does an aspirin a day keep cancer away?
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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
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