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FRONTIERS IN CANCER SCIENCE 2020

2-6 NovemberConference Booklet

Genome Instituteof Singapore

TABLE OF CONTENTS04 20

08 21

2509

The Conference Organizers

Opening Lecture

Welcome from the Organizing Committee

Session 1

Session 2Scientific Program2 November 2020, Monday

3 November 2020, Tuesday

4 November 2020, Wednesday

5 November 2020, Thursday

6 November 2020, Friday

Ali SHILATIFARD

Speaker 01: Puay Hoon TAN

Speaker 02: Rani E GEORGE

Speaker 03: Kenneth KINZLER

Speaker 04: Antoni RIBAS

Speaker 05: Raghav SUNDAR

Speaker 06: Oral Abstract 1 Ying ZHANG

Speaker 07: Oral Abstract 2 Ömer AN

Speaker 08: Ricky JOHNSTONE

Speaker 09: Oral Abstract 3 SINAN XIONG

59

61

33 51

41Closing Lecture

Our Sponsors

Session 3 Session 5

Session 4Marco HEROLD

Speaker 10: Erwei SONG

Speaker 11: Takaomi SANDA

Speaker 12: Ronald A. DePINHO

Speaker 13: Ray DUNN

Speaker 14: Oral Abstract 4 Alvin GUO

Speaker 15: Oral Abstract 5 Chong Teik TAN

Speaker 16: Marco HEROLD

Speaker 17: Oral Abstract 6 Jieqiong ZHANG

Speaker 25: Muthiah MANOHARAN

Speaker 26: Anders SKANDERUP

Speaker 27: Boon Cher GOH

Speaker 28: Oral Abstract 10 Yanjing LIU

Speaker 29: Oral Abstract 11 Daniel HUANG

Speaker 30: Oral Abstract 12 Michal Marek HOPPE

Speaker 18: Kenneth KINZLER

Speaker 19: Melvin CHUA

Speaker 20: Oral Abstract 7 Jianbin CHEN

Speaker 21: Oral Abstract 8 Huili ANG

Speaker 22: Oral Abstract 9 Bryan Nicholas CHUA

Speaker 23: Yee Joo TAN

Speaker 24: Susan CLARK

THE CONFERENCEORGANIZERS

The Frontiers in Cancer Science (FCS) 2020, our 12th annual conference, is proudly and jointly organized by the Cancer Science Institute of Singapore (CSI Singapore), Duke-NUS Medical School (Duke-NUS), Genome Institute of Singapore (GIS), Institute of Molecular and Cell Biology, Lee Kong Chian School of Medicine, (LKCMedicine), National Cancer Centre Singapore (NCCS), National University Cancer Institute, Singapore (NCIS), The N.1 Institute for Health, (N.1) and Yong Loo Lin School of Medicine, NUS (YLLSoM).

The nation’s preferred cancer conference promises to bring together distinguished cancer researchers with complementary knowledge and expertise from across the globe. Learn from a plethora of renowned international and local cancer experts as they share pioneering ideas, novel information and gain invaluable networking opportunities.

CANCER SCIENCE INSTITUTE OF SINGAPORE

The Cancer Science Institute of Singapore (CSI Singapore) was officially launched on 15 October 2008. CSI Singapore aims to position Singapore as a global-leader in the field of Biomedical Sciences. Its mission: to conduct a multifaceted and coordinated approach to cancer research, extending from basic cancer studies all the way to experimental therapeutics and in so doing improve cancer treatment.

CSI Singapore is a state-of-the-art university research institute affiliated with, and hosted at the National University of Singapore. In 2008, it was awarded a $172 million “Research Center of Excellence” grant, one of only five in Singapore, by the National Research Foundation and the Ministry of Eduction.

The institute is an anchor for research expertise in three broad programmes; Cancer Biology & Stem Cells, Experimental Therapeutics, and the RNA Biology Centre; these programmes form expansive platforms for CSI Singapore’s focus on key cancers, namely in gastric, liver, lung and leukaemia which are endemic in the Asian populations.

www.csi.nus.edu.sg

DUKE-NUS MEDICAL SCHOOL The Duke-NUS Medical School (Duke-NUS) is a strategic partnership between the University and the National University of Singapore (NUS). It aims to develop a new generation of physician-scientists and offers an innovative, rigorous medical education program with a distinctive focus on research, aimed at building leaders in medical research, education and patient care.

The Duke-NUS was birthed from the need for a US-style medical school in Singapore. Its beginnings can be traced to 2000, when Singapore launched an ambitious Biomedical Sciences Initiative designed to make the country the biomedical hub of Asia, and to attract both research and health sector manufacturing capabilities to Singapore.

The research at Duke-NUS focuses on 5 “Signature Research Programs”:

1. Cancer and Stem Cell Biology,2. Cardiovascular & Metabolic Disorders,3. Emerging Infectious Diseases,4. Health Services & Systems Research,5. Neuroscience and Behavioral Disorders.

www.duke-nus.edu.sg

FCS 20 2004

GENOME INSTITUTE OF SINGAPOREEstablished in June 2000, the Genome Institute of Singapore (GIS) is the national flagship programme for the genomic sciences in Singapore that is primarily funded by the Agency for Science, Technology and Research. GIS seeks the integration of technology and biology towards answering questions of medical importance. World-renowned and highly-cited in prestigious journals, GIS delivers breakthroughs in today’s genomics revolution.

Housing over 300 scientists, trainees and staff, GIS’s scientific focus is to investigate questions in the realm of functional genomics and integrative biology. To uncover fundamental truths, GIS exploits the intersection between genomics, cell biology, and medicine and takes advantage of the contrasting genetic history of Pan-Asian populations. GIS biological focuses are integrated with technology development in order to create novel solutions to difficult problems.

https://www.a-star.edu.sg/gis/

INSTITUTE OF MOLECULAR AND CELL BIOLOGY The Institute of Molecular and Cell Biology (IMCB) was established in 1987 at the National University of Singapore (NUS) before becoming an autonomous research institute (RI) of the Agency for Science, Technology and Research (A*STAR). Its mission is to develop and foster a vibrant research culture for cutting-edge basic biomedical sciences and for training high-quality Ph.D. students for the flourishing biotechnology and pharmaceutical industries in Singapore.

Funded primarily by Biomedical Research Council (BMRC) of A*STAR, IMCB now boasts about 40 core research labs and 8 core facility units consisting of over 400 research scientists in total. IMCB’s research activities focus on six major fields: Cell Biology, Developmental Biology, Structural Biology, Infectious Diseases, Cancer Biology and Translational Research with core strengths in cell cycling, cell signalling, cell death, cell motility and protein trafficking.

IMCB continues to strive for excellence in biomedical R&D to see the vision of Singapore being a world class hub for the Biomedical Sciences in Asia and beyond.

www.imcb.a-star.edu.sg

LEE KONG CHIAN SCHOOL OF MEDICINE The Lee Kong Chian School of Medicine (LKCMedicine), a partnership between Nanyang Technological University, Singapore (NTU Singapore) and Imperial College London (Imperial), is training a generation of doctors who will put patients at the centre of their exemplary medical care. The School’s primary clinical partner is the National Healthcare Group, a leader in public healthcare recognised for the quality of its medical expertise, facilities and teaching. The School, named after local philanthropist Tan Sri Dato Lee Kong Chian, was officially opened on 28 August 2017 by Deputy Prime Minister Mr Teo Chee Hean.

LKCMedicine aims to be a model for innovative medical education and a centre for transformative research. Graduates of the five-year undergraduate medical degree programme that started in 2013 will have a strong understanding of the scientific basis of medicine, along with interdisciplinary subjects, including engineering, technology and the humanities. Its first doctors graduated in 2018 with a Bachelor of Medicine and Bachelor of Surgery (MBBS), awarded jointly by NTU and Imperial.

www.lkcmedicine.ntu.edu.sg

FCS 20 2005

NATIONAL CANCER CENTRE SINGAPORE

The National Cancer Centre Singapore (NCCS), headed by its Medical Director, Professor William Hwang, is at the forefront of cancer treatment and research.

Designed to provide integrated and holistic patient-centred clinical services, patients can be assessed by more than one specialist during the same visit as the centre allows cross-consultation among oncologists of different specialties. NCCS’ holistic approach not only provides comprehensive multi-disciplinary cancer care, but also develops public cancer education programmes and spearheads cutting-edge clinical and translational research in the understanding, prevention, diagnosis and treatment of cancer.

As a one-stop specialist centre housing internationally qualified oncologists, NCCS hopes to attract and train oncology professionals in its bid to be the global leading cancer centre. As a national and regional centre of research excellence, NCCS research has scaled greater heights, with success in procuring major competitive national grants, publishing an increasing number of scientific papers in high-impact journals, and winning prestigious international awards.

NCCS aims to be the institutional home for cancer professionals and researchers through learning and innovation. It continues to work towards its mission of delivering the best care with the best people and supported by the latest research.

www.nccs.com.sg

NATIONAL UNIVERSITY CANCER INSTITUTE, SINGAPORE The goal of the National University Cancer Institute, Singapore (NCIS) is to provide comprehensive yet personalized care for each and every patient, incorporating cancer awareness, prevention, diagnosis and treatment; and advancing care through research. A broad spectrum of cancer care and services - covering both paediatric and adult cancers, solid and hematologic malignancies, and holistic total

care emphasizing lifestyle wellness, rehabilitation and palliative care - are provided in this one center. Multidisciplinary management of patients is emphasized so that patients receive the best treatment and care from their doctors and nurses.

NCIS has established global reputation in translational research and clinical trials, hence, providing patients with access to research and investigational therapy. NCIS carries out high-level competitive research, houses multiple award-winning clinician-scientists and clinician-investigators, and has been awarded major research grants. Hematology-oncology research at NCIS is conducted under the Haematology-Oncology Research Group (HORG).

HORG has strong emphasis in clinical pharmacology and molecular biology, and has established international credibility in pharmacogenetics research and novel clinical trials in early-phase drug development. Over the years, NCIS through HORG, has formed multiple academic, research and industrial collaborations and conducted clinical trials involving patients with cancers such as nasopharyngeal carcinoma, thyroid cancer, multiple myeloma, hepatocellular carcinoma, gastric cancer and breast cancer.

www.ncis.com.sg

YONG LOO LIN SCHOOL OF MEDICINE, NUSThe NUS Yong Loo Lin School of Medicine is Singapore’s first and largest medical school. Our enduring mission centres on nurturing highly competent, values-driven and inspired healthcare professionals to transform the practice of medicine and improve health around the world.

Through a dynamic and future-oriented five-year curriculum that is inter-disciplinary and inter-professional in nature, our students undergo a holistic learning experience that exposes them to multiple facets of healthcare and prepares them to become visionary leaders and compassionate doctors and nurses of tomorrow. Since the School’s founding in 1905, more than 12,000 graduates have passed through its doors.

FCS 20 2006

In our pursuit of health for all, our strategic research programmes focus on innovative, cutting-edge biomedical research with collaborators around the world to deliver high impact solutions to benefit human lives.

The School is the oldest institution of higher learning in the National University of Singapore and a founding institutional member of the National University Health System. It is Asia’s leading medical school and ranks among the best in the world (Times Higher Education World University Rankings 2019 by subject and the Quacquarelli Symonds (QS) World University Rankings by Subject 2019).

For more information about NUS Medicine, please visit https://medicine.nus.edu.sg/

THE N.1 INSTITUTE FOR HEALTHThe N.1 Institute for Health (N.1) is an internationally-recognised clinical stage research institute focused on N-of-1 medicine, where clinical trials are designed specifically for each patient that is recruited into one of our ongoing clinical studies. We currently have over 10 prospective clinical trials cleared/ongoing.

