Gabriela Chiosis: Chemical Biology Approach to Investigate Regulation of Pathogenic Stress by the Molecular Chaperone Machinery

Projects currently ongoing in the Chiosis laboratory Projects currently ongoing in the Chiosis laboratory Molecular chaperones are ubiquitously expressed proteins with wide-ranging functions in the folding and cellular translocation of a variety of proteins. Whereas these house-keeping functions are well recognized and have been the subject of intense investigation, it is now becoming clearer that chaperones are also co-opted in pathogenic cells to carry out disease-specific specialized roles. It is now believed that in pathogenic systems, chaperones abet transformation and allow for the blossoming of the disease phenotype.

Research in my laboratory aims to investigate and bring answers to several questions:

  • What are the transformation-specific roles taken on by chaperones? How do they manifest?
  • Can we understand and differentiate the disease abetting roles of chaperones from their house keeping functions?
  • Can we discover pharmacologic modulators (chemical tools) that interact specifically with the disease-specific chaperone complexes (species)?

We use a chemical biology approach based on specific Hsp-targeted inhibitors and other chemical tools that we design and synthesize in our laboratory. Specifically, we develop chemical tools that target the disease-regulating but not the normal cell, house-keeping functions of the Hsps. These tools allow for the investigation of mechanisms refractory to other means, such as biochemical and genetic approaches, and provide the springboard for the development of therapeutics.

Patel PD, Yan P, Seidler PM, Patel HJ, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani RA, Gewirth DT, Chiosis G. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol. 2013 Sep 1. doi:10.1038/nchembio.1335. [Epub ahead of print]

Beebe K, Mollapour M, Scroggins B, Prodromou C, Xu W, Tokita M, Taldone T, Pullen L, Zierer BK, Lee MJ, Trepel J, Buchner J, Bolon D, Chiosis G, Neckers L.  Posttranslational modification and conformational state of Heat Shock Protein 90 differentially affect binding of chemically diverse small molecule inhibitors. Oncotarget. 2013 Jul;4(7):1065-74.

Hong F, Liu B, Chiosis G, Gewirth DT, Li Z. α7 helix region of αI domain is crucial for integrin binding to endoplasmic reticulum chaperone gp96: a potential therapeutic target for cancer metastasis. J Biol Chem. 2013 Jun 21;288(25):18243-8. doi: 10.1074/jbc.M113.468850. Epub 2013 May 13.

Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, Liu F, Saunders LM, Mullally A, Abdel-Wahab O, Leung L, Weinstein A, Marubayashi S, Goel A, Gönen M, Estrov Z, Ebert BL, Chiosis G, Nimer SD, Bernstein BE, Verstovsek S, Levine RL. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012 Sep 6;489(7414):155-9. doi: 10.1038/nature11303.

Brooks JC, Sun W, Chiosis G, Leifer CA. Heat shock protein gp96 regulates Toll-like receptor 9 proteolytic processing and conformational stability. Biochem Biophys Res Commun. 2012 May 18;421(4):780-4. doi: 10.1016/j.bbrc.2012.04.083. Epub 2012 Apr 23.

Azoitei N, Hoffmann CM, Ellegast JM, Ball CR, Obermayer K, Gößele U, Koch B, Faber K, Genze F, Schrader M, Kestler HA, Döhner H, Chiosis G, Glimm H, Fröhling S, Scholl C. Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33. J Exp Med. 2012 Apr 9;209(4):697-711. doi: 10.1084/jem.20111910. Epub 2012 Mar 26.

Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol. 2011 Sep 25;7(11):818-26. doi: 10.1038/nchembio.670.

Breinig M, Mayer P, Harjung A, Goeppert B, Malz M, Penzel R, Neumann O, Hartmann A, Dienemann H, Giaccone G, Schirmacher P, Kern MA, Chiosis G, Rieker RJ. Heat shock protein 90-sheltered overexpression of insulin-like growth factor 1 receptor contributes to malignancy of thymic epithelial tumors. Clin Cancer Res. 2011 Apr 15;17(8):2237-49. doi: 10.1158/1078-0432.CCR-10-1689. Epub 2011 Mar 3.

Cerchietti LC, Hatzi K, Caldas-Lopes E, Yang SN, Figueroa ME, Morin RD, Hirst M, Mendez L, Shaknovich R, Cole PA, Bhalla K, Gascoyne RD, Marra M, Chiosis G, Melnick A. BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy. J Clin Invest. 2010 Nov 1. doi:pii: 42869. 10.1172/JCI42869. [Epub ahead of print]

Usmani SZ, Bona RD, Chiosis G, Li Z. The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1. J Hematol Oncol. 2010 Oct 26;3:40. doi: 10.1186/1756-8722-3-40.

