Developments in small cell lung cancer G. Giaccone, MD PhD Chief, Medical Oncology Branch and Affiliates National Cancer Institute Bethesda MD USA

Transcription

1 Developments in small cell lung cancer G. Giaccone, MD PhD Chief, Medical Oncology Branch and Affiliates National Cancer Institute Bethesda MD USA Geneva April 20, 2012

2 Neuroendocrine tumors of lung Typical carcinoid Atypical carcinoid Large cell neuroendocrine tumor Small cell neuroendocrine tumor Cancer 2009;115,

3 Neural enzymes, peptides and transmitters may be stored in the dense core neurosecretory granules associated with SCLC.

4 Neuroendocrine tumors of the lung Typical Carcinoid Bertino EM et al. Cancer 2009 Poorly differentiated NE Carcinoma (arrows are mitoses

5 Pathology and Molecular pathogenesis The spectrum of pulmonary neuroendocrine tumors DIPNECH Typical Carcinoid Atypical Carcinoid Large-cell NE carcinoma Small-cell carcinoma Frequency of molecular changes p53 mutations 0 25% 59% 71% DIPNECH = diffuse idiopathic neuroendocrine cell hyperplasia

6 Hypothesized model of origin of lung tumors Cancer Medicine 2003

7 Molecular Genetics of Lung Cancer began with this study Specific Chromosome Defect Associated with Human Small-Cell Lung Cancer: Del 3p (14-23)

8 Molecular changes in pulmonary NE tumors Deletion map of chromosome 3p in neuroendocrine lung tumors Onuki N. Cancer 1999;85:600-7.

9 Karyotypes of lung cancer by CGH SCLC NSCLC Oncogene 2002;21:6877

10 Focal SCNAs Nature 2010;463:899

11 Nature 2010;463:899 Focal SCNAs

12 Amplifications of MYC family members in SCLC and all cancer types Overall (%) high-level a (%) MYC SCLC b All cancers MYCN SCLC All cancers MYCL1 SCLC All cancers a high level: estimate copy number > 3 b estimated >64 copies in some SCLC cell lines (unpublished data) Tumorscape

13 Array CGH study of lung neuroendocrine tumors SCLC tumors SCLC cell lines Bronchial carcinoids GI carcinoids Number Cytogenetic bands with recurrent CN aberrancy gains losses Genes in cytogenetic bands with recurrent CN aberrancy gains losses Cytogenetic bands with very high CN gain & Genes in cytogenetic bands with very high CN gain & & 2-log ratio >3.0 Voortman et al. PNAS 2010

14 SCLC cell lines may be representative of SCLC tumors genomically Karyotpes of SCLC tumors and cells are similar SCLC cell lines have more losses in chr. 2 Only 74 genes were in cytogenetic bands in which the difference of frequencies of CNA between SCLC tumors and cell lines was > 50% and statistically significant

15 In SCLC tumors, karyotypes of samples obtained from metastatic sites are similar to those from lung

16 Frequency of CN alterations Comparison of SCLC tumors, bronchial carcinoids, and carcinoids of GI origin MYC Gain Loss RB1 TP53 Gain: 0.2 Loss: -0.2 Recurrent alteration: 35% Voortman and Lee PNAS 2010

17 High correlation between results obtained by acgh and by real-time PCR The results of acgh are reliable

18 MYC family in SCLC cell lines c-myc L-Myc

19 Common copy number alterations of neuroendocrine tumors Genes micrornas RB1 loss DLK1 gain TP53 loss MYC gain 52 locate in the DLK1-DIO3 domain in chr. 13

20 Potential drug targets for SCLC Genes with high frequencies of copy number alterations Tumorscape Genes All cancers SCLC Our series SCLC tumors Tumorscape Genes All cancers SCLC Our series SCLC tumors PIK3CA gain 21.6% 57.5% 75.8% BCL2 gain 11.9% 47.5% 51.5% AKT1 gain 16.3% 47.5% 63.6% MCL1 gain 36.5% 57.5% 76.8% PTEN loss 24.2% 62.5% 75.8% FRAP1 (mtor) gain 13.4% 45.5% 54.5% PMAIP1 (Noxa) gain 11.7% 45% 66.8% VHL loss 23.6% 80% 75.8% The PI3K-AKT-mTOR and the apoptosis pathways are potential drug targets

21 Cytogenetic bands with very high copy number gain & in SCLC tumors Cytogenetic band Genes encoded Candidate genes 8 p12 - p EIF4EBP1, FGFR1 9 p JAK2 9 p23 - p MPDZ 19 q q * & 2-log ratio >3.0 *chr. 19 encodes 10 transcription factors

22 Copy number gain of the JAK2 gene and the FGFR1 gene in SCLC tumors and cells Tumorscape SCLC tumors Our series SCLC cell lines JAK2 42.5% 27.8% 30.8% FGFR1 27.5% 33.3% 30.8% JAK2 and FGFR1 are potential targets in subgroups of SCLC Tumorscape: acgh data of 26 cancer types and >3000 specimens

23 EIF4EBP1 FGFR1

24 Targeting FGFR1 in SCLC PD173074, a pan-fgfr inhibitor, on 7 SCLC cell lines J-H Lee unpublished data

25 FGFR1 is amplified in squamous cell lung cancer Weiss J et al. Sci Transl Med 2010;2:62ra93-62ra93

26 JAK2

27 IL-6, IFN Myeloproliferative disorder TPO receptor mutation Cytokine receptors Polycythemia vera Essential thrombocythemia Idiopathic myelofibrosis Levine et al Nat Rev Cancer 2007;7:673