N.1 is divided into 3 thrusts:

1) N.1/Onco,2) N.1/Neuro, and3) N.1/Thrive

All 3 thrusts specialize in the use of interventional artificial intelligence (AI) to optimise personalised combination therapy for solid and hematologic cancer patients (N.1/Onco), digital therapeutics to optimise personalised learning and prevent cognitive decline (N.1/Neuro), and training regimens to optimise human physical performance as part of our health and human potential portfolio (N.1/Thrive). We are comprised of a pre-eminent and multidisciplinary team with expertise in engineering, clinical trial innovation, behavioural sciences, strategy, and policy, among other domains.

https://n1labs.org/

CONFERENCE PARTNERTHE AMERICAN ASSOCIATION FOR CANCER RESEARCHFounded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes 47,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 127 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops—the largest of which is the AACR Annual Meeting, with more than 100,000 attendees for the 2020 virtual meetings and more than 22,500 attendees for past in-person meetings. In addition, the AACR publishes nine prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit www.AACR.org

FCS 20 2007

WELCOME FROM THE ORGANIZING COMMITTEE

WELCOME TO THE FRONTIERS IN CANCER SCIENCE 2020, 2 TO 6 NOVEMBER 2020

SUDHAKAR JHAMemberCancer Science Institute of Singapore

DAVID M. VIRSHUPChairmanDuke-NUS Medical School, Singapore

SIN TIONG ONGMemberDuke-NUS Medical School, Singapore

SHAZIB PERVAIZMemberNUS Yong Loo Lin School of Medicine

VINAY TERGAONKARMemberInstitute Of Molecular and Cell Biology, A*STAR Singapore

JOANNE NGEOWMemberLee Kong Chian School of Medicine

DEAN HOMemberThe N.1 Institute for Health

ANAND D JEYASEKHARAN

Member National University Cancer Institute, Singapore

KANAGA SABAPATHYMemberNational Cancer Centre Singapore

WAI LEONG TAMMemberGenome Institute of Singapore, A*STAR Singapore

As an exceptional platform for learning and networking, FCS 2020 enables the exchange of research and clinical knowledge in a dynamic setting, where fresh insights and new partnerships flourish. We believe the coming together of diverse andworld-class research expertise will bring cancer studies a step closer towards new breakthroughs and inventions.

Our sincere thanks to our sponsors for their generous support and invaluable contributions that have made this conference achievable.

We thank you for joining us, and hope you have an enjoyable and highly rewarding meeting.

The Organizing Committee welcomes you to the 12th annual conference of the Frontiers in Cancer Science (FCS).

Jointly organized by nine major research institutes in Singapore, the FCS 2020 is the largest cancer conference in Singapore and promises to bring exciting and groundbreaking research.

We are thankful to our esteemed local and international speakers, who will shed light on the research and clinical issues that shape our field today. We hope that the expertise and experiences shared by our speakers from across the globe will deepen knowledge, enhance research and inspire scientists.

FCS 20 2008

SCIENTIFIC PROGRAM2 November 2020 Monday

3 November 2020 Tuesday

4 November 2020 Wednesday

5 November 2020 Thursday

6 November 2020 Friday

2 November 2020 Monday

7.30am – 8.00am Arrival of Guests - Zoom Webinar

8.00am – 8.10am Opening Address

Ashok VENKITARAMAN Director, Cancer Science Institute of Singapore, National University of Singapore

8.10am – 8.20am Welcome Address

David VIRSHUP Professor and Director, Cancer & Stem Cell Biology Program, Duke-NUS Medical School, Singapore Chairperson, FCS 2020 Organizing Committee

SESSION 1 Chaired by:

Vinay TERGAONKAR Research Director, Institute for Molecular and Cell Biology, A*STAR Singapore

8.20am – 8.25am Introduction of Opening Speaker

Vinay TERGAONKAR Research Director, Institute for Molecular and Cell Biology, A*STAR Singapore

FCS 20 2010

8.25am – 9.05am OPENING LECTURE

Ali SHILATIFARD Professor and Chair, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, USA

Principles of Epigenetics and Chromatin Development and Human Disease

9.05am – 9.15am Opening the AACR-FCS Education Session Margaret FOTI Chief Executive Officer, American Association for Cancer Research (AACR)

9.15am – 10.15am AACR-FCS Education Session 1

Puay Hoon TAN Professor, Division of Pathology, Singapore General Hospital, Singapore

Breast Pathology for Researchers

10.15am – 10.30am BREAK

10.30am – 11.10am Rani E. GEORGE Associate Professor, Pediatric Hematology & Oncology, Dana-Farber Cancer Institute, Harvard Medical School, USA

Deregulated Transcription as a Therapeutic Vulnerability in Cancer

FCS 20 2011

3 November 2020 Tuesday

SESSION 2 Chaired by:

Patrick TAN Executive Director and Senior Group Leader, Genome Institute of Singapore, A*STAR Singapore

8.00am – 9.00am AACR-FCS Education Session 2

Kenneth KINZLER Professor of Oncology, Department of Oncology, The Johns Hopkins Kimmel Cancer Center, USA

Detecting Cancer Driver Mutations in Tumors and Blood

9.00am – 9.20am BREAK

9.20am – 10.00am Antoni RIBAS Professor, Department of Medicine, University of California Los Angeles, USA

Understanding PD-1 Blockade Responses to Melanoma

10.00am – 10.20am Raghav SUNDAR Consultant, Haematology-Oncology, National University Cancer Institute, Singapore

Immune Evasion through Epigenetic Mechanisms in Cancer

10.20am – 10.30am BREAK

FCS 20 2012

10.30am – 10.45am Oral Abstract Speaker 1 – Ying ZHANG PhD Student, Cancer Science Institute of Singapore, National University of Singapore

H3K27me3-rich Genomic Regions (MRRs) can Function as Silencers to Repress Gene Expression via Chromatin Interactions

10.45am – 11.00am Oral Abstract Speaker 2 - Ömer AN Research Scientist, Cancer Science Institute of Singapore, National University of Singapore

“3G” Trial: An RNA Editing Signature for Guiding Gastric Cancer Chemotherapy

11.00am – 11.40am Ricky JOHNSTONE Executive Director Cancer Research, Peter MacCallum Cancer Centre; Head, The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia

Targeting Transcriptional CDKs in Cancer

11.40am – 11.55am Oral Abstract Speaker 3 – Sinan XIONG PhD Student, Yong Loo Lin School of Medicine, National University of Singapore

Super-Enhancer-Driven PPP1R15B is Oncogenic in Multiple Myeloma and Could Be Therapeutically Targeted

FCS 20 2013

4 November 2020 Wednesday

SESSION 3 Chaired by:

Daniel G. TENEN Programme Leader and Senior Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore

8.00am – 8.40am Erwei SONG Professor, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China

Where The Wild Things Are: The Tumor Ecosystem of Breast Cancer

8.40am – 9.00am Takaomi SANDA Principal Investigator and Associate Professor, Cancer Science Institute of Singapore and Department of Medicine, National University of Singapore

Oncorequisite Role of an Aldehyde Dehydrogenase in T-Cell Acute Lymphoblastic Leukemia

9.00am – 9.40am Ronald A. DePINHO Professor, Department of Cancer Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, USA

Targeting the Tumor Microenvironment

9.40am – 10.00am BREAK

10.00am – 10.20am Ray DUNN Associate Professor of Regenerative Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

Mutated in Colorectal Cancer (MCC): a Novel Centrosomal Protein Involved in Intestinal Homeostasis and Disease

FCS 20 2014

10.20am –- 10.35am Oral Abstract Speaker 4 – Alvin GUO Research Fellow, Duke-NUS Medical School, Singapore

Mutant TP53 Interacts with BCAR1 to Contribute to Cancer Cell Invasion

10.35am – 10.50am Oral Abstract Speaker 5 - Chong Teik TAN Research Fellow, Department of Pharmacy, National University of Singapore

MOAP-1-mediated Dissociation of the p62/SQSTM1 Bodies Suppresses the Pro-oncogenic p62-Keap1-Nrf2 Signalling Axis

10.50am – 11.00am BREAK

11.00am – 12.00pm AACR-FCS Education Session 3

Marco HEROLD Associate Professor and Laboratory Head, Walter and Eliza Hall Institute of Medical Research, Australia

Exploiting the CRISPR Toolbox for Advancing Cancer Research

12.00pm – 12.15pm Oral Abstract Speaker 6 - Jieqiong ZHANG PhD Student, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore

Investigating a Role of Negative Elongation Factor (NELF) Complex in Breast Cancer Stem Cells

FCS 20 2015

5 November 2020 Thursday

SESSION 4 Chaired by:

Kanaga SABAPATHY Head, Division of Cellular & Molecular Research, National Cancer Centre Singapore

8.00am – 8.40am Kenneth KINZLER Professor of Oncology, Department of Oncology, The Johns Hopkins Kimmel Cancer Center, USA

Earlier Detection of Cancer: From Bench to Patients

8.40am – 9.00am Melvin CHUA Senior Consultant, Division of Radiation Oncology, National Cancer Centre Singapore

Evolution of Chemoradiotherapy Trials in Nasopharyngeal Carcinoma: Learning from History and Conceptualising the Next Generation of Phenotype-directed Trials

9.00am – 9.15am Oral Abstract Speaker 7 – Jianbin CHEN Research Associate, Genome Institute of Singapore, A*STAR Singapore

Genomic Landscape of Lung Adenocarcinoma in East Asians

FCS 20 2016

9.15am – 9.30am Oral Abstract Speaker 8 – Huili ANG PhD Student, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore

Exploiting DNA Damage Response Pathway: Development of PTK6 Inhibitor for Treatment of Ovarian Cancer

9.30am – 9.45am Oral Abstract Speaker 9 – Bryan Nicholas CHUA Research Assistant, Cancer Science Institute of Singapore, National University of Singapore

Exploiting the PROTAC System for TIP60-ing the Balance in Cancer Treatment

9.45am – 10.15am BREAK

10.15am – 10.35am Yee Joo TAN Joint Senior Principal Investigator, Institute of Molecular and Cell Biology, A*STAR Singapore

Understanding the Spike Protein of SARS-CoV-2 and Its Role in the Development of COVID-19 Diagnostic Tests and Vaccine

10.35am – 11.15am Susan CLARK Professor, Genomics and Epigenetics, Garvan Institute of Medical Research, Australia

3D Epigenome Alterations in Cancer

FCS 20 2017

6 November 2020 Friday

SESSION 5 Chaired by:

Patrick CASEY Senior Vice Dean of Research, Duke-NUS Medical School, Singapore

8.00am – 8.40am Muthiah MANOHARAN Senior Vice President of Drug Innovation, Scientific Advisory Board Member and Distinguished Research Scientists, Alnylam Pharmaceuticals, Cambridge Massachusetts, USA

Moving RNAi Therapeutics from Bench to Market

8.40am – 9.00am Anders SKANDERUP Senior Research Scientist, Genome Institute of Singapore, A*STAR Singapore

Pan-Cancer Analysis of Crosstalk in the Tumor Microenvironment

9.00am – 9.20am Boon Cher GOH Senior Consultant, Haematology-Oncology, National University Cancer Institute, Singapore

Germline Polymorphisms Guide Cancer Therapy: Example of METN375S in Squamous Cell Carcinoma of the Head and Neck

9.20am – 9.40am BREAK

Chaired by:

