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DDR and cell cycle vulnerabilities
Lauren Averett Byers, MD
SCLC Research Consortium MeetingNational Cancer Institute
16 March 2018
NCI Funded SCLC Projects• NIH/NCI R01-CA207295
– Therapeutic strategies for targeting PARP1 in small cell lung cancer
• NIH/NCI U01-CA213273– Novel therapeutic approaches for enhancing antitumor
immunity and overcoming PD-1/PD-L1 inhibitor resistance in SCLC
• Project 1: DNA damage response (DDR) inhibition to enhance anti-PD1/PDL1 response
• UTSW/MDACC Lung SPORE
Wang and Byers, Cancer Discovery 2013
Are there distinct molecular profiles that translate into specific therapeutic vulnerabilities?
Rewiring of Small Cell Lung Cancer promotes increased expression of DDR proteins
Rb
PARP1Chk1ATMATR
Protein expression (RPPA)
Byers et al. Cancer Discovery, 2012
DNA Damage Response (DDR) –a therapeutic vulnerability in SCLC?
G1 S
G2M
G1 checkpointp53
G2 checkpointChk1, ATR, Wee1
DNA damage
Cell CycleRepair DNA
PARP inhibition
Chk1, Wee1, ATR inhibition
G2 checkpointChk1, ATR, Wee1
Byers et al. Cancer Discovery, 2012Cardnell et al. CCR, 2013
Feng et al AACR-NCI-EORTC 2014
talazoparib
PARP inhibition -- PDX
PARP IHC (patient tumors)
Collaborators: Julien Sage, Trudy Oliver
Scientific Reports, Nov 2017
ATRi (VE-822), Chk1i (PF-477736)
IC50
(μM
)
IC50
(μM
)
SCLC cell lines SCLC cell lines0
1
2
3
4
0
1
2
3
4
5
6VX970 AZD6738
cmax cmax
Carl Gay, IASLC Targeted Therapy Mtg 2018
ATRi sensitivity in human cell lines
Wee1 + AXL inhibition combination (Wee1i resistant model)
Biomarkers of Primary Wee1i resistance Biomarkers of Acquired Wee1i resistance
Growing number of PARP, ATR, Chk1, Wee1 and other DDR inhibitors in clinical trials
Bunn, J Thorac Oncol 2016
Sen, Gay, and Byers. TLCR 2018
Recurrent SCLC patients• 1-2 prior regimens• 104 pts treated
Clinical Outcomes• Higher Response Rate in
Veliparib/TMZ arm (39% vs. 14%)
• Higher Overall Survival with combination in patients with biomarker-positive (SLFN11 ≥ 1%) tumors
PR + CRPR + CR
Perc
enta
ge C
hang
e fro
m B
asel
ine
Perc
enta
ge C
hang
e fro
m B
asel
ine
Placebo/TMZ (n=44)
ORR 14%
Veliparib/TMZ(n=49)
ORR 39%
PR + CR
Pietanza and Byers, et al, ASCO 2016; World Lung Cancer Conference 2017
Combination of Temozolomide with the PARP inhibitor Veliparib improves outcomes in relapsed SCLC
Veliparib/TMZ
SLFN11 Negative SLFN11 Positive
Pao, Hutchinson; Nat Med 2012
NSCLC – Genomic Pie Slices
SCLC – Evolving Proteomic Landscape
EMT
cMYC
DLL3
Other
SLFN11
AXL inhibitor
Chk1 inhibitor,
Aurora Kinase
Inhibitor
Rova-T
PARP inhibitor, chemotherapy
Cel
l Lin
es
BI-2536 (p=0.174)
Alisertib (p=0.006)Alisertib (p=0.003)
SCH-1473759 (p=0.001)
TTF1 (protein)cMYC (protein)
NKX2-1 (mRNA)MYC (mRNA)
TTF1 protein high
MYC-high SCLC sensitive to Aurora Kinase inhibition
MYC protein high
MYC high
Targets for non-NE SCLC (TTF1-low/MYC-high)e.g., Aurora, PLK, Chk1
Low DLL3 expression in TTF1-low SCLC
PHOTOGRAPH BY STEVE GSCHMEISSNER, SCIENCE SOURCE (COLORIZED SEM)
New kinds of cancer treatments help the immune system’s T cells (pink) find and attack cancer cells (yellow).
National Geographic Magazine, March 2018
Eventually, …doctors will be able to target more types of cancer with combination treatments, including antibodies that remove immunological barriers.
“I think they will be like bacon…Bacon is good on everything.” -Elfriede Noessner, German Cancer Research Center for Environmental Health
Immunotherapy = Bacon?
Olaparib increases PDL1 (SCLC)
% P
D-L
1 +v
ece
lls
0
10
20
30
40
50
H82 H526 H1048
Untreated (24) Olaparib (24)Untreated (48) Olaparib (48)Untreated (72) Olaparib (72)
Byers, IASLC Santa Monica 2018 (unpublished data) Adapted from Mouw et al.