28 survival AZD1480 kills a SCLC cell line carrying JAK2 gene amplification and induces G2/M arrest and apoptosis NCI-N592, 0.68uM NCI-H620 >10uM AZD1480(uM) NCI-N592: JAK2 amplification NCI-H620: JAK2 deletion NCI-N592 Treated with drug for 48 hours 0μM 0.3μM 1μM 3μM NCI-N592 Treated with drug for 24 hours

29 Features of copy number alterations of pulmonary neuroendocrine tumors Common copy number alteration of all tumor types: Recurrent RB1 loss Recurrent DLK-DIO3 domain gain (including 52 micrornas) More TP53 loss and MYC family members gain in SCLC Chromosome 5 amplification in bronchial carcinoid and carcinoids of GI-origin

30 Somatic mutations in a SCLC cell line insertions deletions Copy number substitutions Rearrangements intra and inter chromosomal Pleasance et al. Nature 463, 184, 2010

31 Cancer genome of NCI-H209 SCLC cell Most mutations in coding and promoter regions are passenger events G>T transversions represent exposure to tobacco carcinogens Pleasance et al. Nature 463, 184, 2010

32 G:C T:A, a smoking signature, in lung cancer and SCLC from IARC TP53 database and from a SCLC genome Oncogene 2002;21:7435 Nature 2010;463:184

33 Mutations in SCLC, from COSMIC

34 Molecular Profiling of Thoracic Malignancies Eligibility Advanced, non-resectable NSCLC, SCLC and thymic malignancies. Tissue Requirements: Biopsiable disease Adequate archival material Previously performed molecular profiling ECOG 2 Normal organ and marrow function

35 Molecularly Targeted Treatment of Advanced Thoracic Malignancies Patient selection: Molecular + NSCLC, SCLC and thymic malignancies Treatment: Targeted therapies Pyroseq, Cap. Electr. (NCI) Sequenom (OHSU) FFPE Core 1 Raffeld s Lab Pack s Lab EGFR, KRAS, NRAS, BRAF, ERBB2, PI3KCA, AKT1 FISH: ERBB2, PIK3CA, PDGFRA, ALK NCI / CTEP protocol 8639 EGFR Mutation* Erlotinib Biopsy FFPE Core 2 Biopsy and molecular profiling KIT, No RAS, RAF, No PTEN No ERBB2 No PDGFR-A No Meltzer s Lab Mutation Giaccone s Lab MEK PI3K, Akt Mutation or Mutation* Mutation* or Amp* Amp* Yes Yes Yes Yes Yes AZD6244, MEK inhibitor Exome sequencing 197 cancer genes and CGH MK2206 PI3K inhibitor Disease Progression Lapatinib NextGen sequencing A Frozen Core 3 Exploratory Sunitinib Analyses and Validation A A = re-biopsy Other* Available study

36 Study Size 600 Patients 5 years Each patient may undergo repeat biopsies Close collaboration with Interventional Radiology and surgery imperative for the study to succeed

37

38

39

40

41 Patient accrual: protocol 11-C-0096 First patient enrolled at NCI February 8, 2011 First patient enrolled at OHSU September 29, 2011 Number of pts. screened 224 Number of pts. consented as of 1/15/2012 Unable to obtain new biopsy/failed new biopsy/unable to obtain archival material Diagnosis not NSCLC, SCLC or thymic on final pathology report Avg. no: of pts. accrued/month Data cut off 1/15/2012

42 Baseline tumor characteristics Histology NSCLC 151 Adenocarcinoma 128 Squamous 15 Adeno-squamous 2 Large cell 2 NOS 4 SCLC 18 Thymic malignancies 47 Thymoma 24 Thymic carcinoma 20 Thymic neuro-endocrine carcinoma 3 2 pts. had other malignancies- neuroendocrine ca of unknown primary and papillary thyroid ca

43 Tissue collection 113 New biopsies performed in 105 patients NSCLC SCLC Thymic Total tumors Number of new biopsies Archival tissue used Unable to obtain new biopsy/insufficient archival material In addition, 2 pts. with other malignancies also had new biopsies 8 patients had repeat biopsies

44 Tumor molecular profile according to histology NSCLC SCLC Thymic tumors EGFR mut KRAS/BRAF/NRAS/HRAS mut PTEN/PIK3CA/AKT mut HER2 ampl/mut KIT mut/pdgfr-a mut/ampl ALK translocation

45 Selected mutations in 5 cases BRCA2 PIK3CA APC TET2 TSC2 NRAS PTEN RB1 TP

46 TP53 mutation

47 RB1 frameshift

48 SCLC sequencing efforts SCLC not included in the TCGA program Single institutions efforts Difficult to get sufficient material and frozen material

49 Acknowledgments Clinic A. Thomas A. Lopez-Chavez A. Rajan R. Kelly C. Carter S. Khozin P. Dennis E. Szabo U. Guha S. Malik B. Scepura A. Berman C. Keen M. Manu G. Chun Lab Y. Wang B. Morrow D. Voeller T. Pham Interventional Radiology B. Wood A. Venkatesan N. Abi-Jaoudeh R. Chang E. Levy Surgery Branch D. Schrump K. Kwong Pulmonary J. Fontana Laboratory of Pathology M. Raffeld L. Xi S. Pack Z. Abdullaev Genetics Branch P. Meltzer K. Killiam C. Lau J. Zhu