Download Lung Cancer Mutation Consortium 1 RC2 CA148394-01

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts
no text concepts found
Transcript
SPORE UPDATE
Fred R. Hirsch, MD, PhD
Lung Cancer SPOREs
University of Texas South Western/
M.D. Anderson Cancer Center
John Minna, Jack Roth
Johns Hopkins University
Stephen Baylin
University of Colorado
Paul Bunn
Vanderbilt University
David Carbone
University of Pittsburgh
Jill Siegfried
Dana Farber/Harvard Cancer Institute
Bruce Johnson
H. Lee Moffitt Cancer Center
Gerold Bepler/Eric Haura
Lung Cancer SPOREs
Selected Highlights
• Epidermal Growth Factor Receptor Mutations and
Gene Amplification in Non-Small Lung Cancer Predict
for Response to TKIs (DFHCC, UCHSC)
• 3p21.3 Tumor Suppressor FUS1-mediated Molecular
Therapy for Lung Cancer (UTSW/MDACC)
• Lung Cancer Proteomics (Vanderbilt U., U. Pittsburgh,
UCLA, U Colorado)
• Methylation Markers in Lung Cancer (JHU, UCHSC)
• Estrogen Receptor-Targeted Therapy in Lung Cancer
(U. Pittsburgh)
• Lung Cancer Biomarkers and Chemoprevention
Consortium
EGFR MUTATIONS AND OTHER MARKERS:
Discovery and Implications
Lung Cancer SPOREs involved:
Dana Farber Harvard Cancer Center (Bruce Johnson,
PI)
University of Colorado (Paul Bunn, PI)
UT Southwestern/MD Anderson CC (John Minna, PI)
Vanderbilt University (David Carbone, PI)
2004
2005
EGFR mutations in non-small cell lung carcinomas predict response to tyrosine kinase
inhibitors (TKIs) (Science, 304:1497, 2004; N Engl J Med, 350:2129,2004)
EGFR gene copy number by FISH: a molecular predictor for response to TKIs (J Natl Cancer
Inst, 97:643, 2005)
Aberrant EGFR signaling and enhanced sensitivity to EGFR inhibitors in lung cancer
(Cancer Res, 65:226, 2005) (N Engl J Med, 352:786, 2005)
2007
MET amplification leads to TKI resistance in lung cancer by activating ERBB3 signaling
(Science, 316:1039, 2007)
Ethnic differences in polymorphisms, mutations, and amplification of the EGFR gene (PLoS
Med, 4:125, 2007)
Serum-based marker predicts responses to EGFR inhibitors (VeriStrat®; J Natl Cancer Inst
99:846, 2007)
2009
2011
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M (Nature, 462:1070, 2009)
Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR
Inhibitors (Science Transl Med, 3:75ra26, 2011)
Univ. of Colorado Lung Ca. SPORE 2011:
4 new or redesigned projects
• Project 1: The FGFR signal pathway in lung cancer
especially of squamous histology. F. Hirsch, MD, PhD
(applied) and L. Heasley, PhD (basic). Collaborators: Drs.
Camidge, Wynes, biostat
• Project 2:Improving Outcomes from EGFR and ALK TKIs.
P. Bunn, MD (applied), J. DeGregori, PhD (basic).
Collaborators: Drs. Doebele, Camidge, Chan, Helfrich,
Casias, Franklin, Aisner, biostat
• Project 3: Role of eicosanoids in the development of lung
cancer. R. Nemenoff, PhD (basic), M. Geraci, MD and R.
Keith, MD (applied) Collaborators: Drs. Winn, Tennis,
Merrick
• Project 4: Biomarkers of lung cancer risk and early
detection. Y. Miller, MD (applied), H. Wolf, MPH (population
science), F. Hirsch, MD, PhD (basic)Collaborators: Drs.
Varella-Garcia, Mascaux, Wynes, Franklin, Merrick
Chromosomal Aneusomy by FISH in sputum
in Lung Cancer Cases and Controls.
% Abnormal
Sensitivity
Specificity
cases
controls
(95% CI)
(95% CI)
Within 12 Mo
(n =89)
77.7
4.5
0.78 (0.63, 0.89)
0.95 (0.85, 0.99)
>12-18 Mo
(n =35)
66.7
15
0.67 (0.38, 0.88)
0.85 (0.62, 0.97)
>18-24 Mo
(n =33)
56.2
0
0.56 (0.30, 0.80)
1.00 (0.80, 1.00)
>24 Mo
(n =108)
44.4
11.3
0.36 (0.24, 0.50)
0.89 (0.77, 0.96)
Latency
PGI2 Signaling Pathways
Fatty
Acid
Arachidonate
O-P-O-X (polar head
group)
PLA2
Free Fatty
Acid
COX 1
Constitutive
COX 2
Inducible
PGH2
PGIS
PGI2
PGIR
Gs AC
Other
signaling
pathways
(PPAR)
cAMP
Biological
Response
Background: Prostaglandin levels are high in normal
lung and and low in NSCLC
Normal
Lung
NSCLC Cell
Lines
PGI2
3,450 ng/g
333 ng/g
PGE2
430 ng/g
PGI2
Synthase
PGH2
PGE2
11,952 ng/g
Synthase
PGIS present
PGIS absent
Survival Time (Months)
Prostacyclin synthase
levels are prognostic.
