The%20Complex%20Molecular%20Landscape%20of%20Squamous%20Cell%20Carcinoma%20Martin%20Sos,%20M.D.%20Department%20of%20Translational%20Genomics%20Center%20of%20Integrated%20Oncology%20K - PowerPoint PPT Presentation

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The%20Complex%20Molecular%20Landscape%20of%20Squamous%20Cell%20Carcinoma%20Martin%20Sos,%20M.D.%20Department%20of%20Translational%20Genomics%20Center%20of%20Integrated%20Oncology%20K

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The Complex Molecular Landscape of Squamous Cell Carcinoma Martin Sos, M.D. Department of Translational Genomics Center of Integrated Oncology K ln Bonn – PowerPoint PPT presentation

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Title: The%20Complex%20Molecular%20Landscape%20of%20Squamous%20Cell%20Carcinoma%20Martin%20Sos,%20M.D.%20Department%20of%20Translational%20Genomics%20Center%20of%20Integrated%20Oncology%20K


1
The Complex Molecular Landscape of Squamous Cell
Carcinoma Martin Sos, M.D. Department of
Translational Genomics Center of Integrated
Oncology Köln Bonn University of
Köln martin.sos_at_uni-koeln.de
2
Disclosures
  • Consultant of Blackfield AG, provider of cancer
    genomics services and genomics-based drug
    discovery/development
  • Patent applications genotype-specific drug
    discovery/ assays and biomarkers (including FGFR)

3
The efficacy of chemotherapy in stage-IV lung
cancer
1.0 0.8 0.6 0.4 0.2 0
Cisplatin/Paclitaxel Cisplatin/Gemcitabin Cisplati
n/Docetaxel Carboplatin/Paclitaxel
Probability ()
0 5 10 15 20 25 30
time (month)
Therapeutisches Plateau Gesamtüberleben lt 12
Monate
Schiller, et al. NEJM 2002
4
Mechanisms of genome alterations in cancer
Meyerson et al., Nat Rev Genet 2010
5
EGFR-mutant lung tumors respond to EGFR
inhibitors such as erlotinib and gefitinib
Pre-therapy
6 weeks of erloti
Paez et al., Science 2004 Lynch et al., NEJM
2004 Pao et al., PNAS 2004)
6
2009 EGFR mutations predict progression-free
survival (IPASS trial, Tony Mok, NEJM 2009)

Gefitinib EGFR M (n132) Gefitinib EGFR M-
(n91) Carboplatin / paclitaxel EGFR M
(n129) Carboplatin / paclitaxel EGFR M- (n85)
Probability of PFS
1.0
Gefitinib, HR0.19, 95 CI 0.13, 0.26,
plt0.0001 No. events M 97 (73.5) No. events M-
88 (96.7) Carboplatin / paclitaxel, HR0.78,
95 CI 0.57, 1.06, p0.1103 No. events M 111
(86.0) No. events M- 70 (82.4)
0.8
0.6
0.4
0.2
0.0
0
4
8
12
16
20
24
Time from randomisation (months)
Hazard ratio lt1 implies a lower risk of
progression in the M group than in the M-
group M, mutation positive M-, mutation
negative
Slide courtesy of Tony Mok, Hongkong
7
Relevance of mutant kinase genes in lung cancer
the case of EML4-ALK fusions
Phase I/II trial of EML4-ALK positive lung
cancer patients with the c-met/ ALK inhibitor
PF-02341066 12 / 18 pts with confirmed
response Kwak et al, 83509, ASCO 2009
Detection of EML4-ALK fusion in NSCLC Rikova,
Cell 2007 Soda, Nature 2007
8
...and more and more to come
  • ROS fusions in lung adenos (app.1) associated
    with response to crizotinib (Rikova et al., Cell
    2007 Bergethon et al., J Clin Oncol 2011 Shaw
    et al. ASCO 2012)
  • RET fusions in lung adenos (app.1) associated
    with sensitivity to RET kinase inhibition (Ju et
    al., Genome Res 2012 Takeuchi et al., Nat Med
    2012 Kohno et al., Nat Med 2012 Lipson et al.,
    Nat Med 2012)

