Does an Aspirin a Day KeepCancer Away?

Jennifer R. Grandis, MDRobert K. Werbe Distinguished ProfessorOtolaryngology – Head and Neck Surgery

UCSFAmerican Cancer Society Clinical Research Professor

Disclosures:

• Co-inventor of cyclic STAT3 decoy• Consultant: xCures Inc, Ciitizen Inc

Team Science!

• ~ 60K new cases/year in USA; ~ 550K/year worldwide

• HPV- and HPV+

• 5-year survival rates ~50-60%

Head and Neck Cancer (HNSCC)

SinonasalCavity

SinonasalCavity NasopharynxNasopharynx

Oral CavityOral CavityOropharynxOropharynx

HypopharynxHypopharynx

Larynx

#PeerView

Two Distinct Forms of Head and Neck Cancer

pRB

E7p16

HPV

p53 E6

pRB

E7p16

HPV

p53 E6

p53 mutp53 mut

p16 p16

3p, 4q, 5q, 8p, 13q del3p, 4q, 5q, 8p, 13q del

HPV-Associated HNSCC: an Emerging Epidemic

The incidence of HPV(+) oropharyngeal HNSCC increased ~225% from 1988 to 2004

HPV is now the primary cause of tonsil cancer in North America and Europe

Ulysses S. Grant

Sigmund Freud

9

J. Robert Oppenheimer

Babe Ruth

Bruce Paltrow

Ann Richards

Michael Douglas

Smoking

Can HNSCC be prevented?

Smoking

Chewing betel quid

Can HNSCC be prevented?

Smoking

Chewing betel quid

Inhalation of airborne pollutants

Can HNSCC be prevented?

Smoking

Chewing betel quid

Inhalation of airborne pollutants

Vaccination

Primary Prevention

Can HNSCC be prevented?

Second primary tumors

◦ 3-6%/year◦ Leading cause of mortality ◦ Tobacco cessation

moderates risk after 5 yrs; insufficient to return risk to baseline

Slaughter, DP et al., Cancer 6(5):963-8, 1953.Leon, X, et al., Head Neck 21(3):204-10, 1999.

An Opportunity for Chemoprevention

High Dose Isotretinoin (retinoic acid) Prevented SPTs (but too toxic)

Treatment: 50-100 mg/m2/day (n=49) vs. placebo (n=51) x 1 year

SPT Development: 4% vs. 24% (p=0.005)

Limitations:- Tolerability: dose reduction

in 33%- Risk returned to baseline

after d/c of treatment

Conclusion: HD isotretinoin is not feasible for chronic administration to healthy patients

Isotretinoin Placebo P value

SPTs 2 (4%) 12 (24%) 0.005

Hong, WK et al., NEJM 323:795-801, 1990.

Low Dose Isotretinoin (Phase III) was Tolerable but Ineffective

Treatment: 30 mg/day (n=590) vs. placebo (n=600) x 3 years

Isotretinoin Placebo HR

SPTs 130 (22%) 131 (22%) 1.06

Khuri, FR et al., JNCI 98(7):441-50, 2006.

There are no FDA-approved chemopreventive agents

for individuals at high risk of developing

HNSCC SPTs!

8 FDA-Approved Drugs in HNSCC

MTX5-FU

BleomycinCisplatin Cetuximab

Docetaxel

PembrolizumabNivolumab

1956 20061957 1973 1978 2016

Yesterday’s Medicine:One size (dose) fits all

Tomorrow’s Medicine: Targeting the genetic changes specific to each

patient’s cancer

Tomorrow’s Medicine: Targeting the genetic changes specific to each

patient’s cancer

Tumor

1892:“If it were not for the great variability among individuals, medicine might as well be a science, not an art.”

Sir William Osler, Physician

MS Lawrence et al. Nature 517, 576-582 (2015) doi:10.1038/nature14129

Genes implicated in HNSCC

34% 56%

PIK3CA Mutational Landscape in HNSCC

Large Randomized Screening Trial (NCI PLCO) Demonstrated a Protective Effect of NSAIDs Against HNSCC Development

No biomarkers of response

Data from unselected populations

No molecular mechanisms

Epidemiologic Evidence in HNSCC

NSAID

PGE2

Sec

retio

n

PGE2Receptor

PGE2Receptor

PP PP

PP PP

RTKeg: EGFR

Pro-ligand

PI3KPI3K

Active ligandeg: TGF-α, AREG

Cleavageeg: TACE, MMPs

STAT MAPK

MutMut

Tumor Growth

What We Know From Studying HNSCC Signaling

1. Lui, Thomas et al. 2003 (CCR)2. Zhang, Thomas et al. 2004 (Oncogene)3. Thomas, Bhola et al. 2006 (Cancer Res)4. Zhang, Bhola et al. 2007 (MCT)5. Zhang, Bhola et al. 2008 (Cancer Res)6. Bhola, Thomas et al. 2011 (MCR)

So, we did a study…

HNSCC cohort with tissue and phenotypic data (why it is important to prospectively collect tissue and phenotypic data!)