Histology of Bronchial Squamous Epithelium
Normal
(Grade 1)
Squamous Metaplasia
(Grade 3)
Mild Dysplasia
(Grade 4)
74% in baseline
bronch
Moderate Dysplasia
(Grade 5)
Severe Dysplasia
(Grade 6)
Carcinoma in situ
(Grade 7)
Iloprost Chemoprevention Trial:
Primary Results
Iloprost
Placebo
Tools for the Identification and the
Detection of Biomarkers in Clinical
Samples and Patients
•
•
•
•
•
Nodule Clinic (Denver CO)
Lung Nodule and/or Dysplasia
Exhaled Breath
Clinical Investigation (Invasive for all)
2 years of follow-up till final validation
Specify the unique VOCs signature for
each of the subtypes of LC
1.SCLC
2.NSCLC
Adenocarcinomas
Squamous cell carcinomas
Large cell carcinoma
Dr. Nir Peled (MD, PhD) Tel Aviv Univesity
http://cancergrace.org/lung/2010/04/05/an-introduction-to-lung-cancer/
NSCLC
SCLC
Pancreas
H460
H526
Mia Paca
Calu3
H187
Panc
H1435
H69
S3.6
H4006
H774
H1975
A549
H820
H1650
(a)
(b)
Compounds Totally Released
NSCLC
SCLC
Compounds Totally Consumed
Abundance [%]
0.0
Diethyl Phthalate
Acetophenone
Isopropyl Myristate
Decanal
Dodecane
Nonanal
Butylated Hydroxytoluene
Hexadecane
1-Heptanol, 4-methylAzacyclotridecan-2-one
Benzene, 1,3-bis(1,1-dimethylethyl)Tridecane, 2-methylDodecane, 2-methylDodecane, 4-methylTridecane, 3-methylTridecane, 6-methyl1-Hexene, 3,4-dimethylDodecane, 3-methyl-
Undecane, 2,4-dimethylTridecane, 5-methylTetradecane, 5-methylTridecane, 4-methylPentanenitrile, 2,2,4-trimethyl2-methyl-, 1-(1,1-dimethylethyl)-2-methyl-1,3-pro
Dodecanoic acid, 1-methylethyl ester
Propanenitrile, 2,2'-azobis[2-methylAcetic acid, octyl ester
Nonane, 5-propylUndecane, 3-methylTetradecane, 2-methyl1-Heptanol, 6-methylBenzenesulfonamide, N-butylCyclopentane, pentyl5-Methyl-1-heptanol
Undecane, 2,6-dimethylDodecane, 5-methylTetradecane, 3-methylDodecane, 5,8-diethylTetradecane, 4-methylTridecane, 7-methylDodecane, 2,6,11-trimethyl1-Hexanol, 5-methyl-2-(1-methylethyl)-, acetate
Dodecane, 2,5-dimethylTridecane, 2,5-dimethyl(S)-(+)-5-Methyl-1-heptanol
0.5
Abundance [%]
NSCLC
SCLC
0.0
Ethylbenzene
Benzene, 1,3-dimethyl-
Furan, tetrahydro-
Decane
1-Hexanol, 2-ethyl-
Octanal
0.5
1.0
Benign Nodules
Age (years)
Active Smokers
Never Smokers
PY (Total)
Nodule Existence
Nodule Size (cm)
Histology
Stage
(N=29)
61.5 ± 6.4
10 (35%)
3 (10%)
44.3 ± 33.3
21 (72%)
1.86±1.1
Non-Cancerous
Dysplasia/Hyperplasia
Infectious/Inflammation
Carcinoid
Malignant Nodules
13
9
5
2
(N=53)
64.9 ± 7.2
19 (36%)
8 (15%)
40.5 ± 27.0
53/53 (100%)
2.7±1.7
NSCLC:
47
Adenocarcinoma
30
Squamous
13
Large Cell
2
Poorly Diff.
2
SCLC
6
NSCLC:
Stage I / II
23 / 4
Stage III / IV
10 / 10
SCLC:
Limited / Ext
3 / 3
P-value
(<0.05)
NS
NS
NS
NS
NS
Malignant/ Benign
SCLC/NSCLC
Sensitivity
Specificity
Accuracy
PPV
NPV
76.2-87.9
83.3-88.2
78.8-88.0
88.9-93.5
66.7-78.9
75
96.56
93.93
96.6
75.0
(A)
(B)
DANA-FARBER
•
Genotypic and Histological Evolution of Lung Cancers Acquiring
Resistance to EGFR Inhibitors.
•
To understand the exact mechanism of the drug resistance acquisition in
NSCLC patients treated with EGFR inhibitors, the investigators analyzed tumor
biopsies from patients at the time they acquired resistance. The disease
underwent various courses: in some patients the resistance gateway
mutation T790 appeared, in others amplification of the MET
tyrosine kinase receptor occurred; another group of patients
developed new patterns of resistance with the amplification of
the EGFR gene and mutations of PIK3CA gene. In a few
patients, lung cancers transitioned from epithelial to
mesenchymal (more aggressive) morphology or they converted
from the non-small cell lung cancer phenotype to small cell
lung cancer. The genetic and histological analysis provides new insights
into drug resistance evolution in lung cancers and suggests that serial
biopsies may be essential in the quest to reverse or even prevent the
development of drug resistance. (Sci Transl Med) - PMID: 21430269
Johns Hopkins SPORE
• Histone deacetylase inhibitors downregulate checkpoint
kinase 1 expression to induce cell death in non-small cell
lung cancer cells
• Histone deacetylase inhibitors have potential as
chemotherapeutic agents, however their mechanism
of action are not completely understood. In this work
we demonstrate that histone deacetylase inhibitors
lead to downregulation of the CHK1 kinase. These
results define a pathway through which Chk1
inhibition can mediate HDACi-induced mitotic entry
and cell death and suggest that Chk1 could be an
early pharmacodynamic marker to assess HDACi
efficacy in clinical samples (PLoS One) - PMCID:
PMC3001870
• http://www.ncbi.nlm.nih.gov/pubmed/21179472
UNIVERSITY OF
PITTSBURGH
•
Combined Analysis of Estrogen Receptor b-1 and Progesterone
Receptor Expression Identifies Lung Cancer Patients with Poor
Outcome
•
A better understanding of the role and interaction of hormone and
growth factor pathways in the lung is necessary to elucidate novel
effective preventative and treatment strategies for lung cancer. This
work examined the combined effect of expression of estrogen
receptor b-1 and progesterone receptor in tissues from lung cancer
patients and the influence of expression of other markers including
the epidermal growth factor receptor and aromatase on patient
survival. The correlations between expression of these markers
and their combined influence on patient survival suggest that
phenotyping these interacting markers together in lung cancer
patients may better predict survival and suggest which patients
could be candidates for hormonal therapy for lung cancer
treatment. (Clin Cancer Res) - PMID: 21062926
http://www.ncbi.nlm.nih.gov/pubmed/21062926
VANDERBILT
•
A platform for rapid detection of multiple oncogenic mutations with
relevance to targeted therapy in non-small-cell lung cancer
•
The identification of somatically acquired tumor mutations is increasingly
important in the clinical management of cancer because the sensitivity of
targeted drugs is related to the genetic makeup of individual tumors. Thus,
mutational profiles of tumors can help prioritize anticancer therapy. We report
herein the development and validation of two multiplexed assays
designed to detect in DNA from FFPE tissue more than 40 recurrent
mutations in nine genes relevant to existing and emerging targeted
therapies in lung cancer. These robust, reliable, and relatively inexpensive
•
assays should help accelerate adoption of a genotype-driven approach in the
treatment of lung cancer. (J Mol Diagn) - PMID: 21227397
http://www.ncbi.nlm.nih.gov/pubmed/21227397
•
Lung adenocarcinoma from East Asian never-smokers is a disease
largely defined by targetable oncogenic mutant kinases
•
In this surgical series, 52 resected lung adenocarcinomas from never-smokers
( 100 cigarettes in a lifetime) at a single institution (Fudan University, Shanghai,
China) were analyzed concurrently for mutations in EGFR, KRAS, NRAS, HRAS,
HER2, BRAF, ALK, PIK3CA, TP53 and LKB1. 90% (47 of 52; 95% CI, 0.7896 to
0.9625) of lung adenocarcinomas from never-smokers were found to harbor
well-known oncogenic mutations in just four genes: EGFR, KRAS, ALK, HER2. (
J Clin Oncol) - PMCID: PMC2974342
http://www.ncbi.nlm.nih.gov/pubmed/20855837
•
SWOG Task Force: Interactions with
SPOREs, Cancer Centers & Other Groups