Sudhakar JHA Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore

FCS 20 2018

9.40am – 9.55am Oral Abstract Speaker 10 – Yanjing LIU Research Fellow, Cancer Science Institute of Singapore, National University of Singapore

Targeted Intragenic Demethylation Initiates Chromatin Rewiring for Gene Activation

9.55am – 10.10am Oral Abstract Speaker 11 – Daniel HUANG Assistant Professor, Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore

Predicting HCC Response to Multikinase Inhibitors with In Vivo Cirrhotic Mouse Model for Personalized Therapy

10.10am – 10.25am Oral Abstract Speaker 12 – Michal Marek HOPPE Research Fellow, Cancer Science Institute of Singapore, National University of Singapore

Patterns of MYC, BCL2 and BCL6 Co-localization at Single-cell Resolution Underlie Their Prognostic Significance in Diffuse Large B-cell Lymphoma

10.25am – 10.40am BREAK

10.40am – 11.20am Marco HEROLD Associate Professor and Laboratory Head, Walter and Eliza Hall Institute of Medical Research, Australia

Finding Critical Cancer Driving Genes using Functional Genomics Screening In Vivo

11.20am – 11.25am Poster Prize AnnouncementPresenter: Daniel G. TENEN

FCS 20 2019

11.25am – 11.30am Closing Remarks

ALI SHILATIFARDProfessor and Chair, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, USA

ABSTRACT:

Epigenetic regulation of gene expression in metazoans is central for establishing cellular diversity, and the perturbation of this process results in pathological conditions. Although transcription factors are essential for implementing gene expression programs, they do not function in isolation and require the recruitment of various chromatin-modifying and remodeling machineries. A classic example of developmental gene expression through chromatin is the regulation of the balanced activities of the Polycomb group (PcG) proteins within the PRC1 and PRC2 complexes, and the Trithorax group (TrxG) proteins within the COMPASS family. Recent large-scale genome sequencing efforts of human cancer have demonstrated that PcG and COMPASS subunits are highly mutated in a large number of human solid tumors and hematological malignancies. I will discuss our laboratory’s latest biochemical and genetic studies defining the molecular properties of COMPASS and PcG families in the regulation of gene expression, during development, the central role they play in cancer pathogenesis, and how we have taken advantage of such basic molecular information to develop targeted therapeutics for the treatment of hematological malignancies, pediatric brain cancer, and other forms of solid tumors.

BIOGRAPHY:Dr. Ali Shilatifard, Professor and Chairman of the Department of Biochemistry and Molecular Genetics and the Director, Simpson Querrey Center for Epigenetics of the Northwestern University Feinberg School of Medicine, is a world renown biochemist and molecular biologist and a respected expert in the field of transcription and epigenetics. As a Jane Coffin Childs postdoctoral fellow, Shilatifard made a seminal contribution to the field of leukemia biology by identifying the first function of any of the MLL translocation partners. Since then, he has continued to contribute to the field of transcription, chromatin biology, and cancer biology through many discoveries including those of the COMPASS and SEC complexes, which are demonstrating to be central to the mechanisms involved in the development of leukemia. Currently, the inhibitors developed in Shilatifard’s laboratory towards the COMPASS family and the SEC are being tested for the treatment of childhood leukemia, brain cancer, and triple negative breast tumors. For his contributions to our understanding of cancer biology. Shilatifard has been recognized by the Leukemia and Lymphoma Society, as the recipient of the Sword of the American Cancer Society, and the AMGEN Award by the American Society of Biochemistry and Molecular Biology. Recently, Shilatifard was selected as an inaugural recipient of the Outstanding Investigator Award from the National Cancer. He has served as a Senior Editor for the journal Science, and is currently serving as the Editor for Science’s open access journal Science Advances. He also serves on the Scientific Advisory Boards of Genentech, and the Max Planck Society.

Principles of Epigenetics and Chromatin in Development and Human Disease

OPENING LECTURE

FCS 20 2020

SESSIONONE

Speaker 01: Puay Hoon TAN

Speaker 02: Rani E. GEORGE

1

PUAY HOON TANProfessor, Division of Pathology, Singapore General Hospital, Singapore

ABSTRACT:

Breast diseases, including breast cancer, represent an important area of active and vigorous global research. In tissue based breast diseases research, the importance of understanding and familiarity with normal and abnormal breast morphology is critical. While collaboration with pathologists is a key part of such investigative endeavours, it is helpful for the scientific team to be conversant with changes in breast tissue that can be correlated with research findings. Likewise, pathologists also benefit from scientific interactions that can help deepen the diagnostic impact of novel findings which may translate to patient care. The breast, both normal and pathological, will be the focus of this presentation.

BIOGRAPHY:Dr Tan Puay Hoon has active interests in breast, urologic and renal pathology, and was a Volume Editor of the 2012 (4th series) WHO Classification of Tumours of the Breast. She is a Standing Editorial Board Member for the 5th series of the WHO Classification of Tumours, IARC, Lyon, and is also an expert member for the Breast volume in this latest series. She sits on the Editorial Boards of Modern Pathology, Breast Cancer Research, Pathology, Seminars in Diagnostic Pathology. She is Associate Editor of Histopathology and the Singapore Medical Journal. Apart from a busy service largely focused on subspecialty surgical signouts, she and her collaborators are recipients of several research grants related to translational studies of breast and prostate cancer. She is author of more than 400 publications, and participates regularly in regional and international meetings.

Dr Tan’s research interests in breast pathology centre around the classification of breast fibroepithelial lesions and their molecular pathogenesis, triple negative breast cancers, and ductal carcinoma in situ. In urologic pathology, she is engaged in prostate and renal cancer studies and was a contributor to the 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs.

She is a Past-President of the International Society of Breast Pathology, and was Councillor for Asia of the International Society of Urological Pathology (2009 – 2015). She is the current President of the Asian Breast Diseases Association, and the Convenor of the Assembly of Asia-Pacific International Academies of Pathology.

Breast Pathology for Researchers

AACR-FCS EDUCATION SESSION

FCS 20 2022

RANI E. GEORGEAssociate Professor, Pediatric Hematology & Oncology, Dana-Farber Cancer Institute, Harvard Medical School, USA

ABSTRACT:

I will discuss targeting aberrant oncogenic transcription in pediatric solid tumors through the disruption of cyclin-dependent kinases with critical roles in transcription regulation. I will also discuss cellular plasticity with epigenetic remodeling and transcriptional reprogramming as a mechanism of therapy resistance in pediatric cancer.

BIOGRAPHY:Dr Rani George is a pediatric oncologist physician-scientist at the Dana-Farber Cancer Institute. Her laboratory studies gene regulatory mechanisms that are aberrant in pediatric solid tumors, specifically neuroblastoma and osteosarcoma, and to identify vulnerabilities that can serve as therapeutic targets. This effort primarily focuses on transcription-associated cyclin-dependent kinases.

Deregulated Transcription as a Therapeutic Vulnerability in Cancer

FCS 20 2023

SESSIONTWO2

Speaker 03: Kenneth KINZLER

Speaker 04: Antoni RIBAS

Speaker 05: Raghav SUNDAR

Speaker 06: Oral Abstract 1 Ying ZHANG

Speaker 07: Oral Abstract 2 Ömer AN

Speaker 08: Ricky JOHNSTONE

Speaker 09: Oral Abstract 3 SINAN XIONG

KENNETH KINZLER

Detecting Cancer Driver Mutations in Tumors and Blood

Professor of Oncology, Department of Oncology, The Johns Hopkins Kimmel Cancer Center, USA

ABSTRACT:

The technological and biological challenges of detecting and defining the somatic mutations that drive human cancer will be discussed.

BIOGRAPHY:Kenneth Kinzler, Ph.D., is Professor of Oncology at the Johns Hopkins University School of Medicine, co-Director of the Ludwig Center at Johns Hopkins University and Associate Director for Basic Research for the Sidney Kimmel Comprehensive Cancer Center (SKCCC). He has studied the genetics of human cancer and its clinical utility for more than 35 years. His team has helped define more than a dozen major cancer genes, delineate the APC/CTNNB1 and TP53 pathways, developed novel genetic tools and pioneered the use of released tumor DNA (e.g. liquid biopsies) as a clinical biomarker for cancer. He has coauthored over 400 peer-reviewed articles on the molecular analyses of cancer. He is a member of the National Academy of Sciences, National Academy of Medicine, National Academy of Inventors, American Academy of Arts and Sciences, and is a Fellow of American Association of Cancer Research Academy

AACR-FCS EDUCATION SESSION

FCS 20 2026

ANTONI RIBASProfessor, Department of Medicine, University of California Los Angeles, USA

ABSTRACT:

Over the past 15 years my laboratory has focused on the understating of melanoma biology and how it interacts with the immune system, with the main goal of clinical translation. We have conducted investigator-initiated and industry-sponsored clinical trials, most focused on the treatment of metastatic melanoma and have involved laboratory-based correlates of mechanism of action and antitumor activity. These clinical trials have included adoptive cell transfer with T cell receptor (TCR) engineered lymphocytes and hematopoietic stem cells, anti-CTLA4 antibodies, anti-PD-1 antibodies, BRAF-targeted therapies and nanoparticle-siRNA. The major focus has been in understanding how best to treat melanoma using tumor immunotherapy and targeted therapies based on the understanding of the biological principles governing their antitumor activity.

BIOGRAPHY:Antoni Ribas, M.D., Ph.D. is Professor of Medicine, Professor of Surgery, and Professor of Molecular and Medical Pharmacology at the University of California Los Angeles (UCLA), Director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center (JCCC), Director of the Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA. Dr Ribas is a physician-scientist who conducts laboratory and clinical research in malignant melanoma, focusing on gene engineered T cells, PD-1 blockade and BRAF targeted therapies. His National Cancer Institute (NCI), State of California and foundation-supported research laboratory develops models of disease to test new therapeutic options, studies mechanism of action of treatments in patients and the molecular mechanisms of therapy resistance.

Dr. Ribas is currently the President of the American Association for Cancer Research (AACR), an elected member of the Fellows of the AACR Academy (FAACR) and the American Society of Clinical Investigation (ASCI), has a Doctor Honoris Causa from the University of Buenos Aires, co-led the Stand Up to Cancer (SU2C)-Cancer Research Institute (CRI)-AACR Immunotherapy Dream Team with the Nobel Laureate James Allison, is the recipient of a NCI Outstanding Investigator Award, was profiled as one of the five Visionaries in Medicine by the New York Times on May 27, 2018, acknowledged as Great Immigrant by the Carnegie Foundation in the New York Times on July 4, 2018, and is the recipient of the 2014 AACR Richard and Hinda Rosenthal Award, the 2018 AACR-CRI Lloyd J. Old Award in Cancer Immunology and the 2019 William B. Coley Award in Basic and Tumor Immunology, Cancer Research Institute (CRI).

Understanding PD-1 Blockade Responses to Melanoma

FCS 20 2027

RAGHAV SUNDARConsultant, National University Cancer Institute, Singapore

ABSTRACT:

Epigenomic alterations in cancer interact with the immune microenvironment to dictate tumor evolution and therapeutic response. Studies in stomach cancer have shown association between epigenetic alternate promoters, immune-editing and immune checkpoint inhibitor resistance. In this talk, I will discuss epigenetic mechanisms coopted by the tumor to evade the immune system and its clinical implications.