9
The genomic evolution of lung adenocarcinoma
Pao et al., Lancet Oncol 2011
10
Peifer et al., Nat Genet, 2012
Hammerman et al., Nature, 2012
Imielinski et al., Cell, 2012
11
Genomic features of 1,000 lung tumors
Chromosomes 1-22
AD
CA
LC
SC
SQ
CLCGP and NGM, Sci Transl Med 2013
12
Automated genomics-based lung cancer diagnosis
CLCGP and NGM, Sci Transl Med 2013
13
Genomic Targets Adenocarcinoma versus Squamous
Gene Lung Adenocarcinoma Lung Squamous Cell
EGFR 14, most at known sites, novel C-terminal deletions Amplification (7), rare non-canonical mutation (L861Q)
KRAS 31 mutation 1, HRAS more common
BRAF 10, 2 V600/601 4, no V600/601
PIK3CA 7 mutation 16 mutation
ERBB2 5 mutation 3 non-canonical, rare amplification (lt5)
FGFRs 2 mutation 10 amplification, 12 mutation
DDRs 3 mutation 4 mutation
Lung adenocarcinoma ALK, RET, ROS
translocations Squamous Tumor suppressor
translocations A case for comprehensive genotyping
Slide courtesy of Peter Hammerman
14
Genomics targets in squamous cell lung cancer
DDR2 mutation
S768R (25 454 reads)
Hammerman P, Sos ML et al., Cancer Discovery
2011 Pitini et al., Lung Cancer 2013
15
FGFR1 amplifications in sqamous cell cancer (SCC)
of the lung from discovery to clinical
evaluation
Weiss J, Sos ML et al. Sci Transl Med 2010
Weiss et al., Sci Transl Med 2010
Heukamp et al, Mod Pathol, 2012
Genomic discovery
Preclinical validation
FISH-diagnostics
Chromosome 8p geography
Clinical evaluation
Malchers et al. Cancer Discovery 2013
FIM trial BGJ398 in FGFR1-ampl. SQLC
Understanding response on the molecular level
ASCO 2014, PI J. Wolf (Confidential)
16
RR FGFR1 amplified lung 16 (RR FGFR-altered
bladder 40)
Lecia Sequist, AACR 2014
17
Massive heterogeneity of the FGFR1 amplicon
Chromosome 8p geography
Samples
Malchers et al. Cancer Discovery 2013
18
MYC expression and FGFR1 dependency
19
MYC sensitizes FGFR1 expressing cells in vivo
  • vehicle
  • BGJ398 (FGFR inhibitor)
  • vehicle
  • BGJ398 (FGFR inhibitor)

Malchers et al. Cancer Discovery 2013
20
MYC expression in an FGFR inhibitor responder
(BGJ398 phase I trial)
MYC
FGFR1 FISH
  • 100mg BGJ398day 56
  • baseline

Malchers and Dietlein et al., Cancer Discovery
2013
21
FGFR3 fusions in squamous cell lung cancer
  • FGFR3-TACC3 fusions in squamous cell lung cancer
  • App 2-3 of the cases
  • Preclinical sensitivity to FGFR inhibition
  • FGFR1 amplifications, FGFR2 mutations

Kim et al., JCO 2013 Wu et al., Cancer Discovery
2013
22
Targeting RAS in lung cancer
  • Picomolar affinity for GTP ? gt1000-fold
    difference to
  • ATP-competitive TK-inhibitors
  • Only Glycine-12 Cysteine mutants are being hit
  • Allows irreversible binding with covalent
    inhibitors
  • Can be used for binding affinity screens

Glycine-12
Ostrem J., Peters U., Sos ML, et al., Nature 2013
23
Irreversible RAS-Inhibitors
KRAS-G12C Abhängige Zellen
Ostrem J., Peters U., Sos ML, et al., Nature 2013
24
Summary
  • Genomics can guide therapeutically relevant
    diagnoses in lung cancer
  • The amplicon structure of FGFR1 in squamous cell
    lung cancer is complex
  • Novel drugs might enhance the window of
    opportunity for precision medicine in SQLC
    patients

25
POSITIONS ARE AVAILABLE!!! martin.sos_at_uni-koeln.de
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