PARP inhibition increases PDL1 expression and may activate innate immune response
Jiao et al, CCR 2017
0 2 4 6 8 1 1 1 3 1 5 1 8 2 0 2 2 2 5 2 7 2 9 3 2 3 4 3 7 3 9 4 1 4 3 4 6 4 8 5 0 5 3 5 5 5 7 6 0 6 2 6 4 6 6
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
D a y s o f tre a tm e n t
Tu
mo
r v
olu
me
mm
3
V e h ic le (n = 5 )
O la p a r ib (n = 5 )
a n t i-P D -L 1 (n = 5 )
O la p a r ib + a n ti-P D -L 1 (n = 5 )
Co-targeting PARP1 (olaparib) and PD-L1 causes significant tumor regression in SCLC model
Naoto Morikawa, John Heymach
0
200
400
600
800
1000
1200
0 3 6 9 12 15 18 21
VehicleLY2606368anti-PD-L1LY2606368+anti-PD-L1
Days elapsed
Tum
or v
olum
e m
m^3
±SEM
***
## Complete tumor regression in 60% mice
##
*
Tum
or v
olum
e m
m^3
0200400600800
100012001400
0 3 6 9 121518210
200400600800
100012001400
0 3 6 9 12151821
0200400600800
100012001400
0 6 12 180
200400600800
100012001400
0 3 6 9 12151821
Days elapsed
Vehicle
CHK1i
anti-PD-L1
CHK1i+anti-PD-L10
1
2
3
Vehicle +LY2606368
SCLC tumors (B6129F1)p< 0.001FC= 3.07
PDL1
pro
tein
(RPP
A)
Sen et al, WCLC 2017
Co-targeting CHK1 and PD-L1 causes significant tumor regression in SCLC model
Chk1i increases PDL1
CTC-derived xenograft models (CDXs)
Leptomeningeal Disease (SC39)
Junya Fujimoto, John Heymach, Hai Tran, Ignacio WistubaMDACC Lung Moon Shot Program
(unpublished)
Allison Stewart Carl Gay
Max
imal
% B
asel
ine
Cha
nge
1000
700
500
200100
60
20
-30
-100
cisplatin prexasertib talazoparib
PDSD
PR
CDX in vivo response matches clinical response of patient to chemotherapy
Allison Stewart, Carl Gay (Byers Lab), unpublished
Single cell RNAseq analysis of CDX models to explore tumor heterogeneity
CHGA
SC39 SC4 SC49
mR
NA
Expr
essi
on0
2
4
6
SYP
mR
NA
Expr
essi
on0
1
2
3
SC39 SC4 SC49
PC2
-20
-1
5
-10
-5
0
5
10
15
-10 0 10 20
NKX2-1
Allison Stewart, Carl Gay, Yuanxin Xi, Jing Wang, unpublished; Funded by SWOG/JAX Pilot
DLL3
PC2
-20
-1
0
0
10
PC1-10 0 10 20
SC4
SC39
SC49
L-MYC is associated with tumor propagation in SCLC
Jahchan et al., 2016
MYCNMYCLMYC
SC39 SC39 SC39
SC4 SC4 SC4
SC49 SC49 SC49
CDX tumors - Single cell RNAseq
Allison Stewart, Carl Gay, Yuanxin Xi, Jing Wang, unpublished
Conclusion
• Activity of DNA damage response (DDR) and cell cycle inhibitors observed in SCLC models (e.g., PARP1, Chk1, Wee1, ATR inhibitors), many now in the clinic
• Candidate biomarkers for specific DDR inhibitors identified, with initial validation of SLFN11 in TMZ-veliparib treated patients (CTEP/NCI trial)
• DDR-IO combinations enhance anti-tumor effect in syngeneic and spontaneous GEMM models, warrant further investigation in the clinic
• CTC-derived xenograft models (CDXs) provide an opportunity for increasing the number of drug resistant models for translational research
• Single cell RNAseq data reveals intra-tumoral heterogeneity. Contribution of tumor heterogeneity to resistance is being further investigated.
Acknowledgements
Byers Lab:Triparna SenCarl GayAllison StewartRobert CardnellKavya RamkumarCarminia Della Corte
Bioinformatics:Jing WangYuanxin XiPan TongLixia DiaoLerong Li
Other MD Anderson:John HeymachDon GibbonsBonnie GlissonJunya FujimotoIgnacio WistubaJohn De GrootBingliang Fang
Other CollaboratorsJulien SageTrudy OliverJohn MinnaAdi Gazdar
Paul Robson Lab--Siva Vijayakumar--Mohan Bolisetty
Funding:NIH/NCI 1-U01-CA213273NIH/NCI 1-R01-CA207295MDACC CCSG (P30-CA016672)UTSW/MDACC SPORE (5-P50-CA070907)SWOG ITSC Grant (single cell analysis)Lung Cancer Research FoundationLUNGevity FoundationThe University of Texas MD Anderson Lung Cancer Moon Shot ProgramThe Rexanna FoundationMD Anderson Small Cell Lung Cancer Working Group
Slide Number 1NCI Funded SCLC ProjectsAre there distinct molecular profiles that translate into specific therapeutic vulnerabilities?Rewiring of Small Cell Lung Cancer promotes increased expression of DDR proteinsDNA Damage Response (DDR) – �a therapeutic vulnerability in SCLC?Slide Number 6Slide Number 7Slide Number 8Growing number of PARP, ATR, Chk1, Wee1 and other DDR inhibitors in clinical trialsSlide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Olaparib increases PDL1 (SCLC)Slide Number 16Co-targeting CHK1 and PD-L1 causes significant tumor regression in SCLC modelCTC-derived xenograft models (CDXs)CDX in vivo response matches clinical response of patient to chemotherapySingle cell RNAseq analysis of CDX models to explore tumor heterogeneityL-MYC is associated with tumor propagation in SCLCConclusionAcknowledgements