BIOGRAPHY:

Dr Raghav Sundar is a Consultant Medical Oncologist specializing in Gastro-Intestinal cancers and early phase clinical trials. His research interests are in developing novel genomic biomarkers and precision oncology. His other research interest is in medical device development for chemotherapy-induced neuropathy. Raghav obtained his medical degree from the Yong Loo Lin School of Medicine, National University of Singapore, where his academic distinctions earned him a place in the Dean’s List and the Thambipillai Silver Medal. He topped the country in the Internal Medicine specialty examination obtaining the Master of Medicine (Internal Medicine) and the Gordon Arthur Ransome Gold Medal in Internal Medicine. He was Chief Resident and Chief Senior Resident during his training at the National University Hospital. He subsequently completed his Medical Oncology Senior Residency at the National University Cancer Institute, Singapore (NCIS). He was awarded the National Medical Research Council Overseas Fellowship Award to undergo fellowship training at the Drug Development Unit, Royal Marsden Hospital, UK. He won the Conquer Cancer Foundation of ASCO Merit Award for his work on developing novel anticancer therapeutics. He has secured over $1,500,000 in grant funding and has over 50 publications in high impact peer-reviewed journals including Cancer Discovery, Journal of Clinical Oncology and Annals of Oncology.

Immune Evasion through Epigenetic Mechanisms in Cancer

FCS 20 2028

YING ZHANGORAL ABSTRACT SPEAKER 1

PhD Student, Cancer Science Institute of Singapore, National University of Singapore

ABSTRACT:

The 3-dimensional organization of our genomes is important for gene regulation. The genome is organized into large Topologically-Associated Domains (TADs) and chromatin interactions. Gene transcription is controlled by transcription factors (TFs) that bind to enhancers and promoters to regulate genes. TFs can bind to proximal enhancers in the genome, and enhancers distal to genes can loop to gene promoters via chromatin interactions to activate gene expression. Cancer cells show altered chromatin interactions including altered chromatin loops to key oncogenes such as TERT.

By contrast, gene repression and silencers are poorly understood. We reasoned that H3K27me3-rich regions (MRRs) of the genome defined from clusters of H3K27me3 peaks may be used to identify silencers that can regulate gene expression via proximity or looping. We found MRRs are highly associated with chromatin interactions and interact

H3K27me3-rich Genomic Regions (MRRs) can Function as Silencers to Repress Gene Expression via Chromatin Interactions

preferentially with each other. MRR-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion by either using EZH2 inhibitor (GSK343) or EZH2 knocking out (KO). MRR component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with lower H3K27me3 and higher H3K27ac levels showed losses in chromatin interactions, while new interactions emerged at high H3K27ac regions. The MRR knockout cells also showed changes in phenotype associated with cell identity, and altered xenograft tumor growth. Our results reveal looping silencer examples in human and their mechanisms of functioning through characterizing H3K27me3-rich regions.

FCS 20 2029

Research Scientist, Cancer Science Institute of Singapore, National University of Singapore

ABSTRACT:

Background: Gastric cancer (GC) cases are often diagnosed at an advanced stage with poor prognosis. Platinum-based chemotherapy has been internationally accepted as first-line therapy for inoperable or metastatic GC. To achieve greater benefits, it is critical to select patients who are eligible for the treatment.

Methods: Albeit gene expression profiling has been widely used as a genomic classifier to identify molecular subtypes of GC and stratify patients for different chemotherapy regimens, the prediction accuracy remains to be improved. More recently, adenosine-to-inosine (A-to-I) RNA editing has emerged as a new player contributing to GC development and progression, offering potential clinical utility for diagnosis and treatment. We conducted a transcriptome-wide RNA editing analysis of a cohort of 104 patients with advanced GC and identified an RNA editing (GCRE) signature

“3G” Trial: An RNA Editing Signature for Guiding Gastric Cancer Chemotherapy

ÖMER ANORAL ABSTRACT SPEAKER 2

to guide GC chemotherapy, using a systematic computational approach followed by both in vitro validations and in silico validations in TCGA.

Results: We found that RNA editing events alone stand as a prognostic and predictive biomarker in advanced GC. We developed a GCRE score based on the GCRE signature consisting of 50 editing sites associated with 29 genes and achieved a high accuracy (84%) of predicting patient response to chemotherapy. Of note, patients demonstrating higher editing levels of this panel of sites present a better overall response. Consistently, GC cell lines with higher editing levels showed higher chemosensitivity. Applying the GCRE score on TCGA dataset confirmed that responders had significantly higher levels of editing in advanced GC.

Conclusions: Overall, the GCRE signature reliably stratifies patients with advanced GC and predicts response from chemotherapy.

FCS 20 2030

RICKY JOHNSTONEExecutive Director Cancer Research, Peter MacCallum Cancer Centre; Head, The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia

ABSTRACT:

Acurate control of gene-expression is essential for normal development and deregulation of transcription invariably results in human pathologies, including cancer. The dependency of tumour cells on aberrant gene-expression programs and the reliance on core-transcriptional machinery in these cells has been coined “transcriptional addiction”. Similar to cell cycle regulation, RNA Polymerase II (POLII)-driven transcription should be considered as a unidirectional multistep cycle, consisting of initiation, pausing, elongation, termination and recycling steps, which are tightly controlled by the concerted action of cyclin-dependent kinases (CDKs) and their cognate cyclins, analogous to the cyclin/CDK control of the cell cycle. This session will focus on transcriptional CDKs (eg CDK7,8,9,11,12,13) and discuss how dysregulation of the transcription cycle plays an important role in cancer. We will discuss the development of small molecules targeting transcriptional CDKs as anti-cancer agents and provide a framework for the rational therapeutic application of these agents in oncology.

BIOGRAPHY:Professor Ricky Johnstone is the Executive Director of Cancer Research at the Peter MacCallum Cancer Centre overseeing ~700 staff and students and plays a key role in strategic decision making across the organisation. Prof Johnstone is a cancer researcher who has utilized genetic mouse models of hemopoietic malignancies and solid tumors, especially those drive by the c-Myc oncogene. He uses these models to understand the epigenetic changes that underpin tumor onset and progression and to develop new therapies that target epigenetic and transcriptional regulatory proteins. A major current focus of his research is to utilize unbiased whole-genome editing technologies to understand the molecular events that underpin transcriptional elongation through c-Myc and transcriptional kinases such as CDK9. This provides important information about how tumors may become “addicted” to aberrant rates of gene expression (so-called “transcriptional addiction”) and how these discoveries may be exploited to derive new therapeutic regimens. Prof. Johnstone and his team are advancing these fundamental discoveries to clinical testing through the implementation of clinical trials. He has published more than 230 papers with >17,000 total citations, with key papers in Nature, Cell Reports, PNAS, Nat Comms., Cancer Cell, Blood and Cancer Discovery.

Targeting Transcriptional CDKs in Cancer

FCS 20 2031

PhD Student, Yong Loo Lin School of Medicine, National University of Singapore

ABSTRACT:

Background: Multiple myeloma (MM) cell have high level of endoplasmic reticulum (ER) stress due to the excessive production of monoclonal immunoglobulin. MM cells activate unfolded protein response (UPR) and phosphorylation of eIF2α attenuates protein translation. The PPP1R15B (denoted as R15B hereafter) gene encodes a regulatory subunit of an eIF2α-specific phosphatase complex. Dephosphorylation of eIF2α promotes protein synthesis and cell cycle progression. The roles of R15B in cancers including MM are largely unknown.

Methods: We performed H3K27Ac ChIP-seq on MM cell lines, primary MM patient samples and normal CD138+ plasma cells, memory B cells (controls). ROSE analysis was used to systematically annotate super-enhancers (SEs) and their associated genes between tumors and controls. A combination of public data mining, qRT-PCR, cell proliferation assays were performed to determine the oncogenic effects of R15B in MM.

Super-Enhancer-Driven PPP1R15B is Oncogenic in Multiple Myeloma and Could Be Therapeutically Targeted

SINAN XIONGORAL ABSTRACT SPEAKER 3

Results: We have identified R15B as one of the super-enhancer associated genes specific to MM patient samples and MM cell lines. The expression of R15B was 6- to 50-fold higher in a panel of 8 MM cell lines than normal controls. SE activity was correlated with the expression level of R15B. Higher expression of R15B predicted poor overall survival of MM patients, suggesting its clinical relevance in MM pathogenesis. Salubrinal specially inhibits the phosphatase activity of the PPP1R15B-PP1 complex toward EIF2S1. Therefore, we examine the therapeutic effects of salubrinal on MM cells. Salubrinal inhibited MM cell proliferation in a dose-dependent manner and MM cell line with higher R15B expression was more sensitive to salubribal than cell line with low R15B.

Conclusions: Our integrative approaches identified R15B as a novel SE-driven oncogene. Salubrinal selectively inhibits proliferation of MM cells with high R15B expression. Thus, we propose that targeting R15B could be a new approach for effective anti-myeloma therapy and warrants further clinical investigation.

FCS 20 2032

3SESSIONTHREE

Speaker 10: Erwei SONG

Speaker 11: Takaomi SANDA

Speaker 12: Ronald A. DePINHO

Speaker 13: Ray DUNN

Speaker 14: Oral Abstract 4 Alvin GUO

Speaker 15: Oral Abstract 5 Chong Teik TAN

Speaker 16: Marco HEROLD

Speaker 17: Oral Abstract 6 Jieqiong ZHANG

ERWEI SONGProfessor, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China

ABSTRACT:

It is well established that tumor microenvironment (TME) may prompt tumor initiation, relapse, metastasis and therapeutic resistance. TME is a multicellular system with complex dynamic tumor–stromal interactions. In our studies, we have demonstrated that a positive feedback loop between breast cancer cells and TAMs is essential to cancer metastasis. In addition, we found that ADCP in macrophages could induce cancer immunosuppression, indicating that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment. We have also identified a functional CAF subset that promotes cancer formation and chemoresistance by cell-surface markers CD10 and GPR77. Besides, we also uncovered the involvement of lncRNA NKILA in regulating AICD of TILs and the potential of engineering lncRNAs in adoptively transferred T cells immunotherapy. Recently, we found that NET-DNA abundant in the liver pre-metastasis niche acted as a chemotactic factor to attract cancer cells. In addition, we identified the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells. These studies shed light on the potential of TME-targeting therapeutic strategies, and provided a range of molecular targets for therapies against malignant tumors and prediction of therapeutic benefit.

BIOGRAPHY:

Erwei Song is Professor of Department of Breast Surgery at Sun Yat-sen Memorial Hospital of Sun Yat-sen University (SYSU), Academician of the Chinese Academy of Sciences, “Cheung Kong Scholar” Chair Professor, CMB Distinguished Professor and Fellow of the Royal Society of Biology (UK). Currently, he serves as Dean of Zhongshan School of Medicine and President of Sun Yat-sen Memorial Hospital, SYSU. He is keen to address scientific questions derived from clinical practice, and studies the microenvironment of malignant tumors, mainly on breast cancers, and unraveled the regulatory mechanisms of non-coding RNAs (ncRNAs) related to tumor microenvironment. While studying in Harvard, he published studies on siRNA in Nature Medicine , which was selected as one of the “Top Ten breakthroughs of the year 2003” by Science. He has published 146 SCI research articles, including Nature (1 paper), Cell (3 papers), Cancer Cell (3 papers), Nature Immunology, Nature Cell Biology, Science Translational Medicine, Nature Communications (3 papers), etc. He was invited to contribute a review article on tumor microenvironment for Nature Reviews Drug Discovery and chair an international Cell Symposium for Cell Press on “Functional RNAs”. He now serves as the associate editor for BMC Cancer, Cancer Science and Science China-Life Sciences, and the reviewing editor for Journal of Biological Chemistry. He has won numerous awards, including the “Ho Leung Ho Lee Foundation Award” and the prestigious “National Natural Science Award” by the State Council of China.