Chronic NSAID use defined as > 6 months (generally baby ASA)

PIK3CA FISH on TMAs

PIK3CA sequencing (all exons)

HPV by ISH and p16 IHC

266 cases for final analysis

Disease-specific and overall survival recorded

NSAIDs Use Associated with Improved Survival in HNSCC

Matt Hedberg Noah PeyserHedberg et al. J Exp Med 216: 419-427, 2019

HNSCC cellsendogenousWT or MTPIK3CA

NSCLC cellsendogenousWT or MTPIK3CA

Isogenic HNSCC cellsengineered for

WT or MTPIK3CA

Cell line models

Apop

totic

Cel

ls (%

)

WT MT0

10

20

30

40

Apop

totic

Cel

ls (%

)

NSCLC lines withendogenous WT or MT

PIK3CA

p < 0.0001p = 0.0049 p < 0.0001

HNSCC and NSCLC Cells with PIK3CAAlterations Exhibit Enhanced Response to NSAIDs

HNSCC lines withendogenous WT or MT

PIK3CA

Isogenic HNSCC lines Engineered for

WT or MT PIK3CA

WT MT

Apo

ptos

is (%

)

Apo

ptos

is (%

)

Apo

ptos

is (%

)

WT MTWT MT/AMP

Day

Frac

tiona

l Tum

or v

olum

e

0 5 10 15 20 250

2

4

6

8 VehicleSulindac

WT

DayFr

actio

nal T

umor

vol

ume

0 5 10 15 20 250

2

4

6

8 VehicleSulindac

MT

HNSCC PDXs with PIK3CA Alterations Exhibit Enhanced Response to NSAIDs

COX2

-Tubulin

CA

L33

HSC

2

DET

RO

IT56

2

TR14

6

PEC

APJ

34

FAD

U

CA

L27

PEC

APJ

49

TU13

8

SCC

1

SCC

4

SCC

9

SD1

SCC

47

93-V

U-1

47T

SCC

90

MT PIK3CA WT PIK3CA

HNSCC Cells with Endogenous Mutant PIK3CA Have Elevated COX2

Pare

ntal

PTEN

KO

cl5

PTEN

KO

cl2

4

PTEN

COX2

pAKT(S473)

AKT

pPRAS40(T246)

PRAS40

GAPDH

Vect

or

WT

PIK

3CA

MT

PIK

3CA

pAKT(S473)

anti-Flag

COX2

AKT

pPRAS40(T246)

PRAS40

GAPDH

Isogenic HNSCC Cells Engineered forMutant PIK3CA or PTEN Loss Have Elevated COX2

WT MT

Fold

cha

nge

in C

OX

2 m

RN

AR

elat

ive

to v

ecto

r cel

ls

Mutant PIK3CA Induces COX2 mRNA

WT MT

WT MTParental

HNSCC Cells with Mutant PIK3CA Have Elevated PGE2

Plas

ma

PGE 2

(pg/

ml/1

000m

m3 )

WT MT0

500

1000

1500P=0.0011

Tum

or P

GE 2

(pg/

mg)

WT MT0

500

1000

1500

2000

2500P=0.078

HNSCC PDXs with Mutant PIK3CA Have Elevated Circulating and Tumor PGE2

Plasma Tumor

PG

E2

(pg/

ml/1

000m

m3 )

Vehicle Aspirin Vehicle Aspirin0

200

400

600

800

WT MT

HNSCC PDXs with Mutant PIK3CA Respond to NSAIDs with Large Loss of PGE2

Pare

ntal

PTEN

KO

cl5

PTEN

KO

cl

6

COX2

GAPDH

Vect

or

WT

PIK

3CA

MT

PIK

3CA

GAPDH

COX2

PD-L1

GAPDHGAPDH

PD-L1

MOC1 (Mouse Oral Cancer) Cells Engineered for Mutant PIK3CA or Loss of PTEN Exhibit Elevated COX2 and PD-L1

P = 0.022

% C

D8

cells

PAR

E545

K0

10

20

30

40 P = 0.018

% N

K c

ells

PAR

E545

K10

15

20

25

MOC1 Tumors with Mutant PIK3CA Exhibit Reduced CD8+ T Cells and NK Cells

REGISTER

Surgery

Biopsy

Pre‐Operative Window14‐28 Days

Key Eligibility Criteria:• HPV(‐) HNSCC• Oral cavity, p16‐

oropharynx, hypopharynx, or larynx

• Stage I‐IVa• ECOG 0‐1• Planned for oncologic 

surgery

Celecoxib 200 mg PO BID

CT Scan

CT Scan

RANDOMIZE

Placebo 200 mg PO BID

Tumor Biomarkers• Genomic: PIK3CA mutations/amplification; 

PTEN loss• TME: flow cytometry, nanostringBlood Biomarkers• Peripheral immune cell distribution, activation• Serum Th1 and Th2 cytokine profiles

Proposed Window Trial of NSAIDs in PIK3CA Mutant HNSCC

Patrick Ha

Proposed Clinical Trial Schema

RA

ND

OM

IZE

1:1

*

*Stratify: PIK3CA Alteration (yes vs. no) Composite Stage/HPV Status (AJCC v.8)

Stage II-III HPV- vs. Stage IV HPV- vs. Stage III HPV+

Eligibility (n=300):• HNSCC s/p curative

treatment• No evidence of disease• High risk for recurrence

• Oral Cavity: Stage III-IVb• HPV- Oropharynx,

Hypopharynx: Stage II-IVb• Larynx: Stage III-IVb• HPV+ Oropharynx: Stage III

• ECOG 0-1• Tissue available for

PIK3CA sequencing/FISH

ASA 81 mg daily2 years

Placebo daily2 years

Median DFS1) PIK3CA-altered2) PIK3CA-WT

Julie Bauman

Acknowledgements

UCSF• Jennifer Grandis, MD• Noah Peyser, PhD• Hua Li, PhD• Neil Bhola, PhD• Yan Zeng• Tian Ran Zhu, MD• Toni Brand, PhD• Mi-Ok Kim, PhD• Patrick Ha, MD• Richard Jordan, DDS, PhD• Scott VandenBerg, MD, PhD• Trevor Bivona, MD, PhD

University of Arizona• Julie Bauman, MD

University of Pittsburgh• Matthew Hedberg, MD, PhD• William Gooding• Simon Chiosea, MD• Lin Wang, MD• Jonas Johnson, MD• Uma Duvvuri, MD, PhD• Robert Ferris, MD, PhD