Sydney Catalyst

2017 Post Graduate and

Early Career Researcher

Symposium

ABSTRACT BOOKLET AND PROGRAM

Friday 28th April, 2017

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WELCOME MESSAGE

On behalf of the Organising Committee, it is my pleasure to welcome you to the 2017 Sydney Catalyst Post-graduate student and early-career researcher (PG&ECR) symposium. I attended one of the very first Sydney Catalyst education events on a cold winter night during 2012, and have taken part in many since, but I am

especially excited about the program that we’ve put together for today.

Sydney Catalyst now has more than 600 members from 30 member groups in NSW and one of its goals is to facilitate professional development, communication, and collaboration across the consortium. The annual

PG&ECR Symposium is an important part of that, providing a unique opportunity for post-graduate students and early-career researchers from across the translational spectrum to come together and learn from each other. As you will see there is great diversity in the presentations ranging from basic sciences, clinical trials

and studies, psychosocial and implementation research.

We are also excited to welcome two keynote speakers, both of whom will be sharing their experience in

developing outstanding careers in translational cancer research. Our first keynote speaker is Professor

Barbara Fazekas de St Groth, who’ll be speaking on the topic of “Translating immunology into cancer care”

and generously sharing some of what she has learned about crossing the Ts, communicating across the

translational research spectrum, bridging gaps and bringing multi-disciplinary teams together. Our second

keynote speaker is Dr Thomas Cox, who’ll also be sharing some of what he has learned so far in his career,

including his journey to the Garvan Institute, where he has established a new lab as head r, of the Matrix and

Metastasis Group.

Today’s program also includes a great panel discussion about why and how to include consumers in

research. Involving cancer consumers in research ensures that what we do as researchers is relevant and of

benefit to consumers and can also support the dissemination and translation of research results. We are incredibly grateful for the time our panellists are taking to be with us today; thank you John Stubbs, John

Fullagar, Jo Shaw and Rhiannon White.

I have really enjoyed being involved in the planning for this Symposium and would like to thank the other members of organising committee; Merran Findlay, Mun Hui and Reichelle Yeo, as well as the Sydney

Catalyst Central Office team for their work behind the scenes to bring this great meeting together.

We hope this year’s Symposium will give you an appreciation of the breadth of excellent research being conducted by your peers and colleagues and that you take with you inspiration, cutting-edge knowledge and

new contacts.

Dr Phillip Fromm, Chair, PG&ECR Symposium Organising Committee

ORGANISING COMMITTEE

Phillip Fromm (Chair), CINSW Early Career Research Fellow, Dendritic Cell Research

Reichelle Yeo, PhD Candidate, Centenary Institute

Merran Findlay, Senior Oncology Dietitian and NHMRC Translating Research Into Practice (TRIP) Fellow at Royal Prince Alfred Hospital and The Chris O’Brien Lifehouse

Mun Nga Hui, Medical Oncologist and Research Fellow, Chris O’Brien Lifehouse

Danielle Miller, Sydney Catalyst Research Manager

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PROGRAM Friday 28th April 2017 9:30am – 4:30pm Concord Medical Education Centre, Concord Hospital, Sydney Contact on the day – Danielle Miller (0405194090)

9:00-9:30am Registration Coffee and tea on arrival

9:30-9:35am Welcome and Introduction Dr Phillip Fromm CINSW Early Career Research Fellow, Dendritic Cell Research Chair, PG&ECR Symposium Organising Committee

Session 1: Chaired by Dr Mun Hui Medical Oncologist and Research Fellow, Chris O’Brien Lifehouse

9:35-10:15am Keynote Presentation 1 (30 minute keynote presentation + 10 minutes Q&A) Professor Barbara Fazekas De St Groth Director, Ramaciotti Facility for Human Systems Biology, USYD Translating immunology into cancer care

10:15-11:00am Session 1 Abstract Presentations (3 x 12 min. oral presentations)

Angelica Merlot, NHMRC and CINSW Early Career Research Fellow, University of Sydney Exploiting the Unfolded Protein Response against Cancer Progression

Liesbeth Geerligs, PhD Candidate, University of Sydney Hospital-based interventions: a systematic review of barriers and facilitators to support successful implementation

Yang Zhao, Research Officer, Centenary Institute Targeting vascular VE-Cadherin with a first-in-class drug promotes T cell mediated immunotherapy in tumors

11:00-11:15am Morning Tea

Session 2: Chaired by Reichelle Yeo PhD Candidate, Centenary Institute

11:15-12:30pm Abstract Session 2 (5 x 12 min. oral presentations)

Amelia Smit, PhD Candidate, University of Sydney Does personalised melanoma genomic risk information trigger conversations about skin cancer prevention and skin examination with family, friends and health professionals?

Julius Kim, Post-doctoral Fellow, Dendritic Cell Research A dendritic cell (DEC205) targeted adenoviral vector facilitates immune response against human glioma antigen (CMV-IE) and prolongs survival of human glioma murine model

Blake Hsu, PhD Candidate, Dendritic Cell Research Bone marrow graft-versus-host-disease in reduced intensity conditioned major histocompatibility complex matched murine allogeneic hemopoietic cell transplantation

Claire Vennin, PhD Candidate, Garvan Institute of Medical Research Transient manipulation of tissue tension improves chemotherapy, prolongs survivals and delays metastasic spread in stratified patient-derived models of pancreatic cancer

Salman Albeshan, PhD Candidate, University of Sydney Understanding better the beliefs and attitudes toward breast cancer and breast screening practices among women living in Ras al-Khaimah, United Arab Emirates (UAE)

12:30-1:30pm Lunch

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Session 3: Chaired by Danielle Miller Sydney Catalyst Research Manager

1:30pm-2:15pm

Panel Discussion The why and how of involving cancer consumers in research John Stubbs, Sydney Catalyst SAC Member and Consumer Representative John Fullagar, North Shore Prostate Cancer Support Group and Consumer Representative Rhiannon Lee White, Project Officer, Research Grants, Cancer Council NSW Jo Shaw, Research Program Manager and Research Fellow, PoCoG

2:15-3:00pm Abstract Session 3 (3 x 12 min. oral presentations)

Jennifer Hsu, Research Fellow, Dendritic Cell Research Next-Generation Dendritic Cell Vaccines: Providing a Therapeutic Option for Frail Acute Myeloid Leukaemia Patients

Mun Hui, Medical Oncologist and Research Fellow, Chris O’Brien Lifehouse Stromal Smoothened inhibition depletes triple negative breast cancer stem cells and sensitizes to chemotherapy

Brooke Nickel, PhD Candidate, University of Sydney Does calling it cancer matter? The impact of papillary thyroid cancer terminology on anxiety and treatment preferences

3:00-3:15pm Afternoon tea

Session 4: Chaired by Dr Phillip Fromm Research Fellow, Dendritic Cell Research

3:15-3:45pm Abstract Session 4 (2 x 12 min. oral presentations)

Ashleigh Morgan, PhD Candidate, Garvan Institute of Medical Research Targeting the Src/JAK/STAT3 signalling pathway: A novel and promising therapeutic strategy for pancreatic cancer

Marissa Williams, Research Assistant, ADRI Tumour suppressor microRNAs regulate PD-L1 expression in malignant pleural mesothelioma

3:45-3:50 Nominations for The People’s Choice Award

3:50-4:20 Keynote Presentation 2 (20 minute keynote presentation + 10 minutes Q&A) Dr Thomas Cox, Group Leader, Matrix and Metastasis, Cancer Division Garvan Institute of Medical Research Journey to the Garvan

4:20-4:30 Wrap up and prize giving Prizes include: Best T1T2, Best T2T3, Best Consumer/Community Engagement, Best Example of Translation and People’s Choice

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KEYNOTE SPEAKERS Professor Barbara Fazekas De St Groth Director, Ramaciotti Facility for Human Systems Biology, USYD Keynote title: Translating immunology into cancer care Prof Barbara Fazekas de St Groth graduated in medicine with first class honours from the University of Sydney and worked as a Professorial Intern and Resident at Royal Prince Alfred Hospital, Sydney before completing a PhD with JFAP Miller at the Walter and Eliza Hall Institute in Melbourne. She then undertook postdoctoral training with Mark Davis at Stanford University. She returned to Sydney to set up a laboratory at the Centenary Institute, where she established an international reputation for her work using T cell receptor transgenic mouse models and multiparameter flow cytometry to define fundamental

immune processes, including those involved in allergy, autoimmunity and cancer. Her studies on the role of regulatory T cells in mice and humans included the discovery of the gold-standard phenotyping strategy that allows pure populations of human regulatory T cells to be isolated and manipulated for immunotherapy. Her recent studies have uncovered how regulatory T cells fine-tune dendritic cell costimulation to control the CD4 T cell response in allergy, autoimmunity and cancer. In 2016, she was appointed a Professor in the Discipline of Pathology at the University of Sydney, where she is the Director of the Ramaciotti Facility for Human Systems Biology. Her current research involves the use of highly multi-parametric mass cytometry to define immune signatures that predict individual patient disease profiles and responses to cancer immunotherapy.

Dr Thomas Cox Group Leader, Matrix and Metastasis, Cancer Division Garvan Institute of Medical Research Keynote title: Journey to the Garvan Thomas is a cancer cell biologist working in the field of the extracellular matrix (ECM) and ECM remodelling in the progression and metastasis of solid tumours. Thomas graduated with a Ph.D. from the University of Durham, UK in 2008 and immediately moved to the Institute of Cancer Research (ICR) in London as a PostDoc. In 2012 he relocated to Copenhagen University in Denmark to continue his research in the laboratory of Professor Janine Erler.

Thomas then moved to the Garvan Institute of Medical Research in Sydney Australia at the end of 2016 to set up his own group. Thomas currently leads the Matrix and Metastasis Group at the Garvan Institute, Kinghorn Cancer Centre. His group focuses on how the extracellular matrix (ECM) regulates resident cell behaviour and specifically how it contributes to cancer progression, metastasis and response to therapeutics. In particular he works on the role of Lysyl Oxidase (LOX) and Lysyl Oxidase Like (LOXL) family members in regulating both the biochemical and biomechanical properties of the ECM during fibrosis, cancer progression and metastasis. Ultimately, the aim of Thomas’ group is to establish targeting of ECM dynamics as a viable therapeutic approach in the treatment of solid cancers.

PANELLISTS Panel topic: The why and how of involving cancer consumers in research

John Stubbs, Sydney Catalyst SAC Member and Consumer Representative

John Fullagar, North Shore Prostate Cancer Support Group and Consumer Representative

Rhiannon Lee White, Project Officer, Research Grants, Cancer Council NSW

Jo Shaw, Research Manager, PoCoG

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ABSTRACTS

Name Institution Abstract Title T1/2/3 Page

Salman Albeshan Cancer Researchers, University of Sydney main campus

ABTRACT NOT INCLUDED WITHIN AT REQUEST OF AUTHOR Understanding better the beliefs and attitudes toward breast cancer and breast screening practices among women living in Ras al-Khaimah, United Arab Emirates (UAE)

T2/T3 7

Liesbeth Geerligs Chris O'Brien Lifehouse Hospital-based interventions: a systematic review of barriers and facilitators to support successful implementation.

T2/T3 7

Wei-Hsun Hsu ANZAC Research Institute Bone marrow graft-versus-host-disease in reduced intensity conditioned major histocompatibility complex matched murine allogeneic hemopoietic cell transplantation

T1/T2 7

Jennifer Hsu ANZAC Research Institute Next-Generation Dendritic Cell Vaccines: Providing a Therapeutic Option for Frail Acute Myeloid Leukaemia Patients

T1/T2 8

Mun Ngah Hui Chris O'Brien Lifehouse Stromal Smoothened inhibition depletes triple negative breast cancer stem cells and sensitizes to chemotherapy

T1/T2 8

Julius Woongki Kim ANZAC Research Institute A dendritic cell (DEC205) targeted adenoviral vector facilitates immune response against human glioma antigen (CMV-IE) and prolongs survival of human glioma murine model

T1/T2 9

Angelica Merlot Cancer Researchers, University of Sydney main campus

Exploiting the Unfolded Protein Response against Cancer Progression

T1/T2 10

Ashleigh Morgan Garvan Institute includes The Kinghorn Cancer Centre

Targeting the Src/JAK/STAT3 signalling pathway: A novel and promising therapeutic strategy for pancreatic cancer

T1/T2 10

Brooke Nickel Cancer Researchers, University of Sydney main campus

Does calling it cancer matter? The impact of papillary thyroid cancer terminology on anxiety and treatment preferences

T2/T3 11

Amelia Smit Cancer Researchers, University of Sydney main campus

Does personalised melanoma genomic risk information trigger conversations about skin cancer prevention and skin examination with family, friends and health professionals?

T2/T3 11

Claire Vennin Garvan Institute includes The Kinghorn Cancer Centre

Transient manipulation of tissue tension improves chemotherapy, prolongs survivals and delays metastasic spread in stratified patient-derived models of pancreatic cancer.

T1/T2 12

Marissa Williams Asbestos Diseases Research Institute (ADRI)

Tumour suppressor microRNAs regulate PD-L1 expression in malignant pleural mesothelioma

T1/T2 12

Yang Zhao Centenary Institute of Cancer Medicine

Targeting vascular VE-Cadherin with a first-in-class drug promotes T cell mediated immunotherapy in tumors

T1/T2 13

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Salman Mohammed Al-beshan SESSION 2 Cancer Researchers, University of Sydney main campus Understanding better the beliefs and attitudes toward breast cancer and breast screening practices among women living in Ras al-Khaimah, United Arab Emirates (UAE) BIO Salman received a Bachelor degree in Medical Radiation Sciences from King Saudi University (KSU), Saudi Arabia in 2008. He worked at KSU as a joiner lecturer from 2009 to 2012. In 2014, Salman completed his postgraduate qualification; a Master in Diagnostic Radiography from the University of Sydney. Since then, he has been involved with studies related to breast cancer early detection strategies. Salman is a member of the Imaging, Optimisation and Perception Group MIOPeG, the University of Sydney. Salman received a grant in 2015 titled Transforming breast cancer diagnosis in Ras Al Khaimah (RAK); Brennan P, Mackey M, Albeshan S, Hossain S; Sheikh Saud bin Saqr Al Qasimi Foundation for Policy Research/Research Support, United Arab Emirates (UAE).

Liesbeth Geerligs SESSION 1 Chris O'Brien Lifehouse Hospital-based interventions: a systematic review of barriers and facilitators to support successful implementation. ABSTRACT Background: Translation of evidence-based interventions into hospital systems provides substantial benefits to patient care and outcomes, but is often not achieved. The research literature describes a range of barriers and facilitators to successful implementation. This systematic review sought to summarise and explore relationships between these barriers and facilitators within the hospital context and to highlight key factors that need to be addressed by researchers and clinicians. Methods: We searched relevant databases using search terms focused specifically on barriers and facilitators to patient-focused interventions in hospital settings. To be eligible, papers needed to have collected formal data that specifically assessed the implementation process. Results: Of 3767 papers retrieved, 38 papers met inclusion criteria. Barriers and facilitators were grouped into three main factors: system, staff and intervention. Bi-directional relationships were evident between these factors, with the strongest links between staff and intervention factors. Conclusions: Researchers and health professionals designing evidence-based interventions need to consider barriers and facilitators across all three areas to increase the likelihood of implementation success. The interrelationships between factors are also important, as resources leveraged in one area can be used to address barriers in others. BIO Liesbeth is a PhD Candidate and clinical psychologist with 10 years’ experience in clinical practice and a strong background in mental health research. She has worked as a Research officer overseeing large trials at the Black Dog Institute, School of Psychology UNSW and The Urban Mental Health Research Institute at St Vincent's Hospital, and as a consultant in the field of service evaluation, assessing outcomes of government and non-government initiatives. As a clinical psychologist she has worked extensively in both private and public settings, with a focus on psycho-oncology, chronic illnesses and grief. She is currently undertaking a PhD in the field of implementation science focusing on supporting cancer services to implement best practice psychosocial care for patients with cancer. This PhD is within Psychooncology Cooperative Research Group (PoCoG), one of the fourteen national cancer cooperative trial groups in Australia and supported by funding from Sydney Catalyst. Liesbeth has a passion for translational research that bridges the gaps between researchers and clinicians, allowing them to collaborate and share knowledge in order to achieve the best quality of healthcare.

Blake (Wei-Hsun) Hsu SESSION 2 ANZAC Research Institute Bone marrow graft-versus-host-disease in reduced intensity conditioned major histocompatibility complex matched murine allogeneic hemopoietic cell transplantation ABSTRACT Background: The majority of clinical allogeneic haemopoietic cell transplants (alloHCT) are now performed using reduced intensity conditioning (RIC) instead of myeloablative conditioning (MAC). However, the biology underlying RIC

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treatment remains incompletely understood. Methods: We investigated a murine model of major histocompatibility complex (MHC)-matched multiple minor histocompatibility antigen mismatched alloHCT, using bone marrow (BM) cells and splenocytes from C57BL6 (H-2b) donor mice transplanted into BALB.B (H-2b) recipients after optimizing a RIC protocol consisting of 100mg/kg/day fludarabine for 5 days, 60mg/kg/day cyclophosphamide for 2 days, and sub-lethal total body irradiation (TBI). Results: The lowest TBI dose capable of achieving complete donor chimerism in this strain combination was 325cGy. Mice given RIC had a reduced incidence and delayed onset of GVHD and significantly prolonged survival compared to MAC (TBI 850cGy, plus cyclophosphamide 60mg/kg/day for 2 days) transplanted recipients. Compared to syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, with anemia, reduced BM cellularity, and profound reduction in BM B cell lymphopoiesis, associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8+ effector T cells in RIC mice, and elevated blood and BM plasma levels of Th1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice, which was dependent on donor CD8+ effector T cells. Conclusion: We demonstrate that the BM is a major target organ of GVHD driven by CD8+ effector T cells in an informative, clinically relevant, RIC alloHCT mouse model. BIO Blake is a haematologist who completed his undergraduate medical degree in New Zealand at the University of Otago. He moved to Sydney in 2008 and started specialist training in internal medicine and subsequently haematology training at the Royal Prince Alfred Hospital and Concord Repatriation General Hospital. He is currently a 3rd year PhD student at the ANZAC Research Institute under the supervision of Professor Derek Hart where he is studying the biology of graft versus host disease and exploring novel ways of preventing this phenomenon.

Jennifer Hsu SESSION 3 ANZAC Research Institute Next-Generation Dendritic Cell Vaccines: Providing a Therapeutic Option for Frail Acute Myeloid Leukaemia Patients ABSTRACT Relapse of acute myeloid leukaemia (AML) after chemotherapy is common. New therapies are desperately needed for patients who are too frail to benefit from a potentially curative allogeneic haematopoietic cell transplant (alloHCT). Therapeutic dendritic cell (DC) vaccination has the potential to provide immune control with minimal toxicity. Trials using monocyte-derived DC to vaccinate AML patients in complete remission (CR) have demonstrated limited anti-leukaemia T cell responses with modest clinical effects. We are developing a next-generation DC vaccine, made from autologous blood DC, as an immunogenic, low toxicity alternative to alloHCT. After demonstrating that blood DC recover post-chemotherapy, and that they can be purified using our technology, we have demonstrated that blood DC from AML patients in CR can expand functional autologous anti-viral and anti-tumour CD4 and CD8 T cells in vitro. To enhance vaccine efficacy, we are exploring the immune landscape in AML patients in CR to determine whether we can combine our next-generation DC vaccine with immune checkpoint inhibitors such as Nivolumab. Our research supports the feasibility of preparing functional next-generation DC vaccines from AML patients in CR and will offer a therapeutic option to a patient group vulnerable to relapse, with few clinical options. BIO Dr Jennifer Hsu is a translational immunologist with a keen interest in anti-cancer immunity. Throughout her career, Jennifer has studied dendritic cell and T cell interactions and has worked in both academia and industry developing new technologies to bring anti-cancer vaccination into clinical practice. Jennifer joined Prof Derek Hart’s group in 2014, and is based at RPA where she is currently working on dendritic cell-based therapies for haematological malignancies.

Mun Ngah Hui SESSION 3 Chris O'Brien Lifehouse Stromal Smoothened inhibition depletes triple negative breast cancer stem cells and sensitizes to chemotherapy ABSTRACT Triple negative breast cancer (TNBC) presents a major therapeutic challenge, generally characterised by a relatively high relapse rate, drug resistance and an absence of targeted therapies. The tumour stroma facilitates TNBC tumour progression and therapeutic resistance. A majority of TNBC exhibit paracrine Hh signalling, sufficient to drive a proliferative and metastatic phenotype in TNBC models, but the cellular and molecular details of this axis remain elusive. Using a transcriptomic approach, cancer-associated fibroblasts (CAFs) were identified as the primary stromal

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cell type that respond to Hh ligand secreted by TNBC neoplastic cells. Activation of the Hh signalling pathway in CAFs lead to extensive collagen remodelling and FGF5 expression which reciprocally drives the acquisition of a stem cell-like phenotype in adjacent neoplastic cells. Importantly, treatment of TNBC patient-derived xenograft (PDX) models with Smoothened inhibitors (SMOi) significantly reduced the expression of the stem cell marker ALDH1 by neoplastic cells. Furthermore, combination therapy with SMOi plus chemotherapy dramatically improved survival and reduced metastatic burden compared to single agent arms. In the EDALINE phase I clinical trial, positive clinical response was documented in patients whose tumours exhibit Hh pathway activation in response to combination therapy. BIO Dr. Mun Hui is a medical oncologist at the Chris O’Brien Lifehouse who specialises in the treatment of patients with breast cancer and is a research fellow of the Sydney Breast Cancer Foundation. She completed her PhD in breast cancer tumour microenvironment under the mentorship of A/Prof Swarbrick at the Garvan Institute of Medical Research and continues to carry out breast cancer research there. In collaboration with clinical investigators of the Spanish Breast Cancer Trials Group, Dr. Hui’s research in the tumour microenvironment was successfully translated into a phase I trial of therapeutic targeting of the Hedgehog pathway in triple negative breast cancer. She is also a previous recipient of the Sydney Catalyst Top-Up Scholarship award. She currently oversees the breast cancer arm of the New South Wales Early Clinical Trial Alliance (NECTA) at the Chris O’Brien Lifehouse and is a co-investigator of the Sydney Local Health District tumour biobank programme.

Julius Woongki Kim SESSION 2 ANZAC Research Institute A dendritic cell (DEC205) targeted adenoviral vector facilitates immune response against human glioma antigen (CMV-IE) and prolongs survival of human glioma murine model ABSTRACT Anti-tumor immunotherapeutic strategies represent and especially promising set of approaches with rapid translational potential, considering the dismal clinical context of high-grade gliomas.Dendritic cells (DCs) are the body’s most professional antigen-presenting cells, able to recruit and activate T cells against specific antigens and stimulate a robust adaptive immune response. Given these properties, dendritic cell vaccinations, which actively introduce a tumor specific antigen onto dendritic cells, are one of the most advanced and effective anti-tumor immunization approaches. In this study, we developed a DC-specific adenoviral (Ad) vector, named Ad5scFvDEC205FF, which can deliver a glioma specific antigen (CMV-IE) specifically to DCs by targeting their surface receptor, DEC205. To optimize this virus for in vivo systemic administration, the hexon of this Ad5 vector was replaced with that of Ad serotype 3 to minimize coagulation factor X-mediated livery sequestration and toxicity. This novel delivery system successfully and effectively loaded the tumor antigen to DCs and also induced DC maturation. Our data suggest that these virally-infected, antigen-loaded DCs activate CD8+T cells in the antigen specific manner, which resulted in eradication of the glioma cells and a survival benefits in a murine glioma model that either pre-treated with the viral vaccine or received treatment after tumor implantation murine. Furthermore, when the long-term survivors were re-challenged with tumor, cancerous cells were completely rejected, suggesting the formation of long-term immunological memory against the tumor cells. In conclusion, our novel viral-mediated, DC-based immunization approach has significant therapeutic efficacy and potential for rapid translational into the clinic for patients with high grade gliomas. BIO Julius aspires to become an independent, leading scientist in the field of anti-tumor therapy. He wishes to utilise his unique technical skill set and expertise in molecular biology, neurobiology, virology, immunology and adenoviral vector-mediated therapy to improve the therapeutic agents & approaches available for patients suffering from cancer. Julius has developed novel cancer therapies for glioma, studied the relationship between cancer immunology and virotherapy, and explored the role in immunotherapy in conjunction with virotherapy. Julius is an active member of Sydney Catalyst, American Society of Gene and Cell Therapy (ASGCT) and Society of Neuro-Onocology (SNO), and has mentored three students in the laboratory, two of whom have been awarded grants for their work and have actively published manuscripts.

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Angelica Merlot SESSION 1 Cancer Researchers, University of Sydney main campus Exploiting the Unfolded Protein Response against Cancer Progression ABSTRACT The unfolded protein response (UPR) is activated in cancer cells due to genetic mutations and the hostile microenvironment of tumours. This UPR activation has been demonstrated to be a crucial step in oncogenic transformation and cancer development; even eliciting activity of cancer supporting stromal cells. An innovative strategy is to induce lethal activation of the UPR via the use of novel thiosemicarbazone anti-cancer agents (TCs) developed in my lab. TCs form cellular redox active metal complexes and demonstrate potent and selective anti-tumour and anti-metastatic activity in vivo. The most potent of these agents is currently being examined in clinical trials for the treatment of patients with advanced solid tumors in Australia (NCT02688101). Studies assessed the mechanisms by which the potent TC, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazones (Dp44mT), alters the UPR in PANC1 pancreatic cancer cells. Our studies demonstrate that Dp44mT significantly: (1) increased activation of ER stress-associated pro-apoptotic signalling (i.e., p-eIF2α, ATF4 and CHOP); (2) increased phosphorylation of IRE1α and XBP1 splicing; (3) reduced the expression of molecules involved in ER stress-associated cell survival signalling (e.g., XBP1s and p58IPK); (4) activated the transcription factor, ATF6, and its downstream targets (i.e. CHOP and BiP); and (5) activated pro-apoptotic p-CaMKII. Moreover, PERK or IRE1α silencing reduced Dp44mT-mediated migration inhibition, demonstrating that PERK or IRE1α can regulate cell migration and the anti-cancer activity of Dp44mT. Collectively, these results demonstrate that Dp44mT activates the pro-apoptotic pathways of the UPR, re-sensitizing cancer cells to apoptosis while inhibiting cell survival signals. BIO Dr Angelica Merlot is a NHMRC and CINSW Early Career Research Fellow in the Discipline of Pathology and Bosch Institute at the University of Sydney. She graduated with a PhD at the University of Sydney and commenced her postdoctoral training in 2014 in the Molecular Pharmacology and Pathology Program. Her research focuses on the development of anti-cancer drugs and investigating the role of the endoplasmic reticulum in metastasis and cancer progression.

Ashleigh Morgan SESSION 4 Garvan Institute includes The Kinghorn Cancer Centre Targeting the Src/JAK/STAT3 signalling pathway: A novel and promising therapeutic strategy for pancreatic cancer ABSTRACT Introduction: Pancreatic cancer (PC) has a 5-year survival of only 6%, and persists as the 4th most common cause of cancer-related death in Western societies. A more tailored treatment approach may be beneficial as the current standard-of-care cytotoxic agent gemcitabine, in combination with nanoparticle albumin-bound paclitaxel, or FOLFIRINOX offers only a modest increase in overall patient survival in unselected populations. Recent large-scale genomic studies have revealed that the Src/JAK/STAT3 signalling pathway is deregulated in 15-50% of PC. This pathway is yet to be systematically examined in pancreatic cancer, however it is known to play an important role in immunosuppression and tumour progression. Consequently, we hypothesized that targeting pancreatic tumours with activated JAK/STAT3 signalling with selective JAK1/JAK2 or JAK3 inhibitors (Ruxolitinib, Tofacitinib), and an Src inhibitor (Dasatinib) represents a promising novel therapeutic strategy for this disease. Materials and methods: We utilized well-annotated patient-derived cell line models (PDCLs) isolated from sequenced pancreatic cancer patients (International Cancer Genome Initiative), along with cell lines generated from KPC (Pdx1-Cre; KrasLSL.G12D/+; p53R172H/+) mice, an aggressive, metastatic model of PC. Using these pre-clinical models we assessed the in vitro efficacy of therapeutic strategies involving Src/JAK/STAT3 inhibition, using cell proliferation assays and 2D drug synergy screens. Effects on invasion were determined using 3D organotypic assays, which recapitulate the interaction between cancer cells, stromal cells and the extra-cellular matrix (ECM). ECM integrity post-treatment was assessed using second-harmonic generation (SHG) imaging and picrosirius staining. To investigate whether these immune-modulating therapies assist in enhancing the anti-tumour response we utilized a syngeneic, orthotopic KPC mouse model and examined the immune-cell infiltrate using FACS. Results and Discussion: We show that selected JAK inhibitors and Dasatinib inhibit cell proliferation in candidate PDCLs and KPC lines, characterized by activated Src/JAK/STAT3 signalling, with combination therapy being synergistic in the majority of these cell-lines. Cell invasion was significantly inhibited in organotypic matrices, and Src/JAK/STAT3

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inhibition decreased collagen contractility, and reduced fibrillar collagen coverage, suggesting that these compounds may also modulate ECM integrity. We also show that these therapies reduce regulatory T-cells, MDSCs and tumour-associated macrophages. Conclusion: Our findings demonstrate the potential for tailored therapeutic strategies involving Src/JAK/STAT3 inhibition in pancreatic cancer, and suggest that the efficacy of this therapy may be the result of targeting both tumour cells and the tumour microenvironment, as well as by overcoming tumour-induced immunosuppression. BIO Ashleigh Morgan Is a second Year PhD student at The Kinghorn Cancer Centre. She completed her undergraduate degree at UNSW and graduated with a Bachelor Of Advanced Science With Honours, majoring in Genetics, Molecular Biology, Microbiology and Pathology. She completed her Honours year under the supervision of A.Prof Maija Kohonen‐Corish at the Kinghorn Cancer Centre, where she investigated one of the functional mechanisms of the tumour suppressor MCC, in colon cancer. After graduating she joined the Personalised Cancer Therapeutics group, to commence her PhD under the supervision of Dr Marina Pajic and Dr Paul Timpson. Ashleigh received an Australian Post Graduate Award as well as the Sydney Catalyst Top‐Up Scholarship. Her current research is focused on validating predictive biomarkers of therapeutic response to novel treatments in pancreatic cancer, and examining their efficacy as personalized therapeutic strategies.

Brooke Nickel SESSION 3 Cancer Researchers, University of Sydney main campus Does calling it cancer matter? The impact of papillary thyroid cancer terminology on anxiety and treatment preferences ABSTRACT Objectives: Given evidence of overdiagnosis and overtreatment of small papillary thyroid cancers (PTCs) and recent guideline recommendations for more conservative management options for patients diagnosed with PTC, our study aimed to understand how levels of anxiety and preferences for treatment for PTC differ when it is described with and without the cancer term. Methods: We conducted an experimental study with a random sample of healthy men and women across Australia without a history of thyroid cancer and presented them with 3 scenarios that described a hypothetical diagnosis of PTC using the terms “papillary thyroid cancer”, “papillary lesion”, and “abnormal cells”. Primary outcome measures were diagnosis anxiety, treatment choice and treatment choice anxiety. Results: 550 Australians completed the experiment and were included in the analysis. Participants had higher levels of anxiety (p=0.0044) and opted for surgical treatment options (32% vs. 27% vs. 24%) when the diagnosis was called “papillary thyroid cancer” compared to “abnormal cells” and “papillary lesion”. Overall, participants were willing to manage their PTC with active surveillance, however adequate reassurance with this option would be required. Implications: Changing the terminology of small PTCs may be one strategy to reduce overdiagnosis and enable the consideration of more conservative management options. BIO Brooke Nickel is a PhD candidate and psychosocial researcher with the Wiser Healthcare research collaboration in the School of Public Health at the University of Sydney. She is interested in understanding the psychosocial aspects of cancer diagnosis and treatment, with a specific area of interest in examining how different terminologies for precancerous conditions and early stage cancer affect patients’ psychological outcomes and decision making regarding treatment.

Amelia Smit SESSION 2 Cancer Researchers, University of Sydney main campus Does personalised melanoma genomic risk information trigger conversations about skin cancer prevention and skin examination with family, friends and health professionals? ABSTRACT Aims: To explore conversations prompted by receiving personalised genomic risk of melanoma with family, friends and health professionals. Methods: Questionnaires were completed by 103 participants who had received information on their personalised

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genomic risk of melanoma as part of a pilot randomised controlled trial. We conducted semi-structured qualitative interviews with 30 participants. Questionnaire data were analysed according to participants’ genomic risk category (low, average, high), and interview data were analysed thematically. Results: From questionnaires, 74% of participants communicated their genomic risk information with family, 49% with friends. Communication with a health professional differed by risk level: 41%, 16% and 12% for high, average and low-risk, respectively (P=0.01). Qualitative analysis showed that perceived ‘shared risk’ and perceived interest of family and friends were motivations for discussing risk or prevention behaviours. The information prompted conversations with family and health professionals about sun protection and skin checks, and general conversations about melanoma risk with friends. Reasons for not discussing with family included existing personal or family health concerns, or existing high levels of sun protection behaviours among family members. Conclusions: Personalised melanoma genomic risk information can prompt risk-appropriate discussions about skin cancer prevention and skin examinations with family and health professionals. BIO Amelia Smit is a PhD candidate at the Cancer Epidemiology and Prevention Research and the Centre for Values, Ethics and the Law in Medicine, in the School of Public Health at The University of Sydney. Her research focuses on generating new research evidence to guide the translation of knowledge about genomics into Australian healthcare to improve cancer prevention and screening in the population.

Claire Vennin SESSION 2 Garvan Institute includes The Kinghorn Cancer Centre Transient manipulation of tissue tension improves chemotherapy, prolongs survivals and delays metastasic spread in stratified patient-derived models of pancreatic cancer. ABSTRACT The emerging standard of care for patients with inoperable pancreatic cancer (PC) is a combination of gemcitabine and Abraxane, but patient response remains moderate. PC development and metastasis occur in complex settings with reciprocal feedback from micro-environmental cues influencing both disease progression and drug response. In particular, the extracellular matrix (ECM) promotes cell proliferation, metastasis and chemoresistance, however studies assessing chronic ablation of the ECM have yielded conflicting data. Here, we demonstrate that transient manipulation of the ECM using Fasudil, a clinical ROCK inhibitor, in patient-personalised in vitro and in vivo models of PC (i) improves chemotherapy efficacy, (ii) prolongs survival and (iii) delays metastatic spread. Multiphoton-based stratification of patient tumours based on their ECM signature revealed a graded response to Fasudil treatment before Gemcitabine/Abraxane, suggesting that collagen content could be used as a companion biomarker to facilitate the identification of patients who could benefit from Fasudil treatment before chemotherapy. We have demonstrated multi-site benefits using Fasudil treatment in combination with standard-of-care therapy and we have identified a potential companion biomarker. We therefore envision Fasudil potential use to treat PC at several stages. BIO Claire is a PhD research scholar at the Kinghorn Cancer Center in Sydney in the Timpson lab. During her PhD, she has focused on manipulating the stromal tissue that surrounds pancreatic tumours to improve chemotherapy efficacy and to impact on metastatic spread. She uses intravital imaging in mouse models and patient-derived tumours to assess new therapeutic strategies in pancreatic cancer.

Marissa Williams SESSION 4 Asbestos Diseases Research Institute (ADRI) Tumour suppressor microRNAs regulate PD-L1 expression in malignant pleural mesothelioma ABSTRACT Programmed death 1 (PD-1) and its ligand PD-L1 have significant roles in suppressing host immune response in many cancer types. PD-L1 expression is upregulated and associated with poor prognosis in malignant pleural mesothelioma (MPM) but the mechanisms causing its dysregulation are poorly understood. Characterization of the mechanisms leading to PD-L1 upregulation could improve the understanding of its dysregulation in MPM and give depth to its prognostic significance. Of a series of 72 MPM patients, 18 (25%) were found to have positive PD-L1 expression. PD-L1 expression was associated with poor survival and remained an adverse prognostic indicator in multivariate analyses. Reduced microRNA expression was related to elevated PD-L1 levels in the MPM patient panel. The median microRNA

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levels of tumour-suppressor microRNAs miR-15b, miR-16, miR-193-3p, miR-195 and miR-200c were shown to be significantly lower in PD-L1 positive samples. miR-15a and miR-16 are both predicted to target the 3’UTR region of PD-L1, and restoring their expression by transfection with microRNA mimics in MPM cell lines led to downregulation of PD-L1 mRNA and protein expression. Additionally, transfection with miR-193a-3p, with an alternative GU-containing target site also caused PD-L1 downregulation. Collectively, these findings implicate tumour-suppressor microRNAs in the regulation of PD-L1 in MPM. BIO Marissa Williams commenced work at ADRI in February 2012 as a research assistant. She completed her undergraduate degree of Forensic Biology in Biomedical Science at the University of Technology Sydney and went on to undertake an honours project in paediatric oncology at the Tumour bank, Westmead Children’s Hospital. Marissa began her PhD studies at the ADRI in 2015 and was awarded a PhD scholarship from Sydney Catalyst. Her PhD project is based on investigating aberrant microRNA expression in MPM.

Yang Zhao SESSION 1 Centenary Institute of Cancer Medicine Targeting vascular VE-Cadherin with a first-in-class drug promotes T cell mediated immunotherapy in tumours ABSTRACT T-cell infiltration of solid tumours is associated with an improved prognosis and immunotherapy. However, the mechanisms that allow better penetration of CD8+ T cells have not been defined, nor have drugs that assist this process been discovered. The endothelium is one of the major sites for the control of inflammatory cell egress and therefore a target to increase T cell recruitment into tumours. VE-Cadherin is a major endothelial cell specific junctional protein that controls vascular integrity. Its decrease in expression is associated with pathology, including tumours. We have developed an oligonucleotide-based inhibitor of the miR-27/VE-Cadherin interaction (CD5-2) such that transfection into endothelial cells results in an increase in VE-Cadherin expression. In mice, CD5-2 enhances tumour endothelium expression of VE-Cadherin, activates TIE-2 and tight junction pathways and normalizes the vessel structure and function. CD5-2 enhances tumour-specific T cell infiltration and spatially redistributes CD8+ T cells within the tumour parenchyma. Further, CD5-2 treatment enhances the efficacy of anti-PD-1 antibody checkpoint blockage. Thus, CD5-2 is a first-in-class drug that has potential to augment the effects of cancer immunotherapy through its effects on the tumour vasculature. BIO Yang Zhao’s academic experience began at Nanjing University of Chinese Medicine where he graduated with a Bachelor’s degree of Biological Pharmaceutics and a Master’s degree of Pharmacology. He then joined Vascular Biology Program at Centenary Institute and received his PhD from the University of Sydney in 2016. His research interests involve the underlying mechanisms of tumour angiogenesis as well as the therapeutic strategies for tumour development.

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