Where The Wild Things Are: The Tumor Ecosystem of Breast Cancer

FCS 20 2034

TAKAOMI SANDAPrincipal Investigator and Associate Professor, Cancer Science Institute of Singapore and Department of Medicine, National University of Singapore

ABSTRACT:

Aldehyde dehydrogenases (ALDHs) have been implicated as a stem cell marker both in normal and malignant cells. Elevated ALDH activity is observed in various cancers. As an example, ALDH1A2 is aberrantly expressed in over 50% of T-cell lymphoblastic leukemia (T-ALL), a hematological malignancy derived from thymic immature T-cells. ALDH1A2 is induced via an ectopic expression of the oncogenic transcription factor TAL1. Notably, several other oncogenes such as AKT and MYC, which can promote cell proliferation and metabolic processes, are more frequently activated together with ALDH1A2 in TAL1-positive T-ALL cases than in TAL1-negative cases, suggesting collaborative effects. However, the role of ALDH1A2 in the T-ALL pathogenesis has not been elucidated yet. In our latest study, we found that ALDH1A2 has a protective effect from the generation of reactive oxygen species (ROS) in T-ALL cells. Although ALDH1A2 overexpression did not cause leukemia by alone in a transgenic zebrafish model, it reduced the amount of ROS in T-cells and accelerated leukemogenesis induced by the activated AKT protein. Interestingly, gene expression and metabolome profiling demonstrated that ALDH1A2 can promote glycolysis and mitochondria respiration in T-ALL cells, thereby supporting energy production. Taken together, our study suggests that an overexpression of ALDH1A2 may be advantageous for T-ALL cells by promoting metabolic process and protecting the cells from ROS induced by other oncogenic pathways. This mechanism may serve as a “requisite” to acquire additional genetic abnormalities and maintain the hyperproliferative state of T-ALL cells (“onco-requisite”).

BIOGRAPHY:

Dr Takaomi Sanda obtained his MD and PhD degrees from the Nagoya City University, Nagoya, Japan, and trained in clinical hematology and oncology. In 2006-2013, he studied cancer biology in Prof. Thomas Look’s laboratory at the Dana-Farber Cancer Institute, Harvard Medical School, Boston. In 2013, he was awarded the National Research Foundation (NRF) fellowship and joined the Cancer Science Institute of Singapore as a principal investigator. Dr. Sanda has been studying transcription factor abnormalities in T-cell malignancies and neuroblastoma.

Oncorequisite Role of an Aldehyde Dehydrogenase in T-Cell Acute Lymphoblastic Leukemia

FCS 20 2035

RONALD A. DePINHOProfessor, Department of Cancer Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, USA

ABSTRACT:

Targeting immune suppression mechanisms has revolutionized cancer treatment in recent years. While immune checkpoint inhibition has yielded meaningful responses across many cancer types, clinical trials have shown eventual treatment resistance, and in some cancers (e.g., prostate) minimal therapeutic response at all. Our recent work has identified symbiotic interactions between cancer cells and the host tumor microenvironment (TME) in regulating immunity and metabolism, thus providing new candidate therapeutic targets for intractable disease. Here we highlight some of our findings: (1) Paracrine signaling in the tumor microenvironment plays a key role in the oncogenic KRAS-driven metabolic reprogramming of pancreatic cancer cells. Specifically, type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell-intrinsic MYC transcriptional upregulation to drive glycolysis. (2) We explored mechanisms involving the TME as a potential basis for resistance to targeting KRAS in pancreatic cancer. Although oncogenic KRAS is required for pancreatic tumor maintenance, tumors can recur following KRAS extinction. We found that pancreatic cancer cells can alter the TME myeloid cell composition to support oncogenic KRAS-independent tumor growth. (3) We also sought to understand the essential role of CHD1 in PTEN-deficient prostate cancer. We determined that CHD1 deletion causes major remodeling of the TME, and established CHD1/IL-6 as a major regulator of the immunosuppressive TME in PTEN-deficient prostate cancer. These observations of cancer cell/immune cell crosstalk across cancer types open the possibility of new strategies to enhance the effectiveness of current immune cell inhibitor therapies by combination with TME-targeted therapies.

BIOGRAPHY:Ronald A. DePinho, M.D. is past president and distinguished university professor at MD Anderson Cancer Center in Houston, Texas. He studied biology at Fordham University, where he graduated salutatorian, received his M.D. degree with distinction from the Albert Einstein College of Medicine, and performed his residency and postdoctoral training at Columbia-Presbyterian Medical Center. His research career began at Einstein as the Feinberg Senior Faculty Scholar in Cancer Research and an ACS Research Professor. He then joined the Dana-Farber Cancer Institute and Harvard Medical School where he was the founding Director of the Belfer Institute for Applied Cancer Science. During his 6-year tenure as MD Anderson’s president, Dr. DePinho conceived and launched the Cancer Moon Shots Program, dramatically enhanced MD Anderson’s research and training excellence, recruited many world class faculty, and expanded its global network to reach one-third of the human population. His research program has made fundamental contributions to our understanding of cancer, aging and degenerative disorders, whereby the translation of such knowledge has led to clinical advances. For his significant contributions to cancer, aging and healthcare, Dr. DePinho has been recognized with numerous honors and awards. He is a member of the National Academy of Medicine and the National Academy of Science, and a fellow of the American Academy of Arts and Sciences, the American Association of the Advancement of Science and the American Association of Cancer Research.

Targeting the Tumor Microenvironment

FCS 20 2036

RAY DUNNAssociate Professor of Regenerative Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

ABSTRACT:

Mutated in Colorectal Cancer (MCC) is a candidate tumor suppressor gene reported to be somatically mutated in the inherited colorectal cancer (CRC) syndrome Familial Adenomatous Polyposis. However, to date, more than 28 years since its discovery, the mechanisms by which MCC contributes to intestinal cancer as well as its function during normal intestinal tissue homeostasis remain unknown. We determined the subcellular localization and function of the mouse Mcc homolog in the intestinal epithelium and the consequences of its loss in vivo. We find that Mcc expression is restricted to cycling cells within intestinal crypts. At the protein level, Mcc specifically localizes to the centrosome of proliferative cells. As cells undergo terminal differentiation, Mcc re-localizes from the centrosome to the apical membrane in enterocytes where it becomes a component of the Non-Centrosomal Microtubule Organizing Center (NMTOC), which is responsible for the establishment of apico-basal polarity and the maintenance of epithelial integrity. The molecular mechanisms underlying this redistribution are poorly understood. We reveal that phosphorylation of Mcc by Casein Kinases triggers the subcellular redeployment of centrosomal Mcc to the NMTOC. Consistent with a role in the establishment of apico-basal polarity, we have additionally characterized previously unappreciated phenotypes in the adult intestine of Mcc-deficient mice as well as unexpected genetic interactions with the ApcMin

intestinal tumor model. Taken together, these findings reveal clinically relevant insights into the involvement of a novel centrosome component in intestinal tissue homeostasis and disease.

BIOGRAPHY:

Dr. Ray Dunn obtained his Ph.D. in Cell Biology in 1999 from Vanderbilt University under the supervision of Brigid Hogan, PhD FRS. His thesis described how the TGFβ growth factor BMP4 controls primordial germ cell formation in the early mammalian embryo. He then completed a post-doctoral fellowship in the laboratory of Elizabeth Robertson, PhD FRS at Harvard University, where he studied the growth factor Nodal and its intracellular effector proteins Smad2 and Smad3 during axis formation and early germ layer patterning in the developing mouse embryo. In 2004, he joined ES Cell International Pte. Ltd., Singapore as a Research Scientist in the Diabetes Group, eventually being named Program Manager in 2005. In July 2007, he was appointed as a Principal Investigator in the A*STAR Institute for Medical Biology. He joined the LKC NTU School of Medicine as an Associate Professor of Regenerative Medicine in August of last year and holds a joint appointment with the Skin Research Institute of Singapore. He is also currently President of the Stem Cell Society Singapore.

Mutated in Colorectal Cancer (MCC): a Novel Centrosomal Protein Involved in Intestinal Homeostasis and Disease

FCS 20 2037

Research Fellow, Duke-NUS Medical School, Singapore

ABSTRACT:

TP53 is frequently mutated in many cancers. Mutant TP53 has been known to have gain-of-function properties to promote cancer metastasis. However, the underlying mechanisms are still not fully understood. To reveal proteins which cooperate with mutant TP53 to drive cancer metastasis, we screened for novel TP53R273H interacting proteins and identified breast cancer anti-estrogen resistance 1 (BCAR1). We confirmed their interaction through immunoprecipitation assays and revealed that TP53R273H and BCAR1 are in close proximity in the nucleus. Interestingly, while the majority of BCAR1 localizes in the cytoplasm, we found that it translocates into the nucleus in a manner dependent on SRC family kinases (SFKs), which are known to phosphorylate BCAR1 and enhance metastasis. Consequently, inhibiting SFKs prevented BCAR1 phosphorylation and nuclear translocation, thereby disrupting the interaction between TP53R273H and BCAR1. The

Mutant TP53 Interacts with BCAR1 to Contribute to Cancer Cell Invasion

ALVIN GUOORAL ABSTRACT SPEAKER 4

expression of constitutively activated c-SRC, on the other hand, enhanced BCAR1 phosphorylation and the interaction between TP53R273H and BCAR1. Subsequently, we found that the expression of full-length TP53R273H, but not the BCAR1 binding-deficient mutant TP53R273H Δ102-207, promoted cancer cell invasion, suggesting that the interaction between TP53R273H and BCAR1 is critical for enhancing cancer invasion. Using publically available clinical dataset, we found that among the patients with mutant TP53, the high BCAR1 expression group has a shorter overall survival as compared to the low BCAR1 expression group, supporting our model in which TP53R273H cooperates with BCAR1 to adversely affect overall survival in cancer patients. Taken together, our findings suggest a disruption of the TP53R273H-BCAR1 interaction as a potential therapeutic approach for TP53R273H-harboring cancer patients.

FCS 20 2038

CHONG TEIK TANResearch Fellow, Department of Pharmacy, National University of Singapore

MOAP-1-mediated Dissociation of the p62/SQSTM1 Bodies Suppresses the Pro-oncogenic p62-Keap1-Nrf2 Signalling Axis

ABSTRACT:

Sequestration of Keap1 by the p62/SQSTM1-containing aggregates, known as p62 bodies, elicits Nrf2-mediated transcriptional activation of antioxidant genes. While this signaling mechanism is important for cellular anti-oxidative stress defence, hyperactivation of the p62-Nrf2 signaling confers fitness advantage for cancer-initiating cells to promote liver tumorigenesis. Modulator of apoptosis-1 (MOAP-1), a pro-apoptotic Bax-binding protein enriched at the outer mitochondrial membrane, is a short-lived protein regulated by the ubiquitin-proteasome system. Recently, we showed that MOAP-1 mediates Fas-induced apoptosis signaling in liver by facilitating recruitment of tBid to mitochondria (Tan et al., Cell Rep., 2016, 16:174-185). Unexpectedly, we found that MOAP-1 is recruited to p62 bodies in liver cancer cells and in hepatic cells upon exposure to stress signals. Loss of MOAP-1 elevates the levels of p62 bodies, while overexpression of MOAP-1 reduces abundance of p62 bodies in these cells. Mechanistically, MOAP-1 binds to p62 to interfere with its self-oligomerization function, which is

ORAL ABSTRACT SPEAKER 5

essential for maintaining p62 in aggregate state. MOAP-1 deficiency results in enhanced p62 sequestration of Keap1, heightened activation of the Nrf2 target genes and elevation of tumour burden in the liver of mice subjected to the diethylnitrosamine (DEN) treatment. Together, our data define a paradigm of negative regulation of the p62-Nrf2 signaling via disruption of functional p62 bodies by MOAP-1. Moreover, our preliminary study using the wild-type and MOAP-1 KO mice (18-24 months old) mimicking the ageing population in human revealed that about half of the MOAP-1 KO aged mice exhibited abnormalities in liver including tumorigenesis and chronic inflammation, while none of the wild-type mouse displayed notable abnormality. Chronic liver inflammation has been demonstrated to promote tumorigenesis by suppressing immunosurveillance (Shalapour et al., Nature, 2017,551:340-345). Work is ongoing to unravel the intricate role of MOAP-1 in regulating the complex interplay between inflammation and immunity in liver cancer development during ageing.

FCS 20 2039

MARCO HEROLDAssociate Professor and Laboratory Head, Walter and Eliza Hall Institute of Medical Research, Australia

ABSTRACT:

CRISPR/Cas9 mediated genome engineering techniques provide an easy and rapid way to alter genes and their products in mammalian cells. I will talk about the origin of CRISPR and how it can be used as a tool for manipulating genes in vitro and in vivo in cells and the whole organism. Furthermore, I will present some of our own work on how we use CRISPR/Cas9 in haematopoietic cells to identify and validate potential novel drug targets for cancer therapy.

BIOGRAPHY:Marco Herold is a NHMRC Senior Research Fellow and Laboratory Head in the Blood Cells and Blood Cancer Division at the Walter and Eliza Hall Institute of Medical Research (WEHI), Melbourne. During his PhD and first postdoctoral studies at the University of Würzburg (Germany) he was trained in cell death research and mouse genetics. At WEHI, his research team specialises in applying CRISPR gene editing techniques to identify novel gene targets required for the development and sustained growth of cancer cells. Recent findings identified DNA repair as fundamental for TP53-mediated tumour suppression (Janic et al, Nature Medicine 2018). His current research employs genome-wide CRISPR library screening in vivo to discover vulnerabilities that can be exploited for cancer therapy.

Exploiting the CRISPR Toolbox for Advancing Cancer Research

AACR-FCS EDUCATION SESSION

FCS 20 2040

JIEQIONG ZHANGPhD Student, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore

Investigating a Role of Negative Elongation Factor (NELF) Complex in Breast Cancer Stem Cells

ABSTRACT:

The dysregulation of gene expression programs can result in a myriad of diseases, including cancer. Historically, studies of aberrant transcription in cancer has centered on identifying misexpressed transcription factors, genomic mutations and characterizing epigenomic alterations. Here, we are interested in understanding the role of a transcriptional regulator called Negative Elongation Factor (NELF) complex in cancer pathogenesis. The NELF complex consists of 4-subunits and is well-known for governing RNA polymerase II pause-release at promoter-proximal regions. Current studies have illustrated that NELF is essential for early stages of embryogenesis. However, the function of NELF in cancer, especially its transcriptional activity, is rarely demonstrated and remains unclear.

ORAL ABSTRACT SPEAKER 6

To assess the role of NELF in cancer, we started with breast cancer which is the most common form of cancer among women in Singapore. We found that NELF was overexpressed in breast cancer when compared to normal tissues. Furthermore, we found that the NELF complex expression level positively correlated with tumor grades, where advanced late-stage tumors had higher level of NELF. Additionally, the loss of NELF in breast cancer cell lines abrogated several carcinogenic properties, including tumor metastasis in mouse model. We also showed that depletion of NELF impaired maintenance of breast cancer stem cells coupled with reduced epithelial-mesenchymal transition (EMT), both of which are of great significance for tumorigenesis. In summary, we identified that NELF played a vital role in tumor pathogenesis.

FCS 20 2041

SESSIONFOUR4

Speaker 18: Kenneth KINZLER

Speaker 19: Melvin CHUA

Speaker 20: Oral Abstract 7 Jianbin CHEN

Speaker 21: Oral Abstract 8 Huili ANG

Speaker 22: Oral Abstract 9 Bryan Nicholas CHUA

Speaker 23: Yee Joo TAN

Speaker 24: Susan CLARK

KENNETH KINZLER

ABSTRACT:

Dr. Kinzler will give an overview of their team’s latest work on the early detection of cancer. He will discuss both the opportunities and challenges of cancer early detection. He will detail how digital genomics, multi-analyte and multi-sample approaches can be combined to produce clinically viable tests that address these challenges. Specific examples of test and their potential clinical utility will be presented.

BIOGRAPHY:Kenneth Kinzler, Ph.D., is Professor of Oncology at the Johns Hopkins University School of Medicine, co-Director of the Ludwig Center at Johns Hopkins University and Associate Director for Basic Research for the Sidney Kimmel Comprehensive Cancer Center (SKCCC). He has studied the genetics of human cancer and its clinical utility for more than 35 years. His team has helped define more than a dozen major cancer genes, delineate the APC/CTNNB1 and TP53 pathways, developed novel genetic tools and pioneered the use of released tumor DNA (e.g. liquid biopsies) as a clinical biomarker for cancer. He has coauthored over 400 peer-reviewed articles on the molecular analyses of cancer. He is a member of the National Academy of Sciences, National Academy of Medicine, National Academy of Inventors, American Academy of Arts and Sciences, and is a Fellow of American Association of Cancer Research Academy.

Earlier Detection of Cancer: From Bench to Patients

Professor of Oncology, Department of Oncology, The Johns Hopkins Kimmel Cancer Center, USA

FCS 20 2044

MELVIN CHUASenior Consultant, Division of Radiation Oncology, National Cancer Centre Singapore

ABSTRACT:

EBV-associated nasopharyngeal carcinoma (NPC) is extremely sensitive to chemotherapy and radiotherapy. As a result of advances in radiotherapy techniques and combination chemoradiotherapy trials, survival has improved remarkably even for locoregionally advanced NPC patients. With the advent of intensity-modulated radiotherapy (IMRT), sparing of normal tissue organs is now improved, while ensuring adequate dose intensity to the primary tumour. This has led to superior primary tumour local control (>80% rate) and a reduction of normal tissue adverse effects. When cisplatin-based chemotherapy regimes were first introduced as combination therapy with radiotherapy, these modalities cooperated synergistically to enhance radiotherapy cell killing. However, in the modern era of IMRT, the goal of combinatorial chemotherapy has shifted to optimisation of targeting distant metastatic tumour clones. It is in this background that more contemporary combination trial approaches involve investigating the efficacy of adjuvant or neoadjuvant sequential chemotherapy. In my talk, I will discuss the evolution of chemoradiotherapy trials in NPC, including sequencing strategies and choice of drugs. I will also discuss the role of EBV DNA as a liquid biopsy to guide systemic intensification in NPC, and how new trials could be designed in the face of the negative HK-0502 multicentre phase III trial. Finally, I will present our ongoing work to design biomarker-directed trials, including the incorporation of immunotherapy to radical treatment and targeting SSTR2 overexpression, which may shape the landscape of precision treatment in NPC.

BIOGRAPHY:

Dr Melvin Chua is a Clinician-Scientist at the National Cancer Centre Singapore, and Principal Investigator of the Tan Chin Tuan Laboratory of Optical Imaging, Photodynamic and Proton Beam Therapy – Precision Radiation Oncology Programme, Division of Radiation Oncology. His research is supported by the NMRC Clinician-scientist award, and is focused on discovery and translational cancer genomics, and the development of biomarker-directed clinical trials in nasopharyngeal (NPC) and prostate cancers. He graduated from the Yong Loo Lin School of Medicine, National University Singapore in 2002. He obtained his Fellowship in Clinical Oncology from the Royal College of Radiologists, and his Doctorate from the University College London in 2013. He later completed post-doctoral Clinician-scientist fellowships at the Mount Vernon Cancer Centre, UK, and the Princess Margaret Cancer Center, Toronto. Dr Chua is a KOL on NPC and prostate cancer, and he has been invited to speak at >100 international meetings. He is also on the scientific advisory board for the NPC Guangzhou-Singapore Trial Network and a board member on the Head Neck Cancer International Group (HNCIG).

His other academic activities include his roles as the Associate Senior Editor of the International Journal of Radiation Oncology Biology Physics – Official journal of the American Society of Radiation Oncology and Editor-in-Chief, Annals of Nasopharynx Cancer. He also serves on the International Education Steering Group and the Asia-Pacific Regional Council of the American Society of Clinical Oncology (ASCO). He has published over 80 peer-reviewed papers, with a H-index of 22, including highly cited articles in the New England Journal of Medicine, Lancet, Nature, Cell, Journal of Clinical Oncology and JAMA Oncology.

Evolution of Chemoradiotherapy Trials in Nasopharyngeal Carcinoma: Learning from History and Conceptualising the Next Generation of Phenotype-directed Trials

FCS 20 2045

JIANBIN CHENResearch Associate, Genome Institute of Singapore, A*STAR Singapore

Genomic Landscape of Lung Adenocarcinoma in East Asians

ABSTRACT:

Lung cancer is the world’s leading cause of cancer death and shows strong ancestry disparities. To better understand such ancestry disparities, we sequenced and assembled a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), and compared with LUADs from individuals of European ancestry (EUR) using the same analysis pipelines. We found strong ancestry differences in driver mutations, copy number alterations (CNAs), and RNA transcriptomic subgroups. Seven novel LUAD driver genes were identified in the EAS cohort: PARP4 (6%), EPRS (4%), LYST (4%), NCOR2 (2%), PBRM1 (2%), RASA1 (2%), and ZMYM2 (2%). In addition, EAS LUADs had more stable genomes characterized by fewer somatic mutations and fewer CNAs than EUR LUADs. Such difference is much stronger

ORAL ABSTRACT SPEAKER 7

in smokers as compared to non-smokers. From transcriptome clustering, we identified a new EAS-specific subgroup, which was characterized by a less complex genomic profile, better prognosis outcome, and higher immune infiltration, suggesting the possibility of better response in immunotherapy-based treatments. Finally, from integrative analysis across clinical and molecular features, we demonstrated the importance of molecular phenotypes in patient prognostic stratification. We found that EAS LUADs had better prediction accuracy than EUR LUADs, potentially due to their less complex genomic architecture. In sum, this study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.

FCS 20 2046

HUI LI ANGPhD Student, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore

Exploiting DNA Damage Response Pathway: Development of PTK6 Inhibitor for Treatment of Ovarian Cancer

ABSTRACT:

Current standard of care for ovarian cancer is surgery followed by platinum-based or taxane-based chemotherapy. However, employing a blanket treatment against ovarian cancer is not optimal as ovarian cancer is a largely heterogenous disease. Protein Tyrosine Kinase 6 (PTK6, or BRK) is aberrantly expressed in many solid cancers. However, its role in ovarian cancer is not studied. We therefore seek to characterize PTK6 in ovarian cancer, and to develop a small molecule inhibitor to target this marker for the treatment of ovarian cancer. Cell-based functional assays were performed to evaluate depletion of PTK6 expression on cells’ carcinogenic capacity to migrate and invade. qPCR array was performed to identify specific genes involved in cell cycle, cell death and EMT. Cell-based functional assays revealed that depletion of PTK6 expression led to reduction in ovarian carcinoma cells’ carcinogenic capabilities, particularly reduced migration and invasion, reduced proliferation and increased cell death. Conversely, overexpression of PTK6 led

ORAL ABSTRACT SPEAKER 8

to increased cancer progression. Interestingly, a novel association between PTK6 and the DNA damage response (DDR) pathway was also discovered. Knockdown of PTK6 increased protein yH2AX levels. Mechanistically, we identified novel interacting gene partners such as p21, cyclin D and E2F, which are downregulated upon PTK6 knockdown. Immunofluorescence of DNA double-stranded break marker yH2AX and comet assay also revealed that PTK6 knockdown significantly increases DNA damage. This raises possibilities of combinatory therapy with DNA damage inducing platinum compounds. We performed an in-silico ligand-based computation to design a parent structure for PTK6 inhibitor, followed by synthesis of a series of analogues (NU series). A series of in vitro assays were performed on the NU series, and NU7 was chosen as our candidate drug. Modulation by combined use of our in-house PTK6 inhibitor (NU7) may prove to be clinically beneficial to patients particularly in increasing therapeutic efficacy of platinum compounds.

FCS 20 2047

BRYAN NICHOLAS CHUAResearch Assistant, Cancer Science Institute of Singapore, National University of Singapore

ABSTRACT:

In human papillomavirus (HPV)-positive cervical cancer, E3 identified by differential display (EDD1) is upregulated and ubiquitinates the tumor suppressor Tat Interactive Protein 60 kDa (TIP60). This marks TIP60 for proteasomal degradation and ablates its tumor-suppressive functions. We hypothesized that a selective targeting of EDD1 could return it to a more basal level and rescue TIP60. With the lack of small molecules that can target EDD1 directly, we utilized the dTAG PROteolysis TArgeting Chimera (PROTAC) system as a novel approach to degrade EDD1 indirectly. Through pulldown assays, we identified TIP60327-372 as the specific region of TIP60 that binds to EDD1. As dTAG specifically binds to FKBP12F36V only, we generated four fusion proteins

Exploiting the PROTAC System for TIP60-ing the Balance in Cancer Treatment

ORAL ABSTRACT SPEAKER 9

incorporating FKBP12F36V and the TIP60327-372 peptide fragment in different sizes and orientations, to function as an intermediate between dTAG and EDD1. In vitro experiments showed that the TIP60327-372-FKBP12F36V fusion protein was best suited to be used in the dTAG system to degrade EDD1. MG132, a proteasome inhibitor, was used to confirm that the decrease in EDD1 protein level was due to proteasomal degradation. Colony formation assays demonstrated that EDD1 degradation reduced the colony size in dTAG-treated HeLa cells stably expressing TIP60327-372-FKBP12F36V. These data suggest that targeting EDD1 has an anti-proliferative potential and also provide a proof-of-concept that can be exploited to target EDD1 in cancers.

FCS 20 2048

YEE JOO TAN

ABSTRACT:In the past 18 years, 3 different coronaviruses have crossed the species barrier to infect humans, resulting in major health problems and socioeconomic disruption. COVID-19, which is caused by the Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), is an ongoing pandemic with > 25 millions of people around the world infected. To fight this virus, much progress has been made in the development of diagnostic tests and vaccine.

The spike (S) protein is the major structural protein protruding from the surface of the virion and responsible for the “crown-like” morphology of coronaviruses. Understanding the characteristics of S is important for both antibody-based and antigen-based diagnostic tests. As the S protein mediates the entry of virus into host cells, it is also the primary target for several COVID-19 vaccine candidates. The S1 domain in S contains the receptor binding domain (RBD) and is more variable due to virus adaptation to enhance binding to cell receptors in different hosts. On the other hand, the S2 domain, which is responsible for mediating viral-host membrane fusion, is more conserved.

In this talk, I will summarize the current knowledge on the characteristics of the S protein of SARS-CoV-2 and the implications for diagnostic assays as well as vaccine development.

BIOGRAPHY:Dr Tan is an Associate Professor at the Infectious Diseases Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore. She is a Joint Senior Principal Investigator at the Institute of Molecular and Cell Biology (IMCB), A*STA. Dr Tan is a molecular virologist and her research focuses on hepatitis viruses, influenza viruses as well as newly emerged viruses, like the Crimean-Congo hemorrhagic fever virus, severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged in 2002, and SARS-CoV-2, which emerged in 2019 to cause the COVID-19 pandemic. She is also interested in the development of new methods for the production of proteins, design of immunogenic protein fragments as well as novel carriers that can be used to enhance immune responses.

Understanding the Spike Protein of SARS-CoV-2 and Its Role in the Development of COVID-19 Diagnostic Tests and Vaccine

Joint Senior Principal Investigator, Institute of Molecular and Cell Biology, A*STAR Singapore

FCS 20 2049

SUSAN CLARKProfessor, Genomics and Epigenetics, Garvan Institute of Medical Research, Australia

ABSTRACT:

A three-dimensional chromatin state underpins the structural and functional basis of the genome by bringing regulatory elements and genes into close spatial proximity to ensure proper, cell-type specific gene expression profiles. However it is still unclear if the epigenome is involved in shaping the three-dimensional (3D) chromatin architecture and how this is altered in cancer, in particular across large domains. We performed Whole Genome Bisulphite Sequencing (WGBS), ChIP-seq, Hi-C chromosome conformation capture and replication timing sequencing to investigate how 3D chromatin organization in relation to the epigenome is disrupted in cancer. We find a direct relationship between chromatin modifiying enzymes and the pattern of DNA methylation at CpG island promoters (Du et al 2020). In addition we reveal a conserved class of CTCF sites that are important in the maintenance of chromatin structure and gene expression (Khoury et al 2020). Moreover our study provides new insights into the relationship between replication timing, long-range epigenetic deregulation and changes in higher-order chromatin interactions in cancer.

BIOGRAPHY:

Professor Susan Clark, FAA, has a highly acclaimed international reputation for her work in cancer epigenetics. Susan is currently the Director of the Genome and Epigenetics Division at the Garvan Institute of Medical Research in Sydney, Australia. She graduated in 1982 with a PhD in Biochemistry, University of Adelaide and then spent ten years in the Genetic Technology before returning to basic research in gene regulation. Her studies over the last twenty years have initiated profound questions about the importance of epigenetics in early development and in disease, especially in cancer. She has made extensive ground-breaking discoveries relating to DNA methylation patterns in normal and cancer genomes, that have led to the commercialization of new methylation-based tests for early cancer detection. The techniques she pioneered in the early 1990s, including bisulphite sequencing, have revolutionised and now underpin the new era in epigenomic research. She was founding member of IHEC (International Human Epigenome Consortium) and led the formation of the AEpiA (Australian Epigenetics Alliance). She has a number of awards including the RPAH Research Medal in 2002, Julian Wells Medal in 2003, the German “Biochemisch Analytik Preis” for outstanding contribution for Methylation analysis in 2004. In 2006 was elected a Fellow of the World Technology Network for Biotechnology, in 2012 was awarded the Rotary Award for Vocational Excellence. In 2015 she was elected a Fellow of the Australian Academy and in 2017 Ramaciotti Foundation National Medal of Excellence and the 2019 NSW Premiers Prize for Excellence in Medical Biological Sciences.

3D Epigenome Alterations in Cancer

FCS 20 2050

5SESSIONFIVE

Speaker 25: Muthiah MANOHARAN

Speaker 26: Anders SKANDERUP

Speaker 27: Boon Cher GOH

Speaker 28: Oral Abstract 10 Yanjing LIU

Speaker 29: Oral Abstract 11 Daniel HUANG

Speaker 30: Oral Abstract 12 Michal Marek HOPPE

MUTHIAH MANOHARAN

ABSTRACT:Therapeutics that act through the RNA interference (RNAi) pathway have great potential. Synthetic small interfering RNA (siRNAs), which induce gene silencing via the endogenous RNAi process, are chemically modified to increase stability against nuclease degradation, to facilitate their cellular uptake through cell-membrane, and to reduce their immune stimulation. The first RNAi drug to be approved for clinical use was patisiran (ONPATTRO®) for patients with polyneuropathy caused by hereditary ATTR amyloidosis. This siRNA is partially modified with 2’-O-methyl (2’-OMe) and encapsulated in Lipid Nanoparticles. The approval of ONPATTRO® paves the way for a whole new class of RNA-based medicines. A second RNAi therapeutic, givosiran (GIVLAARI®), was recently approved for the treatment of acute hepatic porphyrias. This compound is fully modified with 2’-fluoro (2’-F) and 2’-O-methyl (2’-OMe) to confer stability in the absence of a lipid while maintaining the A-form RNA duplex conformation. Depending on the position of these modifications, they are tolerated by the endonuclease silencer enzyme Argonaute-2 (Ago2), the catalytic component of the RNA-induced silencing complex (RISC). The passenger strand of givosiran is conjugated with a tri-N-acetylgalactosamine (GalNAc), which interacts with the asialoglycoprotein receptor that is highly expressed on hepatocytes, to facilitate specific delivery into the liver for the therapeutic function. Our research group demonstrated for the first time the human therapeutic applications of GalNAc-conjugated oligonucleotides, and this platform has revolutionized the nucleic acid-based therapeutics field with many more compounds in the advanced clinical trials. Potentially many of these compounds will be approved and available for the needy patients in the near future.

BIOGRAPHY:Dr. Muthiah (Mano) Manoharan serves as a Senior Vice President of Drug Innovation, a Scientific Advisory Board Member, and Distinguished Research Scientist at Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. In 2003, he was the first chemist hired at Alnylam. He and his team pioneered the discovery and development of the chemical modifications that make RNA interference-based human therapeutics possible. This work led to ONPATTRO (Patisiran), the first RNAi therapeutic approved by FDA in 2018 for the treatment of TTR amyloidosis-mediated polyneuropathy. Dr. Manoharan and his research group designed, synthesized and demonstrated for the first time the human therapeutic applications of GalNAc-conjugated oligonucleotides at Alnylam, a platform that has revolutionized the nucleic acid-based therapeutics field with several compounds presently in the advanced clinical trials both as siRNAs and antisense oligonucleotides. The first GalNAc-conjugated oligonucleotide, GIVLAARI (Givosiran) was approved by FDA in 2019 for the treatment of Acute Hepatic Porphyria. Dr. Manoharan is an author of more than 215 publications (nearly 45,000 Google Scholar citations with an h-index of 96 and an i10-index of 382) and over 400 abstracts, and an inventor of over 250 issued U.S. patents. Prior to Alnylam, Dr. Manoharan worked in the field of antisense oligonucleotide therapeutics, at Isis Pharmaceuticals (on Carbohydrate modifications like 2’-O-MOE and Conjugates) and at LifeCodes Corporation.

Dr. Manoharan is the winner of the Lifetime Achievement Award of the Oligonucleotide Therapeutics Society (2019) and the M. L. Wolfrom Award from the American Chemical Society(2007). Besides chemistry, Mano enjoys Yoga, workouts and reading and listening to Tamil literature and music.

Moving RNAi Therapeutics from Bench to Market

Senior Vice President of Drug Innovation, Scientific Advisory Board Member and Distinguished Research Scientists, Alnylam Pharmaceuticals, Cambridge Massachusetts, USA

FCS 20 2052

ANDERS SKANDERUPSenior Research Scientist, Genome Institute of Singapore, A*STAR Singapore

ABSTRACT:

Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is key to tumor progression. Here, we deconvoluted 8,000 bulk tumor transcriptomes to infer crosstalk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. This approach recovered known transcriptional hallmarks of cancer and stromal cells and was concordant with single-cell, in-situ hybridization, and immunohistochemistry data. Inferred autocrine cancer cell interactions varied between tissues but often converged on Ephrin, BMP, and FGFR-signaling pathways. Analysis of immune checkpoints nominated interactions with high levels of cancer-to-immune crosstalk across distinct tumor types. Strikingly, PD-L1 was found to be highly expressed in stromal rather than cancer cells. Overall, our study presents a new resource for hypothesis generation and exploration of crosstalk in the TME.

BIOGRAPHY:

Anders Skanderup is a PI at the Genome Institute of Singapore. His group is interested in computational and data-intensive approaches to decipher the molecular basis of cancer and improve treatments. He holds adjunct positions at NUS School of Computing and National Cancer Center Singapore. Dr. Skanderup received his B.S. in Computer Science, followed by Ph.D. in Bioinformatics, from the University of Copenhagen. He did postdoctoral training at Memorial Sloan-Kettering Cancer Center in New York, developing and applying computational methods to study cancer from high-dimensional cancer genomic datasets.

Pan-Cancer Analysis of Crosstalk in the Tumor Microenvironment

FCS 20 2053

BOON CHER GOH

ABSTRACT:Comprehensive genomic profiling has reached clinical implementation to guide therapeutics based on identification of driver somatic genomic events in tumours that can be inhibited by drugs. On the other hand, cancer related germline polymorphisms are usually studied in the context of pharmacogenetics of chemotherapy to avoid intolerable toxicity from polymorphisms of drug metabolising enzymes that impair inactivation of chemotherapeutic agents. Currently it is known that germline polymorphisms of specific genes can reveal therapeutic opportunities due to functional modifications of proteins. Examples of these include BRCA loss of function that reveal susceptibility to PARP inhibitors, bcl-2 inhibitors for BIM1 polymorphisms that promote resistance to EGFR TKIs in EGFR mutant lung cancer, mek inhibition in neurofibromatosis type 1 for treatment of neurofibromas. Our recent work showed that the polymorphism of c-MET that results in a substitution of asparagine by serine in the 375 position in the sema extracellular domain is predominant in South and East Asians and promotes aggressive biological behaviour of squamous cell carcinoma of the head/neck and lung. Mechanistically METN375S preferentially dimerises with HER2, exploiting HER2 oncogenic signalling. Consequently, METN375S positive cells confer resistance to MET inhibitors like crizotinib, but are sensitive to HER2 blockade including afatinib and trastuzumab. This is being validated in a clinical trial of HER2 inhibition in patients with SCCHN and lung and who harbour the METN375S

polymorphism.

BIOGRAPHY:Dr Goh was trained in Internal Medicine and Medical Oncology at the National University of Singapore, and was visiting fellow at the University of Chicago Section of Hematology-Oncology and Committee on Clinical Pharmacology. He has contributed much to the development of a clinical trial research infrastructure at the National University Health System, one of the largest clinical research groups in Singapore, and chaired the Cancer Therapeutics Research Group, an Asia Pacific cancer research group. He has mentored many clinical oncology and pharmacology fellows, and has been awarded senior clinician scientist from the Biomedical Research Council and the National Medical Research Council of Singapore since 2005. In addition, he has been competitive in research grants, having held several government awarded research grants in pharmacogenomics and drug development. His research achievements have been in investigating novel agents for treatment of cancer as well as pharmacogenomics of cancer drugs. Internationally, he has served on advisory boards on several pharmaceutical companies in early drug development, and has served on editorial boards of important journals like the Journal of Clinical Oncology and Annals of Oncology. As a responsible member of clinical research, he has also served for several terms as Chairman of the Domain Specific Research Board. Currently he is Director of the Investigational Medicine Unit at the NUHS, and head of Hematology-Oncology, and Deputy Director of the Cancer Science Institute of Singapore.

Germline Polymorphisms Guide Cancer Therapy: Example of MET N375S in Squamous Cell Carcinoma of the Head and Neck

Senior Consultant, Haematology-Oncology, National University Cancer Institute, Singapore

FCS 20 2054

YANJING LIUResearch Fellow, Cancer Science Institute of Singapore, National University of Singapore

ABSTRACT:

Aberrant DNA methylation in the region surrounding the transcription start site is a hallmark of gene silencing in cancer. Currently approved demethylating agents lack specificity and exhibit high toxicity. We have previously described that DNA methyltransferase I (DNMT1), which mediates methylation of genes including tumor suppressors, is regulated by and can be inhibited by certain noncoding RNAs (ncRNAs, which we refer to as DNMT1-interacting RNAs, or DiRs), and the interaction is based on RNA secondary stem-loop structure (Di Ruscio, et al., Nature, 2013). Herein, we develop CRISPR-DiR, an RNA-based gene specific demethylation and activation technology, in which short DiR stem loops have been inserted into CRISPR single guide RNA (sgRNA) scaffold, and therefore the ad hoc edited guides block DNMT1 methyltransferase activity in a locus-specific fashion. Using as an example the methylated and silenced tumor suppressor gene p16, we demonstrate that CRISPR-DiR-induced targeted demethylation of the promoter-exon 1-intron 1

Targeted Intragenic Demethylation Initiates Chromatin Rewiring for Gene Activation

ORAL ABSTRACT SPEAKER 10

(PrExI) region initiates an epigenetic wave of both local chromatin remodeling and distal long-range interactions, culminating in gene-locus specific activation. These results suggest the existence of a specialized “demethylation firing center (DFC)” covering the proximal promoter-exon 1-intron 1 (PrExI) region, which correlates more with gene reactivation than solely the methylated proximal promoter does, and can be switched on by an adaptable and selective RNA-mediated approach for locus-specific transcriptional activation. Through CRISPR-DiR, we demonstrate that demethylation is coupled to epigenetic and topological changes. As CRISPR-DiR facilitates locus specific demethylation and activation using the endogenous cellular machinery, a process that occurs in thousands of gene loci, it represents a more natural demethylation strategy and will be a useful technology for novel scientific discovery, for large-scale screening purposes, and potential therapeutics through RNA-based gene-specific demethylation.

FCS 20 2055

DANIEL HUANGAssistant Professor, Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore Cancer Science Institute of Singapore, National University of Singapore

ABSTRACT:

Background & Aims: Hepatocellular carcinoma (HCC) arises in a cirrhotic, pro-angiogenic microenvironment. Inhibiting angiogenesis is a key mode of action of mutikinase inhibitors and current non-cirrhotic models are unable to predict treatment response. We present a novel mouse cirrhotic model of xenotransplant that predicts the natural biology of HCC and allows personalized therapy.

Methods: Cirrhosis was induced in NOD Scid gamma mice with four months of thioacetamide administration. Patient derived xenografts (PDXs) were created by transplant of human HCC subcutaneously into non-cirrhotic mice and intra-hepatically into both cirrhotic and non-cirrhotic mice. The applicability of cirrhotic PDXs for drug testing was tested with 16 days of either sorafenib or lenvatinib. Treatment response was evaluated by MRI.

Predicting HCC Response to Multikinase Inhibitors with In Vivo Cirrhotic Mouse Model for Personalized Therapy

ORAL ABSTRACT SPEAKER 11

Results: 8 out of 19 (42%) human HCC engrafted in the cirrhotic model compared with only 3 out of 19 (16%) that engrafted in the subcutaneous non-cirrhotic model. Tumor vasculature was preserved in the cirrhotic model but was diminished in the non-cirrhotic models. Metastases developed in 3 cirrhotic PDX lines and predicted early HCC recurrence in all 3 corresponding patients (100%), compared with only 5 out of 16 (31%) of the other PDX lines, P=0.027. The cirrhotic model was able to predict response and non-response to lenvatinib and sorafenib respectively in the corresponding patients. Response to lenvatinib in the cirrhotic PDX was associated with reduction in CD34, VEGFR2 and CLEC4G immunofluorescence area and intensity (all P≤0.03).

Conclusions: A clinically relevant cirrhotic PDX model allows preservation of tumor angiogenesis and prediction of response to multikinase inhibitors for personalized therapy.

FCS 20 2056

MICHAL MAREK HOPPEResearch Fellow, Cancer Science Institute of Singapore, National University of Singapore

ABSTRACT:

MYC, BCL2 and BCL6 have prognostic significance in diffuse large B-cell lymphomas (DLBCL). However, the dynamics of MYC, BCL2 and BCL6 co-expression at the single cell level and the significance of their expression patterns are still unknown. Here we use fluorescence-based quantitative immunohistochemistry (qIHC) to demonstrate that MYC(M), BCL2(2) and BCL6(6) in DLBCL show disordered patterns of co-expression at single-cell resolution, distinct from those of non-malignant lymphoid tissues. Among possible permutations of co-localisation, the clonal fraction M+2+6- was independently

Patterns of MYC, BCL2 and BCL6 Co-localization at Single-cell Resolution Underlie Their Prognostic Significance in Diffuse Large B-cell Lymphoma

ORAL ABSTRACT SPEAKER 12

predictive of poor survival in multiple cohorts of DLBCL. Interestingly, each clonal fraction could be mathematically predicted from single marker readouts, with predicted co-localization correlating well with observed co-localization. In three DLBCL gene expression datasets, the association of M+2+6- extent with poor survival was independently validated via this mathematical model and an enrichment of CCND2 expression in the M+2+6- clonal fraction was demonstrated. These results clarify the interrelationship of MYC, BCL2 and BCL6 in determining outcome of DLBCL, with diagnostic and therapeutic implications.

FCS 20 2057

MARCO HEROLDAssociate Professor and Laboratory Head, Walter and Eliza Hall Institute of Medical Research, Australia

ABSTRACT:

P53 is one of the most potent tumour suppressor genes, which is reiterated by the fact that it is mutated and hence inactivated in ~50% of all human cancers. Since p53 activity is also required for malignant cells to respond to chemotherapy, the identification of new tumour suppressor pathways will be required. Therefore, we performed whole genome CRISPR/Cas9 knockout screening in vivo, using the Eµ-Myc transgenic mouse model. This identified previously unknown genes, which upon deletion/mutation lead to the acceleration of tumour onset. Amongst these novel tumour suppressor genes, we identified the GATOR1 members DEPDC5 and NPRL3, which are known inhibitors of the mTOR pathway. Interestingly, drug mediated inhibition of mTOR activity with rapamycin or Torin1 in GATOR1 deficient Eµ-Myc cells led to efficient killing of these malignant cells, which was in striking contrast to control Eµ-Myc lymphoma cells that were resistant to this treatment. In parallel we conducted CRISPR/Cas9 screens for identifying p53 bound promoter and enhancer elements in haematopoietic cells in vivo. Excitingly, we observed that targeting the NPRL3 promoter led to accelerated tumour onset in the Eµ-Myc transgenic model, suggesting that NPRL3 is under direct transcriptional control of p53. These results indicate that p53 mediated shutdown of the mTOR pathway through upregulation of the GATOR1 member NPRL3 is a critical tumour suppressive function of p53.

BIOGRAPHY:

Marco Herold is a NHMRC Senior Research Fellow and Laboratory Head in the Blood Cells and Blood Cancer Division at the Walter and Eliza Hall Institute of Medical Research (WEHI), Melbourne. During his PhD and first postdoctoral studies at the University of Würzburg (Germany) he was trained in cell death research and mouse genetics. At WEHI, his research team specialises in applying CRISPR gene editing techniques to identify novel gene targets required for the development and sustained growth of cancer cells. Recent findings identified DNA repair as fundamental for TP53-mediated tumour suppression (Janic et al, Nature Medicine 2018). His current research employs genome-wide CRISPR library screening in vivo to discover vulnerabilities that can be exploited for cancer therapy.

Finding Critical Cancer Driving Genes using Functional Genomics Screening In Vivo

CLOSING LECTURE

FCS 20 2058

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FRONTIERS IN CANCER SCIENCE 2020

2-6 NovemberConference Booklet

Genome Instituteof Singapore