Keynote Lecture 1 Advances in Molecular Biology of Pancreatic Cancer: Understanding Genetic Complexity and Molecular Heterogeneity

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1 Keynote Lecture 1 Advances in Molecular Biology of Pancreatic Cancer: Understanding Genetic Complexity and Molecular Heterogeneity Volker Ellenrieder, MD, PhD University Hospital Gӧttingen Gӧttingen, Germany

2 Major Causes for Poor Prognosis Late diagnosis Rapid local tumor growth and early metastasis High recurrence rate after surgery Resistance to conventional therapy

Model of Pancreatic Carcinogenesis PanIN 1-3 Cancer Hruban RH, et al. Clin Cancer Res. 2000;6(8):2969-2972. KRAS, p16, p53, SMAD4.

3 Model of Pancreatic Carcinogenesis PanIN 1-3 Cancer Hruban RH, et al. Clin Cancer Res. 2000;6(8): KRAS, p16, p53, SMAD4... Initiation Malignancy Metastasis? Diagnosis Death Time (years) Yachida S, et al. Nature. 2010;467(7319): Rhim AD, et al. Cell. 2012;148(1-2): Window for intervention

4 PDAC is characterized by low tumor cellularity and a dense microenvironment Neesse A, Ellenrieder V. Z Gastroenterol. 2015;53(4):

5 The Tumor Microenvironment MDSC ECM CAF - stellate cells T cells Cytokines Blood vessel Cancer cells Neesse A, Ellenrieder V. Gut. 2017;66(2):

6 Key Features of Pancreatic Cancer Biology Stroma cells Signaling Signaling Tumor cells Neesse A, Ellenrieder V. Gut. 2017;66(2): Genetic Diversity

7 Key Studies on Pancreatic Cancer Genetics Study Whole-Exome and Genome Sequencing Clinical Cases Xenograft Cell Lines Method Jones Exome Yachida 2010 a 7 Exome Campbell 2010 a 3 10 Genome Liang Genome Biankin Exome Wang Exome Murphy 2014 b,c 10 Exome Waddell Genome Witkiewicz 2015 b 109 Exome Dal Molin Exome a Denotes models from matched primary metastatic cases. b Denotes microdissected cases. c Denotes studies inclusive of PANIN lesions Knudsen ES, et al. Gastroenterology. 2016;150(1):48-63.

8 Pancreatic Cancer Is Genetically Diverse High prevalence: KRAS, TP53, CDKN2A, & SMAD4 Other mutations: High variability and low prevalence

Recurrent Mutations in Pancreatic Cancer PDAC results from a large number of genetic mutations Gene mutations converge on limited number of pathways and processes Pathway components that are altered

9 Recurrent Mutations in Pancreatic Cancer PDAC results from a large number of genetic mutations Gene mutations converge on limited number of pathways and processes Pathway components that are altered in any individual tumor vary widely Discovery of agents that target altered pathways and processes may offer key nodals for therapy PDAC, pancreatic ductal adenocarcinoma Cancer Genome Atlas Research Network. Cancer Cell. 2017;32(2):

10 Integrated Genomic Analysis Revealed Potential Novel Vulnerabilities N = 456 PDAC tissues 32 recurrently mutated genes 10 pathways & processes P. Bailey Bailey P, et al. Nature. 2016;531(7592):47-52.

Defects of DNA Damage Response Mechanisms DNA repair system 9% to 10% of patients with PDAC have germline or somatic BRCA mutations In total, 24% have defects in DDR (mutations in BRCA1/2, PALB2,

11 Defects of DNA Damage Response Mechanisms DNA repair system 9% to 10% of patients with PDAC have germline or somatic BRCA mutations In total, 24% have defects in DDR (mutations in BRCA1/2, PALB2, ATM, CHK1/2...) and/or show a genomic unstable phenotype with DDR insufficiency Accumulation of genetic alterations Promotion of genomic instability Enhance therapeutic resistance Waddell N, et al. Nature. 2015;518(7540): DDR, DNA damage repair Biankin AV, et al. Nature. 2012;491(7424): Sausen M, et al. Nat Commun. 2015;6:7686. Witkiewicz AK, et al. Nat Commun. 2015;6:6744. Ying MF, et al. Genet Mol Res. 2016;15(1).

