The Toretsky Lab


Toretsky

"Our laboratory links together very basic biophysical phenomena of protein interaction as an approach to new drug discovery for cancer. It's a creative, multidisciplinary, frontier challenge."

Jeffrey Toretsky, MD

News

Our paper on YK-4-279 synergy was just published in Science Signaling !!!!! Congratulations everyone!!!!!!!

TITLE: Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in Ewing’s sarcoma

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LAB PHOTOSHOOTING 2017



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Jessica Haladyna awarded St. Baldrick’s Foundation Summer Fellowship that led to our successful resubmission of the YK-4-279 synergy paper to Science Signaling. Thank you St. Baldrick and way to go Jessica!



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The second annual Children’s Cancer Foundation Symposium with talks by Drs. Toretsky and Uren, among others. Learn more about the event here





Dr. Toretsky presented a talk titled “Targeting EWS-FLI1 in Ewing sarcoma” at the annual American Society of Pharmacology and Experimental Therapeutics in Chicago, IL.





First Phase Separation and RNA Processing as Drivers of Cancer and Neurodegenerative Disease Conference in La Jolla, CA led by Co-organizers Jeff Toretsky and Aaron Hoskins. This meeting was supported by an NIH R13, Burroughs-Wellcome Grant, and corporate support, despite the bankruptcy of ZING, the original sponsor!



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A great article from STAT about Dr. Toretsky's "odyssey" to commercialize the molecule that he and the lab discovered for Ewing Sarcoma Enjoy the full article here





Congratulations to Megan and Jessica on receiving their white coats!! More about The White Coat Ceremony at the Georgetown University School of Medicine here





Dr. Toretsky will present a talk titled "Oncogenesis through splicing leads to therapeutic opportunity" at the upcoming 1st International Caparica Conference in splicing in Lisbon, Portugal, September 12th - 14th, 2016.





Congratulations to Saravana for receiving a Travel Award to attend the 2016 Bermuda Principles Impact on Splicing Conference! The conference will take place on November 8-10th, 2016 in the exotic holiday island of Bermuda!! Congrats, Saravana!





Dr. Toretsky will present a talk titled "Small Molecule Targeting of the Intrinsically Disordered Oncoprotein EWS-FLI1" at the upcoming Intrinsically Disordered Proteins Gordon Research Conference in Les Diablerets, Switzerland, June 26 - July 1, 2016.





Congratulations to Elizabeth Borowiec for the GUROP Summer Research Fellowship Award 2016!!! Congrats, Lizzie!!





Congratulations to Haydar and the rest team on their recent publication in The Journal of Biological Chemistry !! Well done, guys!!

Ezrin Inhibition Upregulates Stress Response Gene Expression



The 2015 winner of the NFL Players Association Georgetown Lombardi Award, Devon Still visits our lab and meets Dr. Toretsky







Congratulations to Dr. Toretsky, who was honored by Hyundai Hope On Wheels at an outdoor ceremony at Georgetown Lombardi

What we do

Targeting the Achilles heel of Ewing sarcoma

Our lab focuses on Ewing sarcoma, since the tumors contain a unique target that is not found in non-tumor cells. This unique target offers an opportunity to create new medicines that will more specifically eliminate tumor growth while sparing normal cells. In 2009, Dr. Toretsky and his team revealed the molecule called YK-4-279 that targets Ewing sarcoma with an article in Nature Medicine. YK-4-279 has the potential to be a potent new strategy in the fight against not only Ewing sarcoma, but also other cancers and diseases with similar characteristics.Direct screening for small molecules that bind to EWS-FLI1 required recombinant protein along with surface plasmon resonance technology. Once a lead compound was identified, a network of collaborators in medicinal chemistry, biochemistry, structural biology, and pharmacology helped advance the molecule YK-4-279, as an inhibitor of EWS-FLI1, towards a clinical trial. Significant efforts failed to obtain a commercial partner to license YK-4-279 due to the extraordinarily rare incidence of Ewings sarcoma. Therefore, in 2014 Dr. Toretsky cofounded Tokalas, Inc. to advance an analog of YK-4-279 to a clinical trial that is commencing in the spring of 2016.


Current Collaborators:
Aykut Üren, Georgetown University

Stefan Zollner, Muenster, Germany

Michael Hogarty, Children's Hospital of Philadelphia

Heinrich Kovar, St. Anna's Kinderspital, Vienna, Austria


The emerging role of spliceosome in Ewing sarcoma

Alternative splicing has been implicated as an oncogenic process and provides both a categorization of cancer as well as an opportunity for more effective targeted treatments. Spliceosomal network interactions, including proteins that recognize splice enhancer and silencer regions, are critical for the regulation of alternative splicing leading to oncogenic protein isoforms. Interrogation of complete protein networks remains challenging because it is difficult to modify single interactions while preserving overall network architecture. We hypothesized that EWS-FLI1, Ewing sarcoma (ES) oncoprotein, modulates post-transcriptional gene regulation through novel protein interactions. EWS-FLI1 has multiple connections to the spliceosome and reduction of EWS-FLI1 alters significant numbers of exon skipping and intron inclusion events identified from RNA-seq. Assessment of aberrant splicing driven by EWS-FLI1 may inform oncogenesis and reciprocally, EWS-FLI1 activities may inform splicing mechanisms.


