Marker-guided Targeted Therapy, PAPRi and Immune Checkpoint Therapy

Transcription

1 Marker-guided Targeted Therapy, PAPRi and Immune Checkpoint Therapy Plenary Lecture 4 April 6, 3018 Global Breast Cancer Conference 2018 Incheon, Korea Mien-Chie Hung, PhD 洪明奇 Vice President for Basic Science Professor and Chair Molecular and Cellular Oncology

2 Progress free survival (%) Progress free survival (%) Progress free survival (%) Objective response rate (ORR): 34% Total Olaparib was approved to treat ovarian cancer with BRCA mutation by the US FDA in Dec 2014 BRCA mutations Wt BRCA Lancet oncology, 15:852, 2014

3 Figure 2 Goal Improving Progress Free Survival Improve even more? How? OvCa, The Lancet Oncology ,

4 Blocking c-met-mediated PARP1 phosphorylation enhances PARP inhibitor response Summary : B Du et al, Nature Med, 2016 PARP1 ROS c-met P p-parp1 PARP inhibitor DNA repair ROS enhances the association of PARP1 with c- Met c-met regulates PARP inhibitor response c-met phosphorylates PARP1 at Tyr907 Phosphorylation of PARP1 increases DNA damage repair and resistance to PARP inhibitors py907 and c-met expression are correlated in TNBC patient samples C-Met is overexpressed in 30-50% of TNBC. Combinational treatment of PARP and c-met inhibitors has synergistic effect in TNBC models

5 ROS Induces Association of c-met and PARP1 C-Met/PARP in nucleus

6 Clinical Relevance and Potential Therapeutic Strategy Targeting PARP1 and C-Met in TNBC AG, Rucaparib ABT, Velaparib Cri, Crizotinib Ft,Foretinib No observed acute toxicity, a clinical trial proposed Q, other oncokinases may also contribute to PARPi resistance? Du et al, Nature Med, 2016

7 IC 5 0 ( M ) IC 5 0 ( M ) Cross-resistance of SUM149 PARPi Resistant Individuals to Different PARPi T a la z o p a r ib IC 5 0 (n M ) S U M x x O la p a r ib x S U M x x S U M R u c a p a r ib x x 1 0 x 7

8 Phospho-RTK Antibody Array --- SUM149 derived PARPi Resistant Individuals Receptor Tyrosine Kinase Array IGF-1R EGFR Parental IGF-1R EGFR Clone #19 IGF-1R EGFR Parental + PARPi IGF-1R EGFR Clone #19 + PARPi 14 potential kinases are identified including those in the literature: VEGFR3, c-met, Axl and IGF1R Mei-Kuang Kathy Chen/Yu-Yi Chu

9 Precision PARPi combinational therapy Anti p-cmet Ab PARPi Monotherapy Or chemo-, radio-therapy p-cmet p-vegfr Kinase MET TKI + PARPi py907-parp1 VEGFR TKI + PARPi Precision medicine Dream : 100%? p-y, p-s/t Biomarker New Combinational therapy? More mechanisms and biomarkers need to be discovered

10 Checkpoint blockade activates anti-tumor immunity CTLA4 PD-1 PD-L1 (Nature 2014)

11 A N35 N63 N192 N200 N204 N219 Amino acid position Amino acid position Consensus Consensus Q9NZQ7_HUMAN PD-L1 is glycosylated at Q9NZQ7_HUMAN consensus NXT motif Q9EP73_MOUSE Q9EP73_MOUSE D4AE25_RAT C5NU11_BOVIN Q4QTK1_PIG D4AE25_RAT C5NU11_BOVIN Q4QTK1_PIG F7DZ76_HORSE F7DZ76_HORSE Sequence Logo Sequence Logo B C PD-L1 D N35 N192 N200 N SP ECD TM ICD NXT motif WT N35Q N192Q N200Q N219Q N35/192Q N192/219Q N200/219Q 3NQ 4NQ Non-NXT N63Q N138Q N204Q WT/TM PD-L PD-L1 /TM Tubulin Chiu, IBC Li, Lim, et al, Nature Commun. 2016

12 EGF signaling increases glycosylated PD-L1 protein Mechanisms: EGF/EGFR upregulates B3GNT3 glycosyl transferase that glycosylates PD-L1 Gsk3b phosphorylates PD-L1 preventing from glycosylation and induces PD-L1 degradation.

13 Glycosylation and stabilization of PD-L1 suppresses T cell activity Li and Lim et al, Nature Communications, 2016 ; Cancer Cell, 2018

14 Inhibition of EGFR sensitizes PD-1 blockade therapy in syngeneic mice model Safe dose

15 Immune Checkpoint Therapy Nivolumab anti-pd-1 Ipilimumab anti CTLA4 N Engl J Med 2015; 373:23-34, July 2, 2015

16 Response rate of Immune Checkpoint Therapy?? Tumor heterogeneity, N Engl J Med 2015; 373:23-34, July 2, 2015

17 Response rate of Immune Checkpoint Therapy Tumor heterogeneity, Effective combination therapy, Bystander effect. N Engl J Med 2015; 373:23-34, July 2, 2015

18 Combination of metformin and anti-ctla4 has a synergistic antitumor effect a c b d Metformin-activated AMPK decreases the level of PD-L1 and increases CTL activity Cha, Yang,et,al submitted Next, Bystander effect?

19 Development of mab against glycosylated PD-L1 StCube, Inc

20 STM108 reduces humanized 4T1-hPD-L1 cells growth in BALB/c a b c Antibody-Drug conjugate to enhance therapeutic efficay and induce bystander effect

21 Targeting PD-L1 glycosylation enhances anti-tumor immunity A B C D de e Li, Lim,et,al Cancer Cell, 2018, Feb. MM Auristatin E Other animal models? StCube,Inc

22 gpd-l1 antibody-drug conjugate shows dramatic anti-tumor effect in multiple cancer models Bystander effect?