12 Unstable Genome and BRCA Signature Correlate With Responsiveness to Platinum-Based Therapy Waddell N, et al. Nature. 2015;518(7540):

13 Unstable Genome and BRCA Signature Correlate With Responsiveness to Platinum-Based Therapy CA19.9, U per ml Time, Months Excellent response to platinum-based therapy

14 BRCA Mutations and PARP Inhibition O Shaughnessy J, et al. J Clin Oncol. 2009;27(15S): Abstract 3.

15 Open Questions Can we treat patients with BRCAness (BRCA1/2, PALB2) with PARP inhibitors? Should we combine PARP-inhibitor with platinum or with topoisomerase inhibitor (eg, irinotecan, nal-iri)? Can we maintain patients on a single-agent PARP inhibitor following platinum-based chemotherapy?

16 PARP Inhibition in Clinical Trials Completed Active/Recruiting RUCAPANC

POLO Trial: Phase III Study With Olaparib Olaparib in gbrca-mutated pancreatic cancer whose disease has not progressed on first line

..initial course of chemotherapy for metastatic disease with a platinum-containing regimen,* with the platinum component given for a

(olaparib:placebo) On-treatment assessments No progression: Discontinuation of study treatment visit Death Loss to followup Placebo bid

oxaliplatin Safety follow-up, 30 days after last dose of study treatment Off treatment RECIST follow-up to progression Overall survival

17 POLO Trial: Phase III Study With Olaparib Olaparib in gbrca-mutated pancreatic cancer whose disease has not progressed on first line platinum-based chemotherapy (POLO) Screening...initial course of chemotherapy for metastatic disease with a platinum-containing regimen,* with the platinum component given for a minimum of 16 weeks Olaparib tablets 300 mg bid Progression: Discontinuation of study treatment visit Randomization 3:2 (olaparib:placebo) On-treatment assessments No progression: Discontinuation of study treatment visit Death Loss to followup Placebo bid Withdrawal of consent to all study-related procedures and follow-up *acceptable platinum agents include carboplatin, cisplatin, and oxaliplatin Safety follow-up, 30 days after last dose of study treatment Off treatment RECIST follow-up to progression Overall survival (OS )data (information from hospital records and/or public death registries where available) National Institutes of Health. Available at: Accessed: September 29, Progression PFS2 and survival follow-up

18 Genetic Landscape and Potential Novel Vulnerabilities 38% N = 456 pancreatic cancer tissues Genetic Alterations of Epigenetic Regulators Bailey P, et al. Nature. 2016;531(7592):47-52.

19 Chromatin Modifying Enzymes Writers Erasers Readers Acetylases (HATs) Methyltransferases (EZH2, MLL) Phosphorylases Deacetylases (HDAC) Demethylases (KDM6a) Phosphatases Bromodomain (BRD4) Chromodomain

20 Targeting HDAC in Pancreatic Cancer HDACi monotherapy failed! Is combination with chemotherapy or immunotherapy better? Hessmann E,..., Ellenrieder V. Gut. 2017;66(1):

21 EZH2 in Pancreatic Cancer Proliferation Apoptosis EZH2 Senescence EMT/Stemness.

22 EZH2 Targeting in Pancreatic Cancer Hessmann E,..., Ellenrieder V. Gut. 2017;66(1):

% Change From Baseline Vulnerability to EZH2 Inhibition Depends on SWI/SNF-(BAF) Status in Tumor Cells Best Responses in Patients With Solid Tumors EPZ-6438 SWI/SNF (BAF) Complex SMARCA4 Wildtype

23 % Change From Baseline Vulnerability to EZH2 Inhibition Depends on SWI/SNF-(BAF) Status in Tumor Cells Best Responses in Patients With Solid Tumors EPZ-6438 SWI/SNF (BAF) Complex SMARCA4 Wildtype EZH2 SWI/SNF EPZ % of all human PDAC! Mutant EZH2 No Response Response National Institutes of Health. Available at: Accessed: 27 September Gounder MM, et al. J Clin Oncol. 2017;35(suppl): Abstract Kim KH, et al. Nat Med. 2015;21(12):

24 Targeting Key Signaling and Transcription Hubs Genetic makeup NFAT/STAT3 target genes: PDL-1 GM-CSF CXCL12 CXCL5 MMP11 MMP1 WNT1 WNT10 EGFR...and stemness inhibition! Baumgart S, et al. Cancer Discov. 2014;4(6): Li Y, et al. Proc Natl Acad Sci U S A. 2015;112(6):

$pancreatic adenocarcinoma NCT02231723 Promising activity in patients with refractory, heavily pretreated metastatic pancreatic cancer (N = 71);$ particularly, in patients who are taxane naïve. DCR was observed in 55 (77%), with 1 CR (1.

particularly, in patients who are taxane naïve. DCR was observed in 55 (77%), with 1 CR (1.

25 BBI608 (Napabucasin) = STAT3 Inhibitor Phase Ib trial with napabucasin in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma NCT Promising activity in patients with refractory, heavily pretreated metastatic pancreatic cancer (N = 71); particularly, in patients who are taxane naïve. DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%) N=41 Treatment-related grade 3 adverse effects included diarrhea (4.9%), abdominal pain (4.9%), and nausea (2.4%), and were rapidly reversible Bekaii-Saab TS, et al. J Clin Oncol. 2017;35(suppl 4): Abstract 4106.

26 Ongoing Clinical Trials With Napabucasin NCT Phase III Study of BBI-608 Plus Nab-Paclitaxel With Gemcitabine in Adult Patients With Metastatic Pancreatic Adenocarcinoma Open-label, multicenter, phase III study - Recruiting NCT Phase Ib Clinical Study of BBI-608 in Combination With Standard Chemotherapies in Adult Patients With Metastatic Pancreatic Adenocarcinoma - Recruiting

27 Genetic makeup defines novel vulnerabilities Tumor stroma Responsiveness to external signals Tumor Cell Genetic diversity Cytokines & growth factor release DNA repair, metabolism, epigenetics

28 Targeting the Tumor Microenvironment Stroma cells CAF Stellate cells Tumor stroma Stromal Signaling Hedgehog TGFβ CTGF Immune regulation PD-1/PD-L1 CTLA4 Treg, MDSC ECM Hyaluronic acid collagen I-IV laminin, fibronectin

29 Conclusions Significant advances in our understanding of genetics and biology of pancreatic cancer PDAC is a genetically diverse disease In-depth genome analysis identified core signaling pathways and processes New druggable targets (eg, BRCA2, EZH2, BETi, HA, MSI) and potential biomarkers Extensive crosstalk between cancer cells and tumor environment Genetic makeup of cancer cells define responsiveness to external/internal signals

30 Perspectives & Opportunities Translation into better treatment strategies! Extent molecular stratification approaches to identify additional vulnerabilities Intensify molecular signature/biomarker-directed clinical trials Successful treatment probably requires multimodal targeting Find best drug combinations and sequences

Future Perspectives in mpca. Michel Ducreux, MD, PhD Gustave Roussy Villejuif, France

Future Perspectives in mpca. Michel Ducreux, MD, PhD Gustave Roussy Villejuif, France Future Perspectives in mpca Michel Ducreux, MD, PhD Gustave Roussy Villejuif, France Number of Novel Therapies and Targets in Pancreatic Cancer Are Expanding Garrido-Laguna I, et al. Nat Rev Clin Oncol.