TG Therapeutics, Inc. · NASDAQ:TGTX
TG Therapeutics — Technical Presentation (2015)
16 slides from TG Therapeutics's technical presentation, 2015
Slide 1: Disruption of the mTOR-eIF4F Axis by Targeting PI3Kd and Proteasome
Disruption of the mTOR-eIF4F Axis by Selectively Targeting PI3Kd and Proteasome Potently Inhibits Cap Dependent Translation of c-Myc in Aggressive Lymphomas Changchun Deng, M.D., Ph.D. Mark Lipstein, B.S. Luigi Scotto, Ph.D. Michael Mangone, Ph.D. Owen A. O’Connor, M.D., Ph.D. Columbia University Me
Slide 2: Therapeutic Strategy Targeting c-Myc in Cancer Is Urgently Needed
Therapeutic Strategy Targeting c-Myc in Cancer Is Urgently Needed • C-MYC rearrangement is a risk factor for poor survival in diffuse large B cell lymphoma (DLBCL) Savage et al. Blood 2009; Barrans et al. JCO 2010; Copie-Bergman et al. Blood 2015 • C-MYC expression is a risk factor for poor survival
Slide 3: Potential Strategies to Silence Translation of c-Myc via mTOR-eIF4F Axis
Potential Strategies to Silence the Translation of c-Myc through Targeting the mTOR-eIF4F Axis Carfilzomib TGR-1202 (Cfz) (TG) PI3Kd Bortezomib Idelalisib (Bz) (Cal) eIF4E 4EBP1 Proteasome AKT Amino acids mTOR ? ? P P 4EBP1 eIF4E (eIF4F) eIF4G c-Myc Translation eIF4A Suraweera, A., et al., Mol Cell,
Slide 4: PI3Kd Inhibitors and Proteasome Inhibitors Synergistically Inhibit DLBCL
PI3Kd Inhibitors and Proteasome Inhibitors Synergistically Inhibit DLBCL Observed Inhibition in the DLBCL cell line LY10 Carfilzomib (nM) Bortfezomib (nM) TGR-1202 (mM) Cal-101 (mM)
Slide 5: Dual Inhibition Is Most Synergistic with TG&Cfz
Dual Inhibition of PI3Kd and Proteasome Is Most Synergistic with TG&Cfz Followed by Cal&Cfz > TG&Bz > Cal&Bz Excess Over BLISS (EOB) in the DLBCL cell line LY10 Carfilzomib (nM) Bortfezomib(nM) TGR-1202 (mM) Cal-101 (mM)
Slide 6: Dual Inhibition of PI3Kd and Proteasome Is Most Synergistic with TG&Cfz
Dual Inhibition of PI3Kd and Proteasome Is Most Synergistic with TG&Cfz Followed by Cal&Cfz > TG&Bz > Cal&Bz Ly10 100 O b s e r v e d % In h ib it io n 75 50 25 0 0 25 50 75 100 E x p e c te d % In h ib it io n
Slide 7: TGR-1202&Carfilzomib Most Synergistic in DLBCL, MCL, and Myeloma
TGR-1202&Carfilzomib Is the Most Synergistic Combination in DLBCL, Mantle Cell Lymphoma, and Multiple Myeloma Ly1 S U D H L -2 S U D H L -4 100 100 100 75 75 75 Observed Inhibition (%) 50 50 50 25 25 25 0 0 0 0 25 50 75 100 0 25 50 75 100 0 25 50 75 100 J e k o -1 Z138 M M .1 s 100 100 100 75 75 75
Slide 8: TGR-1202&Carfilzomib Most Synergistic in T Cell Lymphoma
TGR-1202&Carfilzomib Is the Most Synergistic Combination in T Cell Lymphoma H9 HH 100 100 75 75 Observed Inhibition (%) 50 50 25 25 0 0 0 25 50 75 100 0 25 50 75 100 PF382 P12 100 100 75 75 50 50 25 25 0 0 0 25 50 75 100 0 25 50 75 100 Expected Inhibition (%)