Current Collaborators:
Aaron Hoskins, University of Wisconsin

Zia Khan, University of Maryland


Assemblages

A deeper investigation into the mechanism of YK-4-279 has led Dr. Toretsky into the world of phase separation and soft matter. He is particularly interested in understanding how protein complexes he called 'assemblages' occur and how they function in RNA processing. Current drug-discovery dogma suggests that it is very hard to make a small molecule to prevent two structured proteins from interacting. However, small molecules have a greater likelihood of disrupting intrinsically disordered protein-protein interactions.


Current Collaborators:
Daniel Blair, Georgetown University

Julie Forman-Kay, Toronto Sick Children's Hospital

Who we are

Lab members

Garrett

Garrett Graham
PhD candidate

Saravana

Saravana Selvanathan
PhD

Kalliopi

Kalliopi Tsafou
PhD

Alex

Alex Grego
Research Assistant

Ali

Alexandra Logerfo
Research Assistant

Madison

Madison Betcher
Research Assistant

Former Lab Trainees and Staff

Stefan

Stefan Zoellner
University Hospital Muenster, Germany

Eric

Eric Moseley
MCV Medical School Class of 2021


Selected publications

2016

Saygideger-Kont Y, Minas TZ, Jones H, Hour S, Celik H, Temel I, Han J, Atabey N, Erkizan HV, Toretsky JA, Üren A. Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non-Small Cell Lung Cancer Cells. Neoplasia. 2016 Feb;18(2):111-20. doi: 10.1016/j.neo.2016.01.002. PubMed PMID: 26936397.



2015

Minas TZ, Han J, Javaheri T, Hong SH, Schlederer M, Saygide?er-Kont Y, Celik H, Mueller KM, Temel I, Özdemirli M, Kovar H, Erkizan HV, Toretsky J, Kenner L, Moriggl R, Üren A. YK-4-279 effectively antagonizes EWS-FLI1 induced leukemia in a transgenic mouse model. Oncotarget. 2015 Nov 10;6(35):37678-94. doi: 10.18632/oncotarget.5520. PubMed PMID: 26462019; PubMed Central PMCID: PMC4741957.

Zöllner SK, Rössig C, Toretsky JA. Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer. Cancer Metastasis Rev. 2015 Sep;34(3):417-28. doi: 10.1007/s10555-015-9575-z. PubMed PMID: 26277104.

Selvanathan SP, Graham GT, Erkizan HV, Dirksen U, Natarajan TG, Dakic A, Yu S, Liu X, Paulsen MT, Ljungman ME, Wu CH, Lawlor ER, Üren A, Toretsky JA. Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1307-16. doi: 10.1073/pnas.1500536112. Epub 2015 Mar 3. PubMed PMID: 25737553; PubMed Central PMCID: PMC4371969.

Erkizan HV, Schneider JA, Sajwan K, Graham GT, Griffin B, Chasovskikh S, Youbi SE, Kallarakal A, Chruszcz M, Padmanabhan R, Casey JL, Üren A, Toretsky JA. RNA helicase A activity is inhibited by oncogenic transcription factor EWS-FLI1.Nucleic Acids Res. 2015 Jan;43(2):1069-80. doi: 10.1093/nar/gku1328. Epub 2015 Jan 6. PubMed PMID: 25564528; PubMed Central PMCID: PMC4333382.

Celik H, Sajwan KP, Selvanathan SP, Marsh BJ, Pai AV, Kont YS, Han J, Minas TZ, Rahim S, Erkizan HV, Toretsky JA, Üren A. Ezrin Binds to DEAD-Box RNA Helicase DDX3 and Regulates Its Function and Protein Level. Mol Cell Biol. 2015 Sep;35(18):3145-62. doi: 10.1128/MCB.00332-15. Epub 2015 Jul 6. PubMed PMID: 26149384; PubMed Central PMCID: PMC4539380.

2014

Toretsky JA, Wright PE. Assemblages: functional units formed by cellular phase separation. J Cell Biol. 2014 Sep 1;206(5):579-88. doi: 10.1083/jcb.201404124. Review. PubMed PMID: 25179628; PubMed Central PMCID: PMC4151146.

Shah N, Wang J, Selich-Anderson J, Graham G, Siddiqui H, Li X, Khan J, Toretsky J. PBX1 is a favorable prognostic biomarker as it modulates 13-cis retinoic acid-mediated differentiation in neuroblastoma. Clin Cancer Res. 2014 Aug 15;20(16):4400-12. doi: 10.1158/1078-0432.CCR-13-1486. Epub 2014 Jun 19. PubMed PMID: 24947929; PubMed Central PMCID: PMC4134768.


All publications

Thank you

The Toretsky Laboratory is grateful to many philanthropies for support over the years. Our success has been built on your trust along with your ability to share our vision of using multidisciplinary research to better target cancer.



Ongoing supporters include:

Children’s Cancer Foundation (Baltimore MD)

Alan B. Slifka Foundation

Hyundai Hope on Wheels

St. Baldrick's Foundation

Friend’s of Colin



Previous supporters have included:

Burroughs Wellcome Clinical Scientist Award in Translational Research

Go 4 the Goal

Dani’s Foundation

Rutledge Foundation

CureSearch AFLAC

Make Some Noise Foundation

Liddy Shriver Sarcoma Initiative

Amschwand Sarcoma Foundation

Alex’s Lemonade Stand Foundation



Your tax dollars supported us through these NIH grants:

RC4CA156509
R01CA133662
R01CA138212
R01CA88004
R41CA102841
R01CA78843
RR022388

Get in touch!

The Toretsky Lab
Departments of Oncology and Pediatrics
Georgetown University
3970 Reservoir Rd NW
Washington DC, US
202-687-8655
sarcomalab@georgetown.edu

Data & Software

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