. C. Altieri. Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer. Clin Cancer Res
. (2010). 16(19): 4779-88.
Elias, A., M. D. Siegelin
, A. Steinmuller, A. von Deimling, U. Lass, B. Korn and W. Mueller. Epigenetic silencing of death receptor 4 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in gliomas. Clin Cancer Res
. (2009). 15(17): 5457-65.Siegelin, M. D
., D. E. Reuss, A. Habel, A. Rami and A. von Deimling. Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells. Neuro Oncol
. (2009). 11(2): 122-31. PMCID: PMC2718983
Honors and Awards
Rudi-Busse Dissertation Award for the best doctoral thesis in 2007, Johann-Wolfgang-Goethe University, Frankfurt am Main, Germany 2007
Young Investigator Award, Ruprecht-Karls-University, Heidelberg, Germany2009
Post-Doctoral Research Fellowship awarded by German Research Foundation.2012
Stowell-Orbison Award, United States & Canadian Academy of Pathology, Vancouver, BC, Canada.2013
American Association for Cancer Research (AACR) and National Brain Tumor Society Career Development Award for Translational Brain Tumor Research2013
Translational Grant Program, American Brain Tumor Association (ABTA)