Marubayashi S, Koppikar P, Taldone T, Abdel-Wahab O, West N, Bhagwat N, Caldas-Lopes E, Ross KN, Gönen M, Gozman A, Ahn JH, Rodina A, Ouerfelli O, Yang G, Hedvat C, Bradner JE, Chiosis G, Levine RL. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest. 2010 Oct;120(10):3578-93. doi: 10.1172/JCI42442. Epub 2010 Sep 13.

Cerchietti LC, Lopes EC, Yang SN, Hatzi K, Bunting KL, Tsikitas LA, Mallik A, Robles AI, Walling J, Varticovski L, Shaknovich R, Bhalla KN, Chiosis G, Melnick  A. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nat Med. 2009 Dec;15(12):1369-76. doi: 10.1038/nm.2059. Epub 2009 Nov 22.

Breinig M, Caldas-Lopes E, Goeppert B, Malz M, Rieker R, Bergmann F, Schirmacher P, Mayer M, Chiosis G, Kern MA. Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma. Hepatology. 2009 Jul;50(1):102-12. doi: 10.1002/hep.22912.

Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73. doi: 10.1073/pnas.0903392106. Epub 2009 May 5.

Wang L, Xie C, Greggio E, Parisiadou L, Shim H, Sun L, Chandran J, Lin X, Lai C, Yang WJ, Moore DJ, Dawson TM, Dawson VL, Chiosis G, Cookson MR, Cai H. The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J Neurosci. 2008 Mar 26;28(13):3384-91. doi: 10.1523/JNEUROSCI.0185-08.2008.

Didelot C, Lanneau D, Brunet M, Bouchot A, Cartier J, Jacquel A, Ducoroy P, Cathelin S, Decologne N, Chiosis G, Dubrez-Daloz L, Solary E, Garrido C. Interaction of heat-shock protein 90 beta isoform (HSP90 beta) with cellular inhibitor of apoptosis 1 (c-IAP1) is required for cell differentiation. Cell Death Differ. 2008 May;15(5):859-66. doi: 10.1038/cdd.2008.5. Epub 2008 Feb 1.

Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC, Kang Y, She Y, Wu N, Felts S, Wipf P, Massague J, Jiang X, Brodsky JL, Krystal GW, Chiosis G. Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol. 2007 Aug;3(8):498-507. Epub 2007 Jul 1.

Luo W, Dou F, Rodina A, Chip S, Kim J, Zhao Q, Moulick K, Aguirre J, Wu N, Greengard P, Chiosis G. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc Natl Acad Sci U S A. 2007 May 29;104(22):9511-6. Epub 2007 May 21.

Hieronymus H, Lamb J, Ross KN, Peng XP, Clement C, Rodina A, Nieto M, Du J, Stegmaier K, Raj SM, Maloney KN, Clardy J, Hahn WC, Chiosis G, Golub TR. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30. Epub 2006 Sep 28.

Chu F, Maynard JC, Chiosis G, Nicchitta CV, Burlingame AL. Identification of  novel quaternary domain interactions in the Hsp90 chaperone, GRP94. Protein Sci. 2006 Jun;15(6):1260-9.

Vilenchik M, Solit D, Basso A, Huezo H, Lucas B, He H, Rosen N, Spampinato C, Modrich P, Chiosis G. Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem Biol. 2004 Jun;11(6):787-97.

Chiosis G, Huezo H, Rosen N, Mimnaugh E, Whitesell L, Neckers L. 17AAG: low target binding affinity and potent cell activity—finding an explanation. Mol Cancer Ther. 2003 Feb;2(2):123-9.

Gorre ME, Ellwood-Yen K, Chiosis G, Rosen N, Sawyers CL. BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood. 2002 Oct 15;100(8):3041-4.

Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem. 2002 Oct 18;277(42):39858-66. Epub 2002 Aug 9.

Chiosis G, Boneca IG. Selective cleavage of D-Ala-D-Lac by small molecules: re-sensitizing resistant bacteria to vancomycin. Science. 2001 Aug 24;293(5534):1484-7.

Chiosis G, Timaul MN, Lucas B, Munster PN, Zheng FF, Sepp-Lorenzino L, Rosen N. A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells. Chem Biol. 2001 Mar;8(3):289-99.

Chiosis G, Rosen N, Sepp-Lorenzino L. LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family. Bioorg Med Chem Lett. 2001 Apr 9;11(7):909-13.