Download presentation
Presentation is loading. Please wait.
Published byAlyssa Mallatt Modified over 9 years ago
1
Imatinib Mesylate modulates Regulators of Quiescence in Gastrointestinal Stromal Tumor (GIST) cells Joshua A. Parry, Matthew F. Brown, Danushka Seneviratne, Stefan Duensing, Anette Duensing University of Pittsburgh Cancer Institute, Pittsburgh, PA
2
Clinical and experimental findings suggest tumor cell quiescence in imatinib-treated GIST Major problems of imatinib therapy: therapy resistance incomplete responses Detectable tumor mass under treatment Relapse when imatinib therapy is terminated Tumor cells that do not respond to imatinib by undergoing apoptosis but remain quiescent may be a reservoir for resistant GIST cells Holdsworth, Am J Roentgenol 2007;189:W324-W330 transgenic Kit V558 /+ mouse (in collaboration with C. Antonescu and P. Besmer) PET CT baselineimatinib
3
Tumor cell quiescence Definition: lack of growth/proliferation, “non-dividing state” exit of cell division cycle in G0/G1 reversible In contrast to senescence (= irreversible) Molecular regulators: p27 Kip1 DREAM complex Problem for cancer therapy: quiescent cells do not respond to anticancer agents that target proliferating cells quiescent cells are unlikely to undergo apoptosis
4
Regulation of quiescence proliferating cells cells in G0/G1 APC inactive SKP2 high p27 low CDK active SKP2 low p27 high CDK inactive APC active DREAM active DREAM inactive D R E A M D M R E A
5
Effects of imatinib on regulators of quiescence GIST882
6
p27 Kip1 upregulation in mouse xenografts GIST882 xenografts
7
p27 Kip1 and SKP2 - risk for progression Risk of progression (NCCN) < 63.7% p27 pos. cells > 63.7% p27 pos. cells Total None, very low, low, intermediate 61319 High639 Total121628 Risk of progression (NCCN) ≤ 5 SKP2 pos. cells/HPF > 5 SKP2 pos. cells/HPF Total None, very low, low, intermediate 170 High459 Total21526 SKP2 (p<0.0001) p27 Kip1 (p=0.0797)
8
Non-apoptotic cells enter quiescence after imatinib
9
Quiescent cells can re-enter the cell cycle
10
Imatinib and the DREAM complex mammalian DREAM complex (DP, RB-like (p130), E2F and MuvB=LIN) E2F target gene
11
Conclusions imatinib leads to cell cycle exit and cellular quiescence modulation of the APC CDH1 – SKP2 – p27 Kip1 axis modulation of the DREAM complex members quiescent cells readily re-enter the cell cycle after removal of imatinib compounds that modulate these pathways as potential antitumor agents in GIST?
12
Acknowledgments Duensing Lab Joshua Parry Danushka Seneviratne Matthew Brown Julianne Baron Ying Liu Sophie Perdreau Payel Chatterjee Stefan Duensing American Cancer Society (#RSG-08-092-01-CCG) GIST Cancer Research Fund Life Raft Group (#UPCC-AD-100108) University of Pittsburgh Shih-Fan Kuan Brigham & Women's Hospital Jonathan Fletcher Katolieke Universiteit Leuven Maria Debiec-Rychter Patrick Schöffski Dana Farber Cancer Institute James DeCaprio Larisa Litovchick Memorial Sloan Kettering Peter Besmer Cristina Antonescu
14
Pro-apoptotic Activity of Bortezomib in Gastrointestinal Stromal Tumors (GIST) cells Sebastian Bauer 1, Joshua A. Parry 2, Thomas Mühlenberg 1, Payel Chatterjee 2, Shih-Fan Kuan 2, Jonathan A. Fletcher 3, Stefan Duensing 2, Anette Duensing 2 1 University of Duisburg-Essen, Essen, Germany 2 University of Pittsburgh Cancer Institute, Pittsburgh, PA 3 Brigham & Women’s Hospital, Boston, MA
15
IMATINIB KIT activity tumor cell quiescence risk of relapse when taken off imatinib! GIST APC CDH1 - SKP2 - p27 Kip1 DREAM complex
16
IMATINIB apoptosis tumor cell quiescence risk of relapse when taken off imatinib! GIST APC CDH1 - SKP2 - p27 Kip1 DREAM complex KIT activity
17
apoptosis tumor cell quiescence risk of relapse when taken off imatinib! GIST OTHERCOMPOUNDS? APC CDH1 - SKP2 - p27 Kip1 DREAM complex
18
Histone H2AX is upregulated after imatinib treatment variant of core histone H2A randomly incorporated into nucleosomes rapidly phosphorylated at serine 139 in response to genotoxic stress γ-H2AX mediates DNA damage response reactions potential tumor suppressor Serine 139 1 142 histone H2AXnucleosome
19
Upregulation of H2AX is causatively involved in GIST cell apoptosis imatinib 72h
20
H2AX upregulation is due to increased protein stability IB: ubiquitin Ubiquitin/26S proteasome pathway Mani and Gelmann, JCO 2005; 23:4776-4789
21
Inhibition of the proteasome induces apoptosis in GIST dose responsetime course Bortezomib: Velcade™ (Millennium Pharmaceuticals) proteasome inhibitor FDA-approved for: multiple myeloma mantle cell lymphoma
22
Bortezomib mechanism of action
24
Mechanism of action of Bortezomib RT-PCRqRT-PCR
25
Bortezomib inhibits ongoing gene transcription
26
Bortezomib is effective in imatinib-resistant GIST 24 h 48 h
27
Bortezomib is effective in imatinib-resistant GIST GIST004: imatinib-resistant GIST (short-term culture) Kit +/K641E transgenic mice
28
Inhibition of NF-kB signaling is not involved in Bortezomib-induced apoptosis in GIST bortezomib
29
Conclusions Bortezomib induces apoptosis in GIST cells dual mechanism of action upregulation of H2AX transcriptional inhibition of KIT NOT inhibition of NF-kB signaling new therapeutic option for imatinib-resistant GIST patients
30
Acknowledgments Duensing Lab Joshua Parry Matt Brown Dee Seneviratne Julianne Baron Payel Chatterjee Anna Chin Stefan Duensing American Cancer Society (#RSG-08-092-01-CCG) GIST Cancer Research Fund Life Raft Group (UPPCC-AD-100108) Universität Duisburg-Essen Sebastian Bauer Thomas Mühlenberg Brigham & Women's Hospital Jonathan Fletcher University of Pittsburgh Shih-Fan Kuan Cleveland Clinic Brian Rubin Oregon Health & Science University Christopher Corless Michael Heinrich
Similar presentations
© 2024 SlidePlayer.com Inc.
All rights reserved.