Slide 9: Synergistic in Primary CLL and MCL Cells but Not Toxic to Healthy Lymphocytes
TGR-1202 and Carfilzomib Are Synergistic in Primary CLL and MCL Cells but Not Toxic to Healthy Lymphocytes C fz T G 7 .5 m M + C fz Bz C a l 7 .5 m M + B z T G 2 .5 m M + C fz T G 5 m M + C fz C a l 2 .5 m M + B z C al 5m M + B z a. CLL #1 b . CLL #1 100 100 C e ll V ia b ilit y ( % ) 75 75 50 50 25
Slide 10: Synergistically Induce Apoptosis in Lymphoma Cell Lines and Primary Cells
TGR-1202 and Carfilzomib Synergistically Induce Apoptosis in Lymphoma Cell Lines and Primary Lymphoma Cells PARP Cleavage (A:LY7) (C: PF382) PARP PARP b-Actin b-actin (D: CLL-1) PARP (B: LY10) b-actin PARP (E: CLL-2) b-Actin PARP b-actin Caspase 3/7 Activity (F: LY10) 10 Cal-Bort - Cal+Bortb TG-Cfz
Slide 11: Synergistically Inhibit Phosphorylation of 4EBP1 and Expression of c-Myc
TGR-1202 and Carfilzomib Synergistically Inhibit Phosphorylation of 4EBP1 and Expression of c-Myc (A: DLBCL) (B: T-ALL) P-Akt P-4EBP1 4EBP1 c-Myc HIF1a Actin GAPDH (C:CLL-1) (D: CLL-2) P-4EBP1 4EBP1 c-Myc B-Actin (E: MM) P-4EBP1 4EBP1 C-Myc B-Actin
Slide 12: Combination Inhibits Cap Dependent Translation of c-Myc in DLBCL
TGR-1202 and Carfilzomib in Combination Inhibit Cap Dependent Translation of c-Myc in DLBCL (B) 150% (A) MYC % control mRNA level of 100% c-Myc 50% Actin 0% (C) (D) 150% MYC % control mRNA level of 100% C-Myc 50% B-Actin 0% (E) Cap dependent translation of Myc (F) R/F Luc (%control) 100% p=0.0013 Lu
Slide 13: Combination Inhibits the c-Myc Transcription Program in DLBCL
TGR-1202 and Carfilzomib in Combination Inhibit the c-Myc Transcription Program in DLBCL Gene Set 52 : SCHUHMACHER Gene Set 70 : DANG RES Running Enrichment Score (RES) Gene Set 29 : SCHLOSSER Gene Set 32 : KIM RES Gene List Index Gene List Index
Slide 14: Overexpression of eIF4E Suppresses Synergistic Cytotoxicity
Overexpression of eIF4E Suppresses the Synergistic Cytotoxicity of TGR-1202 and Carfilzomib and Increases the Protein Level of c-Myc 100% No Transduction 80% GFP-EV GFP-eIF4E Viability 60% 40% 20% 0% TG5mM & TG5mM & TG5mM & Cfz5nM Cfz6nM Cfz7nM TG5mM & TG5mM & TG5mM & Control Cfz5nM Cfz6nM Cfz7nM c-
Slide 15: Silence c-Myc through Simultaneous Targeting of PI3Kd and Proteasome Pathways
Silence c-Myc through Simultaneous Targeting of the PI3Kd and Proteasome Pathways TGR-1202 PI3Kd Translation mTOR pp-4EBP1 eIF4F c-Myc Proteasome Carfilzomib • Optimize c-Myc-silencing therapy by targeting phosphorylation of 4EBP1 • Phase I/II clinical trial of TGR-1202 and carfilzomib in relapsed a
Slide 16: Thank you!
Thank you! Owen A. O’Connor, M.D., Ph.D. Mark Lipstein, B.S. Luigi Scotto, Ph.D. Michael Mangone, Ph.D. Xavier O. Jirau Serrano, B.S. Center for Lymphoid Malignancies Columbia University Medical Center Shirong Li, Ph.D. & Suzanne Lentzsch, M.D., Ph.D. Hematology & Oncology, CUMC Nicholas Tatonetti,