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