23 Bystander effect of gpd-l1-adc In vitro In vivo

24 Proposed model Li, Lim, et al, Cancer Cell, 2018, Feb 3. Bystander effect

25 This is time to

26 Rnase5 (ANG) as a new ligand for EGF Receptor Rnase5 may serve as a serum biomarker to predict response to EGFR target therapy. There are 13 RNases in human, do they serve as ligands for other receptor tyrosine kinases and serum biomarkers? Wang, Lee et al; Cancer Cell, 2018,Apr

27 B o u n d /F re e h R N a s e 5 B o u n d /F re e lig a n d s brnasea and hrnase5 can directly bind to EGFR as a ligand C b R N a s e A N u m b e r o f in te ra c tio n (p e r c e ll) D R elative bound hr N ase E G F h R N a s e 5 a m p h ire g u lin K d (n M ) h R N a s e 5 (n M ) R e la tiv e b o u n d h R N a s e R e la tiv e b o u n d lig a n d s Biological function of hrnase5/ Angiogenin (ANG)-EGFR axis in vivo?

28 P e rc e n t s u rv iv a l Activation of EGFR by hrnase5/ang renders pancreatic cancer cells more sensitive to erlotinib (Oncogene Addiction) Orthotopic model A s P C -1 /v e c to r/l u c A s P C -1 /v e c to r/l u c w ith e rlo tin ib A s P C -1 /A N G /L u c A s P C -1 /A N G /L u c w ith e rlo tin ib T o ta l F lu x (p h o to n /s e c, ) D a y s N S * * A s P C -1 /v e c to r/l u c A s P C -1 /v e c to r/l u c w ith e rlo tin ib A s P C -1 /A N G /L u c A s P C -1 /A N G /L u c w ith e rlo tin ib * * * D a y s

29 m o u s e p la s m a A N G (n g /m l) m o u s e p la s m a A N G (n g /m l) Human plasma hrnase5/ang but not EGF/TGFa level is elevated in plasma samples from pancreatic cancer patients and ikras p53 L/+ mice ikras p53 L/+ mouse plasma C re + tu m o r C re - litte rm a te c o n tro l m o u s e p la s m a A N G (n g /m l) N S w e e k 1 a fte r D o x in d u c tio n * * * * * * w e e k s a fte r D o x in d u c tio n * * * * * e rlo tin ib tre a tm e n t w e e k s a fte r D o x in d u c tio n C re + tu m o r (Human samples were provided by Drs. Xifeng Wu and Donghui Li; Mouse samples were provided by Dr. Haoqiang Ying)

30 P e rc e n t s u rv iv a l P e rc e n t s u rv iv a l P e rc e n t s u rv iv a l High levels of plasma RNase5 (ANG) render PDAC patients more sensitive to erlotinib Optimal cutoff median value (434.2 ng/ml) mean value (441.3 ng/ml) H R = % C I (0.4 0 to ) P = e rlo tin ib (n = 4 5 ) M e d ia n = 8.5 m o n th s n o n -e rlo tin ib (n = 2 5 ) M e d ia n = 6.6 m o n th s High ANG H R = % C I (0.1 6 to ) P = e rlo tin ib A N G > n g /m l (n = 2 2 ) M e d ia n = 9.5 m o n th s n o n -e rlo tin ib A N G > n g /m l (n = 1 3 ) M e d ia n = 5.6 m o n th s M o n th s M o n th s Collaborators (MDACC): Donghui Li, Laura Prakash, Matthew Katz, David Fogelman, Milind Javle, Anirban Maitra H R = % C I (0.8 8 to ) P = e rlo tin ib A N G < n g /m l (n = 2 3 ) 8 0 M e d ia n = 7.0 m o n th s n o n -e rlo tin ib A N G < n g /m l (n = 1 2 ) M e d ia n = m o n th s M o n th s

31 Proposed Model Wang, Lee et al; Cancer Cell, 2018,Apr hrnase5/ang acts as an EGFR ligand in PDAC High hrnase5/ang level serves as a serum biomarker to predict erlotinib response New insight into ligand-receptor relationship between RTK and RNase families

32 Vesicle-Membrane Associated trafficking Pathway ( V-MAP ) of cell surface EGFR to nucleus DNA repair DNA synthesis Transcriptional activation Lo, et al, Cancer Cell,2005 Wang et al, Nature Cell Biol, 2016 Giri, et al; Mol Cell Biol, 2005 Hsu and Hung; J Biol Chem, 2007 Wang et al; J Biol Chem, 2010 ; 2012 Wang et al, BBRC, 2011 Du et al, Oncogene 2013

33 Single Molecule 3D Tracking collaborate with Dr. Tim Yeh(UT Austin) Nature Communication, 2015Communication, in press 20 3D circularly laser scanning with active feedback control Beam 1 (0 ns) Beam 2 (+3 ns) Beam 3 (+6 ns) Beam 4 (+9 ns) z piezo stage Idealized image-space projection z y x dichroic excitation filter beam stop scan lens tube lens y rotation x rotation y galvo mirrors collection lens x H7422P-40 PMT

34 Nature Communication, 2015 EGFR travels from cell membrane to nucleus cell membrane nucleus EGFR trajectory

35 A blind man s elephant: Each blind man perceives the elephant something different.

36 Thank you for your attention! Working together to make cancer history and better tomorrow

37 Hung s Lab, a Happy Family

38 Hung Group