Discovery of Essential Growth Drivers in Cancer Brings Magical Drugs to Patients
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1 Discovery of Essential Growth Drivers in Cancer Brings Magical Drugs to Patients Hiroyuki Mano, MD, PhD Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Japan
2 What to target? Chronic myeloid leukemia (CML) BCR ABL PTK Kinase Kinase BCR-ABL fusion PTK Imatinib (Glevec) to suppress ABL activity Inhibit the essential growth drivers
3 Retroviral cdna expression library cdna synthesis from Lung cancer specimens LTR LTR Retroviral vector cdna-expression library
4 Focus formation assay with 3T3 cdna library Negative control Positive control (vras)
5 Discovery of EML4-ALK (Soda et al. Nature 448: , 2007)
6 Activation of EML4-ALK Normal ALK EML4-ALK Ligand-binding Activation Constitutive activation Growth Cancer
7 (PNAS 105:19893) EML4-ALK Tg mice
8 In vivo effect of anti-alk inhibitor Day 0 Day 25 (PNAS 105:19893)
9 Blog by a ALK-positive patient (
10 Doctor helicopter to Kansai Airport (Nov 27, 2008) (O 2 3L/min) (Courtesy of Dr. Tanio)
11 Flew to Incheon Airport (O2 6L/min) Arriving at Incheon Airport Ambulance car to Seoul National University Hospital Crizotinib treatment starting at Nov 28
12 ALCAS screening 916 specimens 808 specimens (754 patients) with good RNA (Cln Cancer Res 18:5682)
13 ALCAS screening EML4-ALK was positive among 36 specimens (4.46%) for 32 patients (4.24%) in NSCLC (6.11% for adenocarcinoma) Pathologically, EML4-ALK positive tumors have acinar structure, mucin production. Mutually exclusive to EGFR mutations Enriched young patients (average = 48.3 years old), and in non-smokers or light-smokers (Cln Cancer Res 18:5682)
14 Aother Japanese patient
15 Aother Japanese patient
16 CR + PR = 81%
17 CR + PR = 81% (NEJM 363:1693)
18 Accelertion in drug development BCR-ABL Target Approval EGFR BRAF EML4-ALK
19 Paradigm shift in clinical trials Current Crizotinib Phase I Phase I/II 10 ~ 15 yrs Phase II Phase III Safty/dose escalation (Unselected patients) Efficacy (tens to hundreds) 4 yrs Approval Phase III Safety/dose/efficacy (only EML4-ALK + ) Comparison to standard care Comparison to standard care (Double-blind on hundreds to thousnads) Approval Discussion on clinical trial design in personalized medicine (Cell 6:1079)
20 Deep sequencing of ALK cdna Coverage Primary Wild Mismatch cdna position Relapse cdna position rs G4374A C4493A (N Engl J Med 363:1734)
21 Deep sequencing of ALK cdna EML4 Primary Relapse Coverage Wild Mismatch EML4 cdna position ALK cdna position rs G4374A C4493A (N Engl J Med 363:1734)
22 C1156Y and L1196M: TKI resistant mutations Crizotinib Wild C1156Y L1196M (N Engl J Med 363:1734)
23 2nd generation ALK inhibitors Astellas ASP3026 US/Japan Chugai Pharmaceuticals CH US/Japan ARIAD AP26113 US Xcovery X-396 US Novartis LDK378 US/Japan
24 2nd generation ALK inhibitors Astellas (Lancet Oncol 2013) ASP3026 US/Japan Response = 94%! Chugai Pharmaceuticals CH US/Japan ARIAD AP26113 US Response against crizotinib-resistant = 47% Xcovery X-396 US (Shaw et al. ESMO 2012) Novartis LDK378 US/Japan
25 Annual cancer related deaths Japan (2005) Total st Lung nd Stomach rd Liver th Colorectal th Pancrease World (2004) Total st Lung nd Stomach rd Colorectal th Liver th Breast EML4-ALK is present in 4-5% of NSCLC (~1/3 of <50 years old)
26 ALKoma NSCLC EML4-ALK Nature 448:561 KIF5B-ALK Clin Cancer Res 15:3143 Lymphoma NPM-ALK Science 263:12281 CLTC-ALK Blood 95:3204 IMT TPM3/4-ALK Am J Pathol 157:377 Renal medullary VCL-ALK Am J Pathol 157:377 carcinoma Ovarian stromal sarcoma FN1-ALK Cancer Res 72:3312 Spitz tumor ALK fusions AGBT 2012 meeting Neuroblastoma ALK mutations Nature 455:971 Thyroid anaplastic cancer ALK mutations Cancer Res 71:4403
27 ALKoma Cancer Discovery 2:495
28 What about other fusions? FISH-based screening of 1500 NSCLC cases CD74 SLC34A2 EZR LRIG3 TPM3 SDC4 ROS1 (Nat Med 18:378) ROS1 fusion = 1.2% of adenocarcinoma
29 What about other fusions? FISH-based screening of 1500 NSCLC cases Dramatic effects with crizotinib for ROS1-fusion CD74 SLC34A2 ROS1 EZR LRIG3 TPM3 SDC4 (Nat Med 18:378) (JCO 30:863) ROS1 fusion = 1.2% of adenocarcinoma
30 Discovery of RET fusions FISH-based screening of 1500 NSCLC cases KIF5B RET CCDC6 RET fusion = 1.2% of adenocarcinoma (Nat Med 18:378)
31 HT1080 fibrosarcoma Mutation screening Functional sreening with NGS NRAS(Q61K) RAC1(N92I) (Kawazu et al. PNAS 110:3029)
32 Discovery of RET fusions FISH-based screening of 1500 NSCLC cases Investigator-initiated trials in Japan by National Cancer Center (from Jan 2013) LURET study with vandetanib KIF5B CCDC6 RET RET fusion = 1.2% of adenocarcinoma (Nat Med 18:378)
33 RAC1(N92I) and NRAS(Q61K) are transforming Mock NRAS(Q61K) RAC1 RAC1(N92I) RAC1(G12V) (Kawazu et al. PNAS 110:3029)
34 RAC1 is the essential driver 100 Control sirna NRAS-siRNA1 Cell number 10 NRAS-siRNA2 RAC1-siRNA1 RAC1-siRNA2 RAC1-siRNA1 + NRAS-siRNA1 RAC1-siRNA2 + NRAS-siRNA Days (Kawazu et al. PNAS 110:3029)
35 RAC family mutations Mutation RAC1(N92I) RAC1(P29S) RAC1(C157Y) RAC2(P29L) RAC2(P29Q) Cancer type Fibrosarcoma HT1080 Malignant melanoma specimens*, Triplenegative breast cancer MDA-MB-157, Oral squamous cell carcinoma specimens, Pancreatic cancer PK-59 Lung adenocarcinoma specimens Triple-negative breast cancer HCC1143 Chronic myeloid leukemia KCL22 *Nat Genet 44:1006, Cell 150:251
36 Cancer Therapeutics in the Future Targeting growth-related molecules Nucleus Targeting essential growth drivers
37 Collaborators Mano group Jichi Med Univ Yoshihiro Yamashita Toshihide Ueno Manabu Soda Azusa Yamato Univ Tokyo Eirin Sai Masahito Kawazu Mizuo Ando Kazutaka Fukumura Hiroyuki Yamaguchi Takahiko Yasuda The Cancer Institute Kengo Takeuchi Yuichi Ishikawa University of Tokyo Sch. Pharmaceutical Sciences Toshiaki Katada Kenji Kontani Yoshitaka Ogita
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