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The FGF2-FGFR1 Autocrine signaling Pathway Functions as a Novel Oncogene Driver in NSCLC and approaches to inhibit FGFR.
Fred R. Hirsch, MD, PhD
Lynn Heasley, PhD
Murry Wynes, PhD
Paul A. Bunn Jr. MD
Ross Camidge, MD, PhD
University of Colorado Anschutz Medical Campus
Normal and Malignant Growth Control
Endocrine Paracrine Autocrine
LUNG CANCER GROWTH FACTORS
SCLC NSCLC
BK TGF
GRP (Bombesin) EGF
IGF-1 NGF
IGF-2 IGF-1
FGF FGF
Primarily Evaluated in: 1992-2000, 2000-2009, 2006-
Blume-Jensen and Hunter (2001) Nature 411:355-65
Receptor Tyrosine Kinases as Oncogene Drivers in NSCLC
Blume-Jensen and Hunter (2001) Nature 411:355-65
Receptor Tyrosine Kinases as Oncogene Drivers in NSCLC
FGFR structure, signaling, and dysregulation in cancer.
Brooks A N et al. Clin Cancer Res 2012;18:1855-1862
©2012 by American Association for Cancer Research
The FGFR1 gene is amplified, but not mutated, in a significant fraction of lung cancers
Frequent and Focal FGFR1 Amplification Associates with Therapeutically
Tractable FGFR1 Dependency in Squamous Cell Lung Cancer.
Weiss et al. Sci Transl Med. 2010 Dec 15;2(62):62ra93.
Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung
Cancer.
Dutt et al. PLoS ONE. 2011 6(6): 220351.
Amplification of FGFR1 is relatively frequent in SCC and may be “the oncodriving” event.
SNP Array
~10% of SCC Amplification of 8p11-12
FGFR1 in this region
FISH Assay with BAC probe
~22% of SCC Amplification
of FGFR1 Weiss et al. Sci Transl Med. 2010 Dec 15;2(62):62ra93.
*FGFR1 amplification
FGFR inhibitors are effective in amplified cell lines
Heasley et al.
Dutt et al.
Weiss et al.
FGFR TKIs
AZD 8020, AZD4547
BDJ398
Ponatinib
Dovitinib
Brivanib
Many VEGFR TKIs
Bayer
Others
FGFR 1,2,3,4
A phase II study of ponatinib in cohorts of patients with lung cancer preselected
using FGFR1 candidate predictive biomarkers.
University of Colorado SPORE
Drs. Camidge (PI), Bunn, Heasley, Wynes
and Hirsch
Protein
FGFR1 IHC
Collaborative Enzyme
Enhanced Reactive-
ImmunoAssay
In Situ Hybridization
- FGFR1 Black &
Chromosome 8 Red
mRNA Gene Copy
Number
In Situ Hybridization
Quantitative Nuclease Protection Assay
Quantitative PCR
n=57
FGFR1 gene copy number varies in
NSCLC
5/57 (9%) FGFR1 >4 (clusters)
15/57 (26%) FGFR1 >3
5/57 (9%) FGFR1:CH8 Ratio >2
FGFR-specific TKI sensitivity is NOT significantly
associated with lung cancer cell line histology
SK
-ME
S-1
H52
0
H15
81
H17
03
H1
25
H15
7
H44
1
H46
0
HC
C15
HC
C44
HC
C95
NE
-18
Co
lo69
9
DM
S-1
14
SW
15
73
H66
1
H12
99
H17
34
H14
35
H18
69
H21
26
FGFR1
FGFR2
FGFR3
EGFR
PDGFRα
PDGFRβ
Na/K
ATPase
E-Cadherin
FGFR1 protein levels associated withTKI
sensitivity in lung cancer cell lines
SK
-ME
S-1
H52
0
H15
81
H17
03
H1
25
H15
7
H44
1
H46
0
HC
C15
HC
C44
HC
C95
NE
-18
Colo
69
9
DM
S-1
14
SW
1573
H66
1
H12
99
H17
34
H14
35
H18
69
H21
26
FGFR1
FGFR2
FGFR3
EGFR
PDGFRα
PDGFRβ
Na/K
ATPase
E-Cadherin
FGFR1 protein levels is not always associated
with gene amplification in lung cancer cell lines
O 2+ 4+
In situ hybridization to measure FGFR1 mRNA in
FFPE lung tumor specimens
FGFR1 expression is most significantly
associated with FGFR-specific TKI sensitivity
FGFR1 Gene Copy number >4
FGFR1 mRNA >3
mRNA Gene
2 2 0
Double Negative=15
mRNA Gene
3 0 3
Double Negative=8
mRNA Gene
5 2 3
Double Negative=23
ADC and SCC SCC ADC
FGFR1 gene copy number, alone, may
underestimate FGFR1-driven lung tumors
Trial
In Vitro Studies
Determine potential predictive
biomarkers based on sensitivity
or resistance to ponatinib in cell
lines.
- FGFR1 mRNA
- FGFR1 Protein
- FGFR1 Gene Copy Number
Population Studies
Determine the biomarkers
positivity frequency, overlap,
and associations to age,
smoking, gender and histology
in a lung cancer patient
population. Determine any
prognostic associations.
Phase II
Determine the objective
response rate to ponatinib in
molecularly defined stage IIIB/IV
lung cancer patients.
- FGFR1 mRNA
- FGFR1 Protein
- FGFR1 Gene Copy Number
Expanded Phase II
Choose biomarker associated
with a least a 40% response rate.
M+
vs
M-
Stratify
Ponatinib
vs
Standard Tx
Randomize
ORR
PFS
OS
Putative contribution of FGFR1 to
Oncogene-Defined lung cancer
THANKS TO THE
UCCC “DREAM TEAM"
UC AMC
•Fred R. Hirsch
•Murry Wynes
•Paul Bunn
•Barb Helfrich
•Dan Merrick
•Dara Aisner
•Leila Varella-Garcia
UC AMC
•Ross Camidge
•Robert Doebele
•Aik Choon Tan
•Jihye Kim
•James DeGregori
•Vadyym Zaberezhnyy
•Matias Casas
• Lynn Heasley, PhD
• Lindsay Marek, PRA
• Trista Hinz, PRA
• Katie Singleton, Cancer Biology
• Emily Kleczko, Cancer Biology
• Katie Ware, Cancer Biology