2013 2014 2015 2016 2017 2018 2019 Discovery of RET fusion - - PowerPoint PPT Presentation

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Dec 17, 2023 319 likes •440 views

Takashi Kohno, PhD (tkkohno@ncc.go.jp) Chief, Division of Genome Biology, Research Institute Chief, Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center National Cancer Center , Tokyo, Japan Discovery and

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Takashi Kohno, PhD (tkkohno@ncc.go.jp)

Chief, Division of Genome Biology, Research Institute Chief, Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center National Cancer Center , Tokyo, Japan 1

2012 2013 2015 2016 2017

LURET (vandetanib trial) ALL-RET (Alectinib trial)

Response rate=53%

2018 2014

PhII clin trial of vandetanib Yoh, Goto et al, Lancet Respir Med, 2017 Drug resistance mechanism Nakaoku, Kohno et al, Nat Comm, 2018 Discovery of RET fusion Kohno et al, Nature Med, 2012

2019

Loxo-292 trial LC-SCRUM-Japan: Pan-Japan screening of rare oncogene alterations in lung cancer

Discovery and translation of RET fusion in lung cancer

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Implementation of NCC Oncopanel Test in Japan

IC NGS test for 114 genes Somatic mutation Germline mutation Tumor mutation burden FFPE tumor sample & Peripheral blood Tumor board meeting Clinical trial Off-label use

114 mutation・amplification (whole exon) 13 fusion

ABL1 CRKL IDH2 NF1 RAC2 ALK ACTN4 CREBBP IGF1R NFE2L2 RAD51C AKT2 AKT1 CTNNB1/b-catenin IGF2 NOTCH1 RAF1/CRAF AKT3 AKT2 CUL3 IL7R NOTCH2 RB1 BRAF AKT3 DDR2 JAK1 NOTCH3 RET ERBB4 ALK EGFR JAK2 NRAS RHOA FGFR2 APC ENO1 JAK3 NRG1 ROS1 FGFR3 ARAF EP300 KDM6A/UTX NTRK1 SETBP1 NRG1 ARID1A ERBB2/HER2 KEAP1 NTRK2 SETD2 NTRK1 ARID2 ERBB3 KIT NTRK3 SMAD4 NTRK2 ATM ERBB4 KRAS NT5C2 SMARCA4/BRG1 PDGFRA AXIN1 ESR1/ER MAP2K1/MEK1 PALB2 SMARCB1 RET AXL EZH2 MAP2K2/MEK2 PBRM1 SMO ROS1 BAP1 FBXW7 MAP2K4 PDGFRA STAT3 BARD1 FGFR1 MAP3K1 PDGFRB STK11/LKB1 BCL2L11 FGFR2 MAP3K4 PIK3CA TP53 BRAF FGFR3 MDM2 PIK3R1 TSC1 BRCA1 FGFR4 MDM4 PIK3R2 VHL BRCA2 FLT3 MET POLD1 CCND1 GNA11 MLH1 POLE CD274/PD-L1 GNAQ MTOR PRKCI CDK4 GNAS MSH2 PTCH1 CDKN2A HRAS MYC PTEN CHEK2 IDH1 MYCN RAC1

Japanese FDA approval in Dec, 2018 Reimbursement by National insurance system will start in June, 2019

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Precision Medicine for Ovarian Cancer

“Cancer” with LOF Mutation →Targeting Synthetic Lethal Partner Normal Cells Cancer Cells a A B B (Synthetic) Lethal Survival a: BRCA1/BRCA2 B: PARP1

Synthetic lethality Olaparib etc

“Cancer” with GOF Mutation →Directly Targeting Oncoprotein Normal Cells Cancer Cells a A B B Lethal Survival a: EGFR

Gefitinib etc Crizotinib etc

a: ALK

Vandetanib etc

a: RET

Vemurafenib

a: BRAF Lung Skin Lung Lung Ovary Breast

GOF: Gain of Function LOF: Loss of Function

a: ARID1A B: GSH

Synthetic lethality APR-246

Ovary

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500 1000 1500 2 4 6 8 10 12 Tumor Volume (mm3) Days TOV21G Xenograft APR-246 - APR-246 + ** ** *** *** ** ** 200 400 600 800 5 10 15 20 Tumor Volume (mm3) Days RMG-I Xenograft APR-246- APR-246+

RMG-I:ARID1A＋ TOV21G:ARID1Aー

Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

(Ogiwara H, Takahashi K, …., Okamoto A, Kohno T. Cancer Cell, 2019)

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500 1000 1500 2 4 6 8 10 12 Tumor Volume (mm3) Days TOV21G Xenograft APR-246 - APR-246 + ** ** *** *** ** ** 200 400 600 800 5 10 15 20 Tumor Volume (mm3) Days RMG-I Xenograft APR-246- APR-246+

RMG-I:ARID1A＋ TOV21G:ARID1Aー

Ovarian clear cell carcinoma frequently (50%) shows ARID1A deficiency ARID1A maintains Glutathione (GSH) homeostasis by enhancing SLC7A11 transcription Low SLC7A11 expression causes low basal GSH levels in ARID1A-deficient cancer cells Inhibiting GSH by APR-246 in ARID1A-deficient cancer cells causes apoptosis by ROS

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ARID1A-deficient Ovarian Cancer Cells Lack SLC7A11 Expression

anti-ARID1A (HPA005456, 1:2000 dilution; Sigma-Aldrich) anti-SLC7A11 (ab175186, 1:400 dilution; Abcam)

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MQ p53 activation

GSH inactivation

TrxR

(Bykov VJN et al., 2016)

APR-246 (APREA Therapeutics) Inactivates Glutathione (GSH)

APR-246 clinical trials https://www.aprea.com/pipeline/apr-246/

P53 mutated ARID1A wild type

TOV21G: ARID1A(-), TP53(WT) OCCC

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ARID1A (+) ARID1A (-) SLC7A11 (-) SLC7A11 (+)

APR246 treatment for ovarian clear cell carcinoma (and endometrioid ca?）

Coupling research ・Relationship between response & ARID1A/SLC7A11expression (by IHC) ・Monitoring cfDNA for ARID1A mutation (by Guardant360 test?)

Non-responder? Responder?

Global clinical trial?

Proposal of APR-246 (APREA Therapeutics) Trial

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Guardant 360 Monitoring cfDNA for ARID1A mutation (by Guardant360 test?)

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123 143 163 148 154 167 83 103 115 145 169 198 206 2… 278 293 322 365 50 100 150 200 250 300 350 400 450 2012 2013 2014 2015 2016 2017 Domestic Global Total

No. of Global Trials in NCCH

Types of Global Trials in NCCH

3 10 14 14 21 33 4 6 9 11 18 20 12 14 14 21 23 28 58 67 73 94 102 110 1 5 4 4 3 3 5 1 1 1 2 4 83 103 115 145 169 198 50 100 150 200

2012 2013 2014 2015 2016 2017

IIT Others P-III P-II P-I/II P-I .

Comprehensive alliance between The JikeiUniversity & National Cancer Center

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Takashi Kohno, PhD (tkkohno@ncc.go.jp)

National Cancer Center , Tokyo, Japan

Dr. Kenji Tamura (a PI for early phase clinical trials)

Chairman, Department of Breast and Medical Oncology, National Cancer Center Hospital Director, Outpatient Treatment Center E-mail: ketamura@ncc.go.jp Lancet Oncology, 2017