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GISTs and chemotherapy

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GISTs and chemotherapy

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  1. An unbiased compound screenidentifies unexpected novel treatment options for GISTs S. Boichuk, D.J. Lee, K.R. Mehalek, K.R. Makielski, A. Wozniak, N. Korzeniewski, R. Cuevas, J.P. Zewe, S.F. Kuan, D.S. Seneviratne, M.F. Brown, T. Taguchi,P. Schöffski, M. Debiec-Rychter, A. Duensing17th Annual Meeting, Connective Tissue Oncology SocietyPrague, Czech Republic, November 14-17, 2012

  2. GISTs and chemotherapy • GISTs are believed to be resistant to chemotherapy • estimated response rates: 0-15%

  3. GISTs and chemotherapy? • based on early studies, before the advent of KIT IHC as a • diagnostic marker for GIST • many GISTs may have been mischaracterized • (abdominal leiomyosarcoma – largely chemotherapy-resistant) • actual response rates may be underestimated GIST LMS modified from: Hematol Oncol Clin North America 2009; 23:49–6 modified from: pathology.class.kmu.edu.tw

  4. GISTs and chemotherapy? • based on early studies, before the advent of KIT IHC as a diagnostic marker for GIST • many GISTs may have been mischaracterized abdominal leiomyosarcoma – largely chemotherapy-resistant) • actual response rates may be underestimated • revisit chemotherapy for GIST treatment • chemotherapy does not target KIT/PDGFRA •  bypasses resistance mutations!

  5. NCI “Approved Oncology Drugs Set II” • 89 FDA-approved compounds • “classical” chemotherapies • some targeted therapies • 5 GIST cell lines (IM- sensitive, IM-resistant) • 2 LMS cell lines • luminescence-based assays • apoptosis • cell viability  combined score

  6. GISTs are sensitive to certain chemotherapeutic agents GIST LMS transcriptional inhibitors topoisomerase inhibitors effective ineffective

  7. Mithramycin A (MMA) and mitoxantrone (MXN) are effective inducers of GIST cell apoptosis MMA apoptosis viability MXN apoptosis viability

  8. Mithramycin A stimulates GIST cell death by transcriptional inhibition of KIT expression GIST882 GIST430 RT-PCR qRT-PCR

  9. Mitoxantrone rapidly stimulates DNA double strand breaks GIST882 GIST430

  10. Mithramycin A and mitroxantrone induce apoptosis and tumor regression in primary GIST cells and in vivo histopathologic response hem tu myx nec tu (tumor), myx (myxoid degeneration), nec (necrosis), hem (hemorrhage) intratumoral apoptosis (cleaved caspase 3) imatinib-/sunitinib-resistant, patient-derived GIST cells

  11. Summary • GIST cells are sensitive to certain chemotherapeutic agents • in vitro and in vivo • transcriptional inhibitors (mithramycin A) • toposiomerase II inhibitors (mitoxantrone) • proteasome inhibitor (bortezomib, as previously reported) • exploitation of dependency on key oncogenic proteins (KIT) and/or intrinsic DNA damage response • effective induction of apoptotic response in imatinib-resistant cells • potentially valuable treatment option, in particular for GIST patients with therapy resistance

  12. Acknowledgements Duensing Lab Sergei Boichuk Kathleen Makielski Derek Lee Keith Mehalek Nina Korzeniewski Rolando Cuevas Dee Seneviratne Matt Brown Joshua Parry Ying Liu Nicole Spardy Sophie Perdreau PayelChatterjee Anna Chin Jim Zewe Julianne Baron Michelle Tseng • University of Pittsburgh Pathology • Shih-Fan Kuan • Brigham & Women's Hospital • Jonathan Fletcher • MSKCC • Cristina Antonescu • Peter Besmer • Universität Duisburg-Essen • Sebastian Bauer • Katholieke Universiteit Leuven • Maria Debiec-Rychter • Agnieszka Wozniak • Patrick Schöffski • OHSU • Christopher Corless • Michael Heinrich • Cleveland Clinic • Brian Rubin • UC Davis • Nikolai Tomilin • Joseph Siino • Duke University • Huntington F. Willard • Brian Chadwick • Dana Farber Cancer Institute • James A. DeCaprio • Larisa Litovchick • American Cancer Society • (RSG-08-092-01-CCG) • Life Raft Group • GIST Cancer Research Fund • Liddy Shriver Sarcoma Initiative • UPCI pilot project grant • numerous private donors

  13. The response to mithramycin A and mitoxantrone is time-dependent

  14. Mithramycin A-induced transcriptional inhibition involves a global block of RNA pol II activity GIST882 GIST430

  15. Mithramycin A-induced transcriptional inhibition leads to DNA double strand breaks GIST882